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Sample records for short-term metformin treatment

  1. Effects of metformin on inflammation and short-term memory in streptozotocin-induced diabetic mice.

    Science.gov (United States)

    Oliveira, Wilma Helena; Nunes, Ana Karolina; França, Maria Eduarda Rocha; Santos, Laise Aline; Lós, Deniele Bezerra; Rocha, Sura Wanessa; Barbosa, Karla Patrícia; Rodrigues, Gabriel Barros; Peixoto, Christina Alves

    2016-08-01

    The aim of the present study was to analyze the action of metformin on short-term memory, glial cell activation and neuroinflammation caused by experimental diabetic encephalopathy in C57BL/6 mice. Diabetes was induced by the intraperitoneal injection of a dose of 90mg/kg of streptozotocin on two successive days. Mice with blood glucose levels ≥200dl/ml were considered diabetic and were given metformin hydrochloride at doses of 100mg/kg and 200mg/kg (by gavage, twice daily) for 21 days. On the final day of treatment, the mice underwent a T-maze test. On the 22nd day of treatment all the animals were anesthetized and euthanized. Diabetic animals treated with metformin had a higher spatial memory score. The hippocampus of the diabetic animals presented reactive gliosis, neuronal loss, NF-kB signaling activation, and high levels of IL-1 and VEGF. In addition, the T-maze test scores of these animals were low. Treatment with metformin reduced the expression of GFAP, Iba-1 (astrocyte and microglial markers) and the inflammation markers (p-IKB, IL-1 and VEGF), while enhancing p-AMPK and eNOS levels and increasing neuronal survival (Fox-1 and NeuN). Treatment with metformin also improved the spatial memory scores of diabetic animals. In conclusion, the present study showed that metformin can significantly reduce neuroinflammation and can decrease the loss of neurons in the hippocampus of diabetic animals, which can subsequently promote improvements in spatial memory. Copyright © 2016 Elsevier B.V. All rights reserved.

  2. Short-term combined treatment with liraglutide and metformin leads to significant weight loss in obese women with polycystic ovary syndrome and previous poor response to metformin.

    Science.gov (United States)

    Jensterle Sever, Mojca; Kocjan, Tomaz; Pfeifer, Marija; Kravos, Nika Aleksandra; Janez, Andrej

    2014-03-01

    The effect of metformin on weight reduction in polycystic ovary syndrome (PCOS) is often unsatisfactory. In this study, we investigated the potential add-on effect of treatment with the glucagon-like peptide-1 receptor agonist liraglutide on weight loss in obese nondiabetic women with PCOS who had lost weight during pretreatment with metformin. A total of 40 obese women with PCOS, who had been pretreated with metformin for at least 6 months, participated in a 12-week open-label, prospective study. They were randomized to one of three treatment arms: metformin (MET) arm 1000 mg BID, liraglutide (LIRA) arm 1.2 mg QD s.c., or combined MET 1000 mg BID and LIRA (COMBI) 1.2 mg QD s.c. Lifestyle intervention was not actively promoted. The primary outcome was change in body weight. Thirty six patients (aged 31.3 ± 7.1 years, BMI 37.1 ± 4.6 kg/m²) completed the study: 14 on MET, 11 on LIRA, and 11 on combined treatment. COMBI therapy was superior to LIRA and MET monotherapy in reducing weight, BMI, and waist circumference. Subjects treated with COMBI lost on average 6.5 ± 2.8 kg compared with a 3.8 ± 3.7 kg loss in the LIRA group and a 1.2 ± 1.4 kg loss in the MET group (Pweight loss was stratified: a total of 38% of subjects were high responders who lost ≥5% body weight, 22% of them in the COMBI arm compared with 16 and 0% in the LIRA and MET arm respectively. BMI decreased by 2.4 ± 1.0 in the COMBI arm compared with 1.3 ± 1.3 in LIRA and 0.5 ± 0.5 in the MET arm (Pweight loss. Short-term combined treatment with liraglutide and metformin was associated with significant weight loss and decrease in waist circumference in obese women with PCOS who had previously been poor responders regarding weight reduction on metformin monotherapy.

  3. Short-term antidiabetic treatment with insulin or metformin has a similar impact on the components of metabolic syndrome in women with gestational diabetes mellitus requiring antidiabetic agents: results of a prospective, randomised study.

    Science.gov (United States)

    Zawiejska, A; Wender-Ozegowska, E; Grewling-Szmit, K; Brazert, M; Brazert, J

    2016-04-01

    highest quartile at term. The risk of gestational weight gain and total cholesterol falling within the highest quartile at term was insignificantly reduced in the Metformin Group. In conclusion, short-term antidiabetic treatment with insulin or metformin has a similar impact on markers of metabolic syndrome in women with GDM requiring antidiabetic treatment. Secondly, treatment with metformin is associated with increased triglyceride levels and higher AIP in the third trimester in pregnant women with GDM.

  4. Short- and long-term outcomes of metformin compared with insulin alone in pregnancy: a systematic review and meta-analysis.

    Science.gov (United States)

    Butalia, S; Gutierrez, L; Lodha, A; Aitken, E; Zakariasen, A; Donovan, L

    2017-01-01

    To assess the short- and long-term maternal and fetal impact of metformin in pregnancy compared with insulin. We performed a comprehensive literature search of MEDLINE, EMBASE, BIOSIS, Cochrane Database of Systematic Reviews and ClinicalTrials.gov. Eligible studies were randomized control trials (RCTs) or follow-up of an RCT that: (1) compared metformin with insulin in pregnancy in women with gestational diabetes mellitus or Type 2 diabetes; and (2) reported maternal or fetal outcomes of interest. Two reviewers extracted the data, evaluated study quality and calculated pooled estimates. Sixteen studies (n = 2165 in quantitative analysis) were included. Metformin lowered the risk of neonatal hypoglycaemia [risk ratio (RR) = 0.63; 95% confidence interval (95% CI), 0.45 to 0.87], large for gestational age babies (RR = 0.80; 95% CI, 0.64 to 0.99), pregnancy-induced hypertension (RR = 0.56; 95% CI, 0.37 to 0.85) and total maternal pregnancy weight gain [mean difference (MD) -2.07; 95% CI -2.88 to -1.27]. Metformin did not increase preterm delivery (RR = 1.18; 95% CI 0.67 to 2.07), small for gestational age babies (RR = 1.20; 95% CI, 0.67 to 2.14), perinatal mortality (RR = 0.82; 95% CI, 0.17 to 3.92) or Caesarean section (RR = 0.97; 95% CI, 0.80 to 1.19). Long-term outcome information is limited. Our review found that metformin had no short-term adverse effects on pregnancy, potential benefits in the neonatal period, but limited long-term follow-up information. Prior to routine use, we recommend further follow-up studies of offspring exposed to metformin in utero. © 2016 Diabetes UK.

  5. Short-term effectiveness of low dose liraglutide in combination with metformin versus high dose liraglutide alone in treatment of obese PCOS: randomized trial.

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    Jensterle, Mojca; Kravos, Nika Aleksandra; Goričar, Katja; Janez, Andrej

    2017-01-31

    Liraglutide 3 mg was recently approved as an anti-obesity drug. Metformin is weight neutral, yet it could enhance the therapeutic index of GLP-1 agonist. We compared weight-lowering potential of liraglutide 1.2 mg in combination with metformin to liraglutide 3 mg monotherapy in obese PCOS. Thirty obese women with PCOS (aged 33.1 ± 6.1 years, BMI 38.3 ± 5.4 kg/m 2 ) were randomized to combination (COMBO) of metformin (MET) 1000 mg BID and liraglutide 1.2 mg QD (N = 15) or liraglutide 3 mg (LIRA3) QD alone (N = 15) for 12 weeks. The primary outcome was change in anthropometric measures of obesity. Both treatments led to significant weight loss (-3.6 ± 2.5 kg, p = 0.002 in COMBO vs -6.3 ± 3.7 kg, p = 0.001 in LIRA3). BMI and waist circumference reduction in LIRA3 was greater than in COMBO (-2.2 ± 1.3 vs -1.3 ± 0.9 kg/m 2 , p = 0.05 and -4.2 ± 3.4 vs -2.2 ± 6.2 cm, p = 0.014, respectively). Both interventions resulted in a significant decrease of post-OGTT glucose levels. COMBO significantly reduced total testosterone and was associated with less nausea. Short-term interventions with COMBO and LIRA3 both led to significant improvement of measures of obesity in obese PCOS, LIRA3 being superior to COMBO. However, COMBO further improved androgen profile beyond weight reduction and was associated with better tolerability. The study was retrospectively registered with ClinicalTrials.gov ( NCT02909933 ) on 16 th of September 2016.

  6. The emerging role of metformin in gestational diabetes mellitus.

    Science.gov (United States)

    Gray, Susan G; McGuire, Treasure M; Cohen, Neale; Little, Peter J

    2017-06-01

    Metformin use during pregnancy is controversial and there is disparity in the acceptance of metformin treatment in women with gestational diabetes mellitus (GDM) in Australia. Despite short term maternal and neonatal safety measures, the placental transfer of metformin during GDM treatment and the absence of long-term safety data in offspring has regulators and prescribers cautious about its use. To determine the current role in GDM management, this literature review describes the physiological changes that occur in GDM and other forms of diabetes in pregnancy (DIP) and international changes in guidelines for GDM diagnosis. Management options are considered, with a focus on the evolving evidence for metformin, its mechanism of action, the maternal, foetal and neonatal outcomes associated with its use and benefit vs risk when compared with the current gold standard, insulin. Investigation reveals a favourable balance of evidence to support the safety and long-term benefits, to mother and child, of using metformin as an alternate to insulin for treatment of GDM. Recent findings of the gastrointestinal-directed action of metformin are at least as important as the hepatic effect and the availability of a novel delayed-release metformin dose form to exploit this new information provides a product and therapeutic strategy ideally suited to the use of metformin in GDM. © 2017 John Wiley & Sons Ltd.

  7. Cost-effectiveness analysis of metformin+dipeptidyl peptidase-4 inhibitors compared to metformin+sulfonylureas for treatment of type 2 diabetes.

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    Kwon, Christina S; Seoane-Vazquez, Enrique; Rodriguez-Monguio, Rosa

    2018-02-01

    Patients with type 2 diabetes (T2D) typically use several drug treatments during their lifetime. There is a debate about the best second-line therapy after metformin monotherapy failure due to the increasing number of available antidiabetic drugs and the lack of comparative clinical trials of secondary treatment regimens. While prior research compared the cost-effectiveness of two alternative drugs, the literature assessing T2D treatment pathways is scarce. The purpose of this study was to evaluate the long-term cost-effectiveness of dipeptidyl peptidase-4 inhibitors (DPP-4i) compared to sulfonylureas (SU) as second-line therapy in combination with metformin in patients with T2D. A Markov model was developed with four health states, 1 year cycle, and a 25-year time horizon. Clinical and cost data were collected from previous studies and other readily available secondary data sources. The incremental cost-effectiveness ratio (ICER) was estimated from the US third party payer perspective. Both, costs and outcomes, were discounted at a 3% annual discount rate. One way and probabilistic sensitivity analyses were performed to evaluate the impact of uncertainty on the base-case results. The discounted incremental cost of metformin+DPP-4i compared to metformin+SU was $11,849 and the incremental life-years gained were 0.61, resulting in an ICER of $19,420 per life-year gained for patients in the metformin+DPP-4i treatment pathway. The ICER estimated in the probabilistic sensitivity analysis was $19,980 per life-year gained. Sensitivity analyses showed that the results of the study were not sensitive to changes in the parameters used in base-case. The metformin+DPP-4i treatment pathway was cost-effective compared to metformin+SU as a long-term second-line therapy in the treatment of T2D from the US health care payer perspective. Study findings have the potential to provide clinicians and third party payers valuable evidence for the prescription and utilization of cost

  8. Metformin treatment does not affect the risk of ruptured abdominal aortic aneurysms

    DEFF Research Database (Denmark)

    Kristensen, Katrine L.; Pottegård, Anton; Hallas, Jesper

    2017-01-01

    Objective: Diabetes counteracts formation and rupture of abdominal aortic aneurysms, possibly through arterial matrix accumulation. Use of metformin, on the other hand, reduces arterial accumulation of matrix molecules. Consequently, we hypothesized that metformin treatment may reverse...... the protective role of diabetes on the development and course of aneurysms, that is, that metformin would be associated with aneurysm rupture among individuals with diabetes. Methods: Using nationwide Danish registry data, we performed a nested case-control study on the association between long-term use....... In total, 22.4% of the case population were long-term metformin users compared with 28.8% of the controls. We found a statistically nonsignificant protective effect of long-term metformin use toward RAAA with crude odds ratio (OR) of 0.74 (confidence interval, 0.54-1.00). When adjusted for covariates...

  9. Metformin and insulin receptors

    International Nuclear Information System (INIS)

    Vigneri, R.; Gullo, D.; Pezzino, V.

    1984-01-01

    The authors evaluated the effect of metformin (N,N-dimethylbiguanide), a biguanide known to be less toxic than phenformin, on insulin binding to its receptors, both in vitro and in vivo. Specific 125 I-insulin binding to cultured IM-9 human lymphocytes and MCF-7 human breast cancer cells was determined after preincubation with metformin. Specific 125 I-insulin binding to circulating monocytes was also evaluated in six controls, eight obese subjects, and six obese type II diabetic patients before and after a short-term treatment with metformin. Plasma insulin levels and blood glucose were also measured on both occasions. Metformin significantly increased insulin binding in vitro to both IM-9 lymphocytes and MCF-7 cells; the maximum increment was 47.1% and 38.0%, respectively. Metformin treatment significantly increased insulin binding in vivo to monocytes of obese subjects and diabetic patients. Scatchard analysis indicated that the increased binding was mainly due to an increase in receptor capacity. Insulin binding to monocytes of normal controls was unchanged after metformin as were insulin levels in all groups; blood glucose was significantly reduced after metformin only in diabetic patients. These data indicate that metformin increases insulin binding to its receptors in vitro and in vivo. The effect in vivo is observed in obese subjects and in obese type II diabetic patients, paralleling the clinical effectiveness of this antidiabetic agent, and is not due to receptor regulation by circulating insulin, since no variation in insulin levels was recorded

  10. The short term effect of insulin, metformin and insulin-metformin combination on the liver morphology in high fat diet/streptozotocin induced diabetic albino rats

    International Nuclear Information System (INIS)

    Mubeen, S.; Amjad, Z.; Memon, F.M.

    2016-01-01

    Objective: To evaluate the histological effects of insulin, metformin and insulin-metformin combination on liver morphology in high fat diet (HFD) / Streptozotocin (STZ) induced diabetic albino rats. Study Design: Experimental and comparative study. Place and Duration of Study: Institute of Basic Medical Sciences (IBMS), Dow University of Health Sciences (DUHS), Ojha Campus, Karachi, from January to August 2012. Methodology: The study was conducted on 50 HFD/STZ induced diabetic albino wistar rats which were randomized into 5 groups. One of the groups was treated with insulin, one with metformin, and the other group with insulin-metformin combination for 4 weeks. One of the groups was left untreated. One group was control group. After the treatment period, the rats were sacrificed and livers were isolated, weighed, processed and stained to analyse the difference in hepatic morphology in each treated and untreated groups, then the results were compared with control rats. Results: Statistically significant difference (p < 0.0001) was seen between the groups by using Kruskill Wallis Test. To further investigate the effectiveness of insulin, metformin and insulin-metformin combination, Mann-Whitney U-test was applied. Statistically significant difference was noticed when diabetic rats were given insulin-metformin combination (p < 0.0001). Conclusion: The combination therapy was observed to have better effects on liver morphology than insulin and metformin used separately. (author)

  11. Metformin reduces serum CA199 levels in type 2 diabetes Chinese patients with time-effect and gender difference.

    Science.gov (United States)

    Zhang, Dandan; Hou, Wolin; Liu, Fang; Yin, Jun; Lu, Wei; Li, Ming; Zheng, Taishan; Lu, Fengdi; Bao, Yuqian; Jia, Weiping

    2015-02-01

    This study was designed to clarify the influence of metformin on serum carbohydrate antigen 199 (CA199) levels and its associated factors in Chinese type 2 diabetes mellitus (T2DM) patients. In total, 1,253 T2DM patients were enrolled, including a non-metformin group (n = 616), a short-term metformin group (at least 1 week to 2 years; n=325), and a long-term metformin group (≥ 2 years; n = 312). Their clinical and biochemical characteristics were collected and compared. After 1 year, the biochemical parameters were re-examined in 296 patients. Sex hormones were determined, and associations between CA199 and other variables were assessed. At baseline, the incidence of abnormal CA199 levels was 14.7%, 8.9%, and 4.7% in the non-metformin, short-term metformin, and long-term metformin groups, respectively. CA199 levels in females were significantly higher than in males (P non-metformin controls vs. 17.62 ± 10.87 U/mL in the short-term group vs. 10.54 ± 8.14 U/mL in the long-term group; P = 0.000). The correlation and multiple stepwise regression analysis revealed that glycosylated hemoglobin, metformin, gender, total cholesterol, and follicle-stimulating hormone were independent impact factors on CA199 concentrations (all P Binary logistic regression revealed that the risk of abnormal CA199 concentrations of the total population with short-term metformin or long-term metformin treatment decreased 11% (odds ratio = 0.89; P = 0.001) and 30% (odds ratio = 0.70; P = 0.000), respectively, at baseline. After a 1-year follow-up, the incidence of high CA199 level decreased in both the short-term and the long-term metformin group compared with that of controls (P < 0.05). The extent of CA199 decrease in the long-term metformin group was the greatest (-17% vs. -4.9% in the short-term group vs. 3% in controls, P = 0.000), and the group's risk of high blood CA199 level was reduced 67% (odds ratio = 0.33; P = 0.023). The reduction in women was more apparent than that in men

  12. Long term treatment with metformin in patients with type 2 diabetes and vitamin B 12

    Directory of Open Access Journals (Sweden)

    Yu V Pankratova

    2012-12-01

    Full Text Available Реферат по статье: De Jager J, Kooy A, Lehert P, Wulffelé MG, van der Kolk J, Bets D, Verburg J, Donker AJ, Stehouwer CD. Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B-12 deficiency: randomised placebo controlled trial. BMJ. 2010 May 20;340:c2181.

  13. Effects of short-term metformin treatment on insulin sensitivity of blood glucose and free fatty acids.

    Science.gov (United States)

    Iannello, S; Camuto, M; Cavaleri, A; Milazzo, P; Pisano, M G; Bellomia, D; Belfiore, F

    2004-01-01

    Based on the known effect of metformin (MET) in improving insulin sensitivity in type 2 diabetes, with the scope to focus the effects on glycaemic and free fatty acids (FFA) levels, we studied the effects of a short-term treatment with this drug in obese subjects and obese patients with diabetes or family history of diabetes (FHD). We used a method to allow us to evaluate the possible difference of insulin sensibility with regard to the insulin action on glycaemia and blood FFA, both in the basal state and during oral glucose tolerance test (OGTT). Insulin sensitivity was investigated before and after MET treatment (850 mg bid for 10 days) in seven obese subjects with normal glucose tolerance and without FHD and 13 obese patients with diabetes (n=7) or FHD (n=6). By using specifically designed formulae, we calculated four insulin-sensitivity indices (ISI) from basal level (b) and area values (a) (during OGTT) of insulinaemia, glycaemia (gly) or FFA (ffa), namely: ISI (gly)-b, ISI (gly)-a, ISI (ffa)-b and ISI (ffa)-a. In patients with diabetes or FHD, MET improved ISI (gly)-b (0.79 +/- 0.06 vs. 0.59 +/- 0.07, p<0.001) and ISI (gly)-a (0.69 +/- 0.09 vs. 0.51 +/- 0.07, p<0.05), whereas only minor changes occurred for ISI (ffa)-b and ISI (ffa)-a. In contrast, in simple obese subjects, MET induced further deterioration of both ISI (gly)-a (0.47 +/- 0.07 vs. 0.64 +/- 0.10, p<0.01) and ISI (ffa)-a (0.43 +/- 0.07 vs. 0.55 +/- 0.08, p<0.05). Fasting level and total area of lactate were high in the obese patients and were not affected by MET. A statistically significant increase (p<0.01), however, was observed for the 'decremental' area of lactate in obese subjects with diabetes or FHD, which might probably contribute to the reduction of insulin resistance induced by the drug in these patients. Although the low number of subjects studied precludes absolute conclusions, data would suggest that MET improved ISI towards glucose but not towards FFA, in the diabetic and

  14. Metformin og obstetriske patienter

    DEFF Research Database (Denmark)

    Pedersen, Katrine Dahl; Bülow, Nathalie Søderhamn; Aaboe, Kasper

    2015-01-01

    Polycystic ovary syndrome (PCOS) is associated with insulin resistance, infertility, obesity and gestational complications. Metformin is widely used in fertility treatment of women with PCOS, due to a suggested positive effect of continued metformin treatment beyond the first trimester on pregnancy...... complications. Larger randomized trials have failed to confirm this. Metformin treatment has not been found to be superior to insulin treatment in women with gestational diabetes and may be associated with long-term consequences in the children in the form of overweight and disturbed glucose metabolism....

  15. Short-term therapeutic effects of combined therapy with metformin hydrochloride for aplastic anemia

    Directory of Open Access Journals (Sweden)

    Xue-chun LU

    2012-03-01

    Full Text Available Objective To screen and select new drugs for aplastic anemia (AA and evaluate their clinical efficacy by clinical bioinformatics methods. Methods First, we established genome expression profiles of AA patients, and conducted similarity analyses with the pharmacogenomics database to screen and select drugs with possible efficacy. Intractable AA patients who received immunosuppressors and/or androgen for more than six months showing no clinical efficacy were enrolled in the study to evaluate therapeutic effects of the therapeutic regime. Clinical efficacy and adverse effects were evaluated after six months. Results The clinical bioinformatics results showed therapeutic effects of metformin hydrochloride on AA. Forty-three intractable AA patients (15 with severe AA were treated with metformin hydrochloride combined with cyclosporin A (CsA and stanozolol. Twenty-seven transfusion-dependent patients (100% became transfusion independent after a 6-month therapy. The hemoglobin level completely returned to normal in 37 out of 40 anemia patients (92.5%. In the 40 patients with platelet count lower than 20×109/L, the platelet count of 28 patients (90.3% increased to higher than 50×109/L. The white cell count increased to higher than 3.5×109/L in 30 out of 35 patients (88.6% with white cell count lower than 2.5×109/L. Among 40 anemic patients, 1 was found to have abnormal renal function, but it recovered to the normal range after ending CsA treatment. Eighteen patients were found to have elevated transaminase levels which were lowered to normal range after using liver protectants and reducing the dosage of stanozolol. There were no instances of hypoglycemia in all patients throughout the treatment. Conclusion Combination of metformin hydrochloride, CsA and stanozolol is effective in refractory aplastic anemia with acceptable toxicity.

  16. [Metformin and the obstetric patient].

    Science.gov (United States)

    Pedersen, Katrine Dahl; Bülow, Nathalie Søderhamn; Aaboe, Kasper; Galsgaard, Julie; Odgaard, Helle Sand; Mathiesen, Elisabeth Reinhardt; Lauenborg, Jeannet

    2015-12-07

    Polycystic ovary syndrome (PCOS) is associated with insulin resistance, infertility, obesity and gestational complications. Metformin is widely used in fertility treatment of women with PCOS, due to a suggested positive effect of continued metformin treatment beyond the first trimester on pregnancy complications. Larger randomized trials have failed to confirm this. Metformin treatment has not been found to be superior to insulin treatment in women with gestational diabetes and may be associated with long-term consequences in the children in the form of overweight and disturbed glucose metabolism.

  17. Understanding the benefit of metformin use in cancer treatment

    Directory of Open Access Journals (Sweden)

    Goodwin Pamela J

    2011-04-01

    Full Text Available Abstract Biguanides have been developed for the treatment of hyperglycemia and type 2 diabetes. Recently, metformin, the most widely prescribed biguanide, has emerged as a potential anticancer agent. Epidemiological, preclinical and clinical evidence supports the use of metformin as a cancer therapeutic. The ability of metformin to lower circulating insulin may be particularly important for the treatment of cancers known to be associated with hyperinsulinemia, such as those of the breast and colon. Moreover, metformin may exhibit direct inhibitory effects on cancer cells by inhibiting mammalian target of rapamycin (mTOR signaling and protein synthesis. The evidence supporting a role for metformin in cancer therapy and its potential molecular mechanisms of action are discussed.

  18. Extracorporeal Treatment for Metformin Poisoning

    DEFF Research Database (Denmark)

    Calello, Diane P; Liu, Kathleen D; Wiegand, Timothy J

    2015-01-01

    diverse professions, presents its systematic review and clinical recommendations for extracorporeal treatment in metformin poisoning. METHODS: A systematic literature search was performed, data extracted, findings summarized, and structured voting statements developed. A two-round modified Delphi method...... was used to achieve consensus on voting statements and RAND/UCLA Appropriateness Method to quantify disagreement. Anonymized votes and opinions were compiled and discussed. A second vote determined the final recommendations. RESULTS: One hundred seventy-five articles were identified, including 63 deaths...... appears to be amenable to extracorporeal treatments. Despite clinical evidence comprised mostly of case reports and suboptimal toxicokinetic data, the workgroup recommended extracorporeal removal in the case of severe metformin poisoning....

  19. Predictors of HbA1c levels in patients initiating metformin

    NARCIS (Netherlands)

    Martono, Doti P; Hak, Eelko; Lambers Heerspink, Hiddo; Wilffert, Bob; Denig, Petra

    2016-01-01

    Objective: The aim was to assess demographic and clinical factors as predictors of short (6 months) and long term (18 months) HbA1c levels in diabetes patients initiating metformin treatment. Research design and methods: We conducted a cohort study including type 2 diabetes patients who received

  20. Metformin treatment for Type 2 diabetes in pregnancy?

    Science.gov (United States)

    Simmons, David

    2010-08-01

    Metformin lowers blood glucose by reducing hepatic glucose output, increasing insulin sensitivity and enhancing peripheral glucose uptake. Metformin is widely used in women with Type 2 diabetes of child-bearing age, many of whom become pregnant. Studies to date in Type 2 diabetes in pregnancy, gestational diabetes and polycystic ovarian syndrome are reassuring. Metformin is not considered teratogenic. There is sufficient evidence that metformin is safe used throughout pregnancy, with no worsening of obstetric or perinatal outcomes. Women may benefit from the lesser weight gain. The long-term risks to the offspring remain inadequately researched, with no evidence of harm up to 2 years, and no suggestions of later complications in countries using metformin for many years. Metformin is recommended for use in pregnancies complicated by Type 2 diabetes, but women should be informed of the evidence regarding its associated risks and benefits to enable an informed choice over its use. 2010 Elsevier Ltd. All rights reserved.

  1. Long-term use of metformin and colorectal cancer risk in type II diabetics

    DEFF Research Database (Denmark)

    Cardel, Majken; Jensen, S. M.; Pottegård, Anton

    2014-01-01

    of prescriptions for a cumulative dose of 2000 g within 5 years prior to the index date. To control for potential confounders, we used unconditional logistic regression. We generated adjusted odds ratios (OR) for the association between metformin and CRC and performed subanalyses for selected subgroups...... and for the dose-response relation. We identified 2088 cases and 9060 controls during the study period. The association between long-term metformin use and CRC gave an adjusted OR at 0.83 (95% CI 0.68-1.00). A protective effect on CRC with long-term use of metformin was only evident for women (OR 0.66 vs. 0.......99 for men). There was a significant dose-response association of metformin use > 250 defined daily dose (DDD) and for the duration of metformin use > 1 year. We found an indication of a protective effect of long-term metformin use against CRC in type II diabetics, although this effect was only seen in women....

  2. Metformin in the treatment of polycystic ovary syndrome.

    Science.gov (United States)

    Motta, Dra Alicia Beatriz

    2008-01-01

    Polycystic ovary syndrome (PCOS) is one of the most frequent diseases that affects women in their reproductive age. The heterogeneity of PCOS makes not only the diagnosis but also the choice of an adequate treatment difficult. The biguanide, N, N' dimethyl-biguanide: Metformin is an antidiabetic drug that increases glucose utilization in insulin-sensitive tissues and is useful in the reduction of both insulin resistance and circulating androgens as well as restoring ovulation. However, metformin is being clinically used without a complete understanding of the mechanism involved. The present review explores some of the actions and efficacy of metformin in the treatment of PCOS during different reproductive periods.

  3. Research: Treatment Study to determine the durability of glycaemic control with early treatment with a vildagliptin–metformin combination regimen vs. standard-of-care metformin monotherapy—the VERIFY trial: a randomized double-blind trial

    Science.gov (United States)

    Del Prato, S; Foley, J E; Kothny, W; Kozlovski, P; Stumvoll, M; Paldánius, P M; Matthews, D R

    2014-01-01

    Aims Durability of good glycaemic control (HbA1c) is of importance as it can be the foundation for delaying diabetic complications. It has been hypothesized that early initiation of treatment with the combination of oral anti-diabetes agents with complementary mechanisms of action can increase the durability of glycaemic control compared with metformin monotherapy followed by a stepwise addition of oral agents. Dipeptidyl peptidase-4 inhibitors are good candidates for early use as they are efficacious in combination with metformin, show weight neutrality and a low risk of hypoglycaemia. We aimed to test the hypothesis that early combined treatment of metformin and vildagliptin slows β-cell deterioration as measured by HbA1c. Methods Approximately 2000 people with Type 2 diabetes mellitus who were drug-naive or who were treated with metformin for less than 1 month, and who have HbA1c of 48–58 mmol/mol (6.5–7.5%), will be randomized in a 1:1 ratio in VERIFY, a 5-year multinational, double-blind, parallel-group study designed to compare early initiation of a vildagliptin–metformin combination with standard-of-care initiation of metformin monotherapy, followed by the stepwise addition of vildagliptin when glycaemia deteriorates. Further deterioration will be treated with insulin. The primary analysis for treatment failure will be from a Cox proportional hazard regression model and the durability of glycaemic control will be evaluated by assessing treatment failure rate and the rate of loss in glycaemic control over time as co-primary endpoints. Summary VERIFY is the first study to investigate the long-term clinical benefits of early combination treatment vs. the standard-of-care metformin monotherapy with a second agent added by threshold criteria. PMID:24863949

  4. Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota.

    Science.gov (United States)

    Forslund, Kristoffer; Hildebrand, Falk; Nielsen, Trine; Falony, Gwen; Le Chatelier, Emmanuelle; Sunagawa, Shinichi; Prifti, Edi; Vieira-Silva, Sara; Gudmundsdottir, Valborg; Pedersen, Helle K; Arumugam, Manimozhiyan; Kristiansen, Karsten; Voigt, Anita Yvonne; Vestergaard, Henrik; Hercog, Rajna; Costea, Paul Igor; Kultima, Jens Roat; Li, Junhua; Jørgensen, Torben; Levenez, Florence; Dore, Joël; Nielsen, H Bjørn; Brunak, Søren; Raes, Jeroen; Hansen, Torben; Wang, Jun; Ehrlich, S Dusko; Bork, Peer; Pedersen, Oluf

    2015-12-10

    In recent years, several associations between common chronic human disorders and altered gut microbiome composition and function have been reported. In most of these reports, treatment regimens were not controlled for and conclusions could thus be confounded by the effects of various drugs on the microbiota, which may obscure microbial causes, protective factors or diagnostically relevant signals. Our study addresses disease and drug signatures in the human gut microbiome of type 2 diabetes mellitus (T2D). Two previous quantitative gut metagenomics studies of T2D patients that were unstratified for treatment yielded divergent conclusions regarding its associated gut microbial dysbiosis. Here we show, using 784 available human gut metagenomes, how antidiabetic medication confounds these results, and analyse in detail the effects of the most widely used antidiabetic drug metformin. We provide support for microbial mediation of the therapeutic effects of metformin through short-chain fatty acid production, as well as for potential microbiota-mediated mechanisms behind known intestinal adverse effects in the form of a relative increase in abundance of Escherichia species. Controlling for metformin treatment, we report a unified signature of gut microbiome shifts in T2D with a depletion of butyrate-producing taxa. These in turn cause functional microbiome shifts, in part alleviated by metformin-induced changes. Overall, the present study emphasizes the need to disentangle gut microbiota signatures of specific human diseases from those of medication.

  5. Metformin: Multi-faceted protection against cancer

    Science.gov (United States)

    Cufí, Sílvia; Oliveras-Ferraros, Cristina; Bosch-Barrera, Joaquim; Joven, Jorge; Martin-Castillo, Begoña; Menendez, Javier A.

    2011-01-01

    The biguanide metformin, a widely used drug for the treatment of type 2 diabetes, may exert cancer chemopreventive effects by suppressing the transformative and hyperproliferative processes that initiate carcinogenesis. Metformin's molecular targets in cancer cells (e.g., mTOR, HER2) are similar to those currently being used for directed cancer therapy. However, metformin is nontoxic and might be extremely useful for enhancing treatment efficacy of mechanism-based and biologically targeted drugs. Here, we first revisit the epidemiological, preclinical, and clinical evidence from the last 5 years showing that metformin is a promising candidate for oncology therapeutics. Second, the anticancer effects of metformin by both direct (insulin-independent) and indirect (insulin-dependent) mechanisms are discussed in terms of metformin-targeted processes and the ontogenesis of cancer stem cells (CSC), including Epithelial-to-Mesenchymal Transition (EMT) and microRNAs-regulated dedifferentiation of CSCs. Finally, we present preliminary evidence that metformin may regulate cellular senescence, an innate safeguard against cellular immortalization. There are two main lines of evidence that suggest that metformin's primary target is the immortalizing step during tumorigenesis. First, metformin activates intracellular DNA damage response checkpoints. Second, metformin attenuates the anti-senescence effects of the ATP-generating glycolytic metabotype-the Warburg effect-, which is required for self-renewal and proliferation of CSCs. If metformin therapy presents an intrinsic barrier against tumorigenesis by lowering the threshold for stress-induced senescence, metformin therapeutic strategies may be pivotal for therapeutic intervention for cancer. Current and future clinical trials will elucidate whether metformin has the potential to be used in preventive and treatment settings as an adjuvant to current cancer therapeutics. PMID:22203527

  6. Acute renal metabolic effect of metformin treatment assessed with hyperpolarized magnetic resonance imaging

    DEFF Research Database (Denmark)

    Qi, Haiyun; Nielsen, Per Mose; Schroeder, Marie

    2017-01-01

    Metformin is the primary anti-diabetic drug in type-2 diabetes patients. However, controversy exists on its use in patients with renal impairment. Here we investigated the acute metabolic effects of metformin treatment in rat kidneys, with hyperpolarized 13C pyruvate and Clark......-electrodes. A significantly altered metabolic phenotype was observed 30 min post metformin treatment. Anaerobic metabolism was elevated in the cytosol, indicated by increased lactate/pyruvate ratio, and mitochondrial aerobic metabolism was reduced, indicated by decreased bicarbonate/pyruvate ratio. Acute metformin treatment...... increased renal blood flow with higher O2 saturation and did not change tubular O2 consumption. These results indicate that metformin reduces mitochondrial respiration and enhances anaerobic metabolism, even with enough oxygen supply, within only 30 min of treatment....

  7. Association of Metformin Treatment with Reduced Severity of Diabetic Retinopathy in Type 2 Diabetic Patients

    Directory of Open Access Journals (Sweden)

    Yue Li

    2018-01-01

    Full Text Available Purpose. To evaluate effects of long-term metformin on the severity of diabetic retinopathy (DR in high-risk type 2 diabetic (T2D patients. Methods. A retrospective chart review study was conducted involving 335 DR patients with T2D ≥ 15 years from 1990 to 2013. The severity of DR was determined by Early Treatment Diabetic Retinopathy Study scale. The associations between metformin and DR severity were evaluated. Comparison with stratification for the use of sulfonylurea and insulin was performed to identify possible confounding effects. Results. Severe nonproliferative diabetic retinopathy or proliferative diabetic retinopathy (SNPDR/PDR was more often diagnosed in nonmetformin users (67/142, 47% versus metformin users (48/193, 25% (p<0.001, regardless of gender and race of the patients. The odds ratio of metformin associated with SNPDR/PDR was 0.37 in all cases (p<0.001, 0.35 in sulfonylurea use cohort (p<0.05, 0.45 in nonsulfonylurea use cohorts (p<0.01, and 0.42 in insulin use cohort (p<0.01. Insulin users had a higher rate of SNPDR/PDR. Metformin had no influence on the occurrence of clinical significant diabetic macular edema. Conclusions. Long-term use of metformin is independently associated with a significant lower rate of SNPDR/PDR in patients with type 2 diabetes ≥ 15 years.

  8. Lifestyle modification and metformin as long-term treatment options for obese adolescents: study protocol

    Directory of Open Access Journals (Sweden)

    Watson Margaret

    2009-11-01

    Full Text Available Abstract Background Childhood obesity is a serious health concern affecting over 155 million children in developed countries worldwide. Childhood obesity is associated with significantly increased risk for development of type 2 diabetes, cardiovascular disease and psychosocial functioning problems (i.e., depression and decreased quality of life. The two major strategies for management of obesity and associated metabolic abnormalities are lifestyle modification and pharmacologic therapy. This paper will provide the background rationale and methods of the REACH childhood obesity treatment program. Methods/design The REACH study is a 2-year multidisciplinary, family-based, childhood obesity treatment program. Seventy-two obese adolescents (aged 10-16 years and their parents are being recruited to participate in this randomized placebo controlled trial. Participants are randomized to receive either metformin or placebo, and are then randomized to a moderate or a vigorous intensity supervised exercise program for the first 12-weeks. After the 12-week exercise program, participants engage in weekly exercise sessions with an exercise facilitator at a local community center. Participants engage in treatment sessions with a dietitian and social worker monthly for the first year, and then every three months for the second year. The primary outcome measure is change in body mass index and the secondary outcome measures are changes in body composition, risk factors for type 2 diabetes and cardiovascular disease, changes in diet, physical activity, and psychosocial well-being (e.g., quality of life. It is hypothesized that participants who take metformin and engage in vigorous intensity exercise will show the greatest improvements in body mass index. In addition, it is hypothesized that participants who adhere to the REACH program will show improvements in body composition, physical activity, diet, psychosocial functioning and risk factor profiles for type 2

  9. Vitamin B12 and homocysteine status during pregnancy in the metformin in gestational diabetes trial: responses to maternal metformin compared with insulin treatment.

    Science.gov (United States)

    Gatford, K L; Houda, C M; Lu, Z X; Coat, S; Baghurst, P A; Owens, J A; Sikaris, K; Rowan, J A; Hague, W M

    2013-07-01

    The aim of the study is to compare the effects of metformin and insulin treatment for gestational diabetes mellitus (GDM) on vitamin B12 and homocysteine (Hcy) status. Women with GDM, who met criteria for insulin treatment, were randomly assigned to metformin (n = 89) or insulin (n = 91) in the Adelaide cohort of the metformin in gestational diabetes (MiG) trial. Fasting serum total vitamin B12 (TB12), holotranscobalamin (HoloTC), a marker of functional B12 status and plasma Hcy concentrations were measured at 20-34 weeks (at randomization) and 36 weeks gestation, then at 6-8 weeks postpartum. Circulating TB12, HoloTC and Hcy were similar in both treatment groups at each time point. Women who were taking dietary folate supplements at randomization had higher serum TB12 and HoloTC at randomization than those not taking folate. Overall, serum TB12 fell more between randomization and 36 weeks gestation in the metformin group than in the insulin group (metformin: -19.7 ± 4.7 pmol/l, insulin: -6.4 ± 3.6 pmol/l, p = 0.004). The decrease in serum TB12 during treatment was greater with increasing treatment duration in metformin-treated (p pregnancy to a greater extent in metformin-treated than in insulin-treated women with GDM, but neither analyte differed between groups at any stage. This adds further evidence supporting metformin as a safe alternative treatment to insulin in GDM. Further investigation is needed to evaluate whether women treated with metformin for longer periods in pregnancy require additional B12 or other supplementation. © 2013 Blackwell Publishing Ltd.

  10. Comparison of Vildagliptin-Metformin and Glimepiride-Metformin Treatments in Type 2 Diabetic Patients

    Directory of Open Access Journals (Sweden)

    Hyun Jeong Jeon

    2011-10-01

    Full Text Available BackgroundThe present study investigated the efficacy and safety of vildagliptin-metformin treatment compared to those of glimepiride-metformin treatment for type 2 diabetes.MethodsIn a randomized, open-label, comparative study, 106 patients with type 2 diabetes were enrolled. The primary endpoint was a reduction in HbA1c from baseline and secondary endpoints included fasting plasma glucose (FPG or 2-hour postprandial glucose (2h-PPG reduction from baseline, as well as HbA1c responder rate and HbA1c reduction according to baseline HbA1c category.ResultsComparable HbA1c reduction was observed with a mean±standard deviation change from baseline to the 32-week endpoint of -0.94±1.15% in the vildagliptin group and -1.00±1.32% in the glimepiride group. A similar reduction in 2h-PPG (vildagliptin group 3.53±4.11 mmol/L vs. the glimepiride group 3.72±4.17 mmol/L was demonstrated, and the decrements in FPG (vildagliptin group 1.54±2.41 mmol/L vs. glimepiride group 2.16±2.51 mmol/L were not different between groups. The proportion of patients who achieved an HbA1c less than 7% at week 32 was 50.1% in the vildagliptin group and 56.0% in the glimepiride group. An average body weight gain of 2.53±1.21 kg in the glimepiride group was observed in contrast with the 0.23±0.69 kg weight gain noted in the vildagliptin group. A 10-fold lower incidence of hypoglycemia was demonstrated in the vildagliptin group, in addition to an absence of severe hypoglycemia.ConclusionVildagliptin-metformin treatment provided blood glucose control efficacy comparable to that of glimepiride-metformin treatment and resulted in better adverse event profiles with lower risks of hypoglycemia and weight gain.

  11. Pioglitazone metabolic effect in metformin-intolerant obese patients treated with sibutramine.

    Science.gov (United States)

    Derosa, Giuseppe; Mereu, Roberto; Salvadeo, Sibilla A T; D'Angelo, Angela; Ciccarelli, Leonardina; Piccinni, Mario N; Ferrari, Ilaria; Gravina, Alessia; Maffioli, Pamela; Cicero, Arrigo F G

    2009-01-01

    Metformin is the drug of choice to treat obese type 2 diabetes patients because it reduces either insulin-resistance and body weight. We aimed to comparatively test the efficacy and tolerability of pioglitazone and sibutramine in metformin-intolerant obese type 2 diabetic patients treated with sibutramine. Five hundred and seventy-six consecutive Caucasian obese type 2 diabetic patients were evaluated during a 12-months period and fifty-two patients were resulted intolerant to metformin at maximum dosage (3,000 mg/day). All intolerant patients to metformin received a treatment with pioglitazone (45 mg/day) and sibutramine (10 mg/day) and they were compared with fifty-three patients treated with metformin (3,000 mg/day) and sibutramine (10 mg/day) for 6 months in a single-blind controlled trial. We assessed body mass index, waist circumference, glycated hemoglobin, Fasting Plasma glucose, postprandial plasma glucose, fasting plasma insulin, postprandial plasma insulin, lipid profile, systolic blood pressure, diastolic blood pressure and heart rate at baseline and after 3, and 6 months. No body mass index change was observed at 3, and 6 months in pioglitazone + sibutramine group, while a significant reduction of body mass index and waist circumference was observed after 6 months in metformin + sibutramine group (psibutramine combination appears to be a short-term equally efficacious and well-tolerated therapeutic alternative respect to metformin-intolerant obese type 2 diabetic patients treated with sibutramine.

  12. Effects of Metformin Treatment on Homocysteine Levels and Metabolic Parameters of Women With Polycystic Ovary Syndrome

    Directory of Open Access Journals (Sweden)

    Soheila Riahinejad

    2016-04-01

    Full Text Available Objective: Polycystic ovary syndrome (PCOS is one of the most common endocrine disorders in women. Metformin is a biguanide commonly used to improve PCOS symptoms. Effect of metformin on the levels of serum homocysteine (Hcy in PCOS women is unclear. The aim of this study is evaluating the effect of metformin administration on serum Hcy levels and metabolic parameters of PCOS patients.Materials and methods: Thirty three patients with PCOS were enrolled in this study who were selected randomly. All patients received metformin from the fifth day of menstrual cycle at a dose of 850 mg (one tablet daily for 3 months. Body mass index, Triglycerides, total cholesterol, high-density lipoprotein cholesterol (HDL-C, low-density lipoprotein cholesterol (LDL-C, fasting blood sugar and homocysteine levels were recorded at entry into the study and after 3 months treatment.Results: BMI, plasma Homocysteine concentrations and fasting blood sugar levels were significantly (p < 0.05 decreased after the treatment period. No significant changes were observed in the lipid profiles of patients. There was a weak negative correlation between homocysteine and LDL cholesterol serum levels (p = 0.04, r = -0.27.Conclusion: Treatment with metformin in PCOS women may lead to beneficial effects in terms of BMI, plasma homocysteine concentrations and fasting blood sugar with no remarkable effect on lipid profile. 

  13. Short-Term Memory and Aphasia: From Theory to Treatment.

    Science.gov (United States)

    Minkina, Irene; Rosenberg, Samantha; Kalinyak-Fliszar, Michelene; Martin, Nadine

    2017-02-01

    This article reviews existing research on the interactions between verbal short-term memory and language processing impairments in aphasia. Theoretical models of short-term memory are reviewed, starting with a model assuming a separation between short-term memory and language, and progressing to models that view verbal short-term memory as a cognitive requirement of language processing. The review highlights a verbal short-term memory model derived from an interactive activation model of word retrieval. This model holds that verbal short-term memory encompasses the temporary activation of linguistic knowledge (e.g., semantic, lexical, and phonological features) during language production and comprehension tasks. Empirical evidence supporting this model, which views short-term memory in the context of the processes it subserves, is outlined. Studies that use a classic measure of verbal short-term memory (i.e., number of words/digits correctly recalled in immediate serial recall) as well as those that use more intricate measures (e.g., serial position effects in immediate serial recall) are discussed. Treatment research that uses verbal short-term memory tasks in an attempt to improve language processing is then summarized, with a particular focus on word retrieval. A discussion of the limitations of current research and possible future directions concludes the review. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

  14. Metformin for treatment of antipsychotic-induced weight gain: a randomized, placebo-controlled study.

    Science.gov (United States)

    Wang, Man; Tong, Jian-hua; Zhu, Gang; Liang, Guang-ming; Yan, Hong-fei; Wang, Xiu-zhen

    2012-06-01

    To evaluate the efficacy of metformin for treatment of antipsychotic-induced weight gain. Seventy-two patients with first-episode schizophrenia who gained more than 7% of their predrug weight were randomly assigned to receive 1000 mg/d of metformin or placebo in addition to their ongoing treatment for 12 weeks using a double-blind study design. The primary outcome was change in body weight. The secondary outcomes included changes in body mass index, fasting glucose and insulin, and insulin resistance index. Of the 72 patients who were randomly assigned, 66 (91.6%) completed treatments. The body weight, body mass index, fasting insulin and insulin resistance index decreased significantly in the metformin group, but increased in the placebo group during the 12-week follow-up period. Significantly more patients in the metformin group lost their baseline weight by more than 7%, which was the cutoff for clinically meaningful weight loss. Metformin was tolerated well by majority patients. Metformin was effective and safe in attenuating antipsychotic-induced weight gain and insulin resistance in first-episode schizophrenia patients. Patients displayed good adherence to metformin. Copyright © 2012 Elsevier B.V. All rights reserved.

  15. Metformin treatment before and during IVF or ICSI in women with polycystic ovary syndrome.

    Science.gov (United States)

    Tso, Leopoldo O; Costello, Michael F; Albuquerque, Luiz Eduardo T; Andriolo, Régis B; Macedo, Cristiane R

    2014-11-18

    The use of insulin-sensitising agents, such as metformin, in women with polycystic ovary syndrome (PCOS) who are undergoing ovulation induction or in vitro fertilisation (IVF) cycles has been widely studied. Metformin reduces hyperinsulinaemia and suppresses the excessive ovarian production of androgens. As a consequence, it is suggested that metformin could improve assisted reproductive techniques (ART) outcomes, such as ovarian hyperstimulation syndrome (OHSS), pregnancy and live birth rates. To determine the effectiveness and safety of metformin as a co-treatment during IVF or intracytoplasmic sperm injection (ICSI) in achieving pregnancy or live birth in women with PCOS. We searched the Cochrane Menstrual Disorders and Subfertility Group Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library), MEDLINE, EMBASE, LILACS, the metaRegister of Controlled Trials and reference lists of articles (up to 15 October 2014). Types of studies: randomised controlled trials (RCTs) comparing metformin treatment with placebo or no treatment in women with PCOS who underwent IVF or ICSI treatment. women of reproductive age with anovulation due to PCOS with or without co-existing infertility factors.Types of interventions: metformin administered before and during IVF or ICSI treatment.Types of outcome measures: live birth rate, clinical pregnancy rate, miscarriage rate, incidence of ovarian hyperstimulation syndrome , incidence of participant-reported side effects, serum oestradiol level on the day of trigger, serum androgen level, and fasting insulin and glucose levels. Two review authors independently selected the studies, extracted the data according to the protocol and assessed study quality. The overall quality of the evidence was assessed using GRADE methods. We included nine randomised controlled trials involving a total of 816 women with PCOS. When metformin was compared with placebo there was no clear evidence of a difference

  16. Metformin treatment in type 2 diabetes in pregnancy: an active controlled, parallel-group, randomized, open label study in patients with type 2 diabetes in pregnancy.

    Science.gov (United States)

    Ainuddin, Jahan Ara; Karim, Nasim; Zaheer, Sidra; Ali, Syed Sanwer; Hasan, Anjum Ara

    2015-01-01

    To assess the effect of metformin and to compare it with insulin treatment in patients with type 2 diabetes in pregnancy in terms of perinatal outcome, maternal complications, additional insulin requirement, and treatment acceptability. In this randomized, open label study, 206 patients with type 2 diabetes in pregnancy who met the eligibility criteria were selected from the antenatal clinics. Insulin was added to metformin treatment when required, to maintain the target glycemic control. The patients were followed up till delivery. Maternal, and perinatal outcomes and pharmacotherapeutic characteristics were recorded on a proforma. Maternal characteristics were comparable in metformin and insulin treated group. 84.9% patients in metformin group required add-on insulin therapy at mean gestational age of 26.58 ± 3.85 weeks. Less maternal weight gain (P pregnancy induced hypertension (P = 0.029) were observed in metformin treated group. Small for date babies were more in metformin group (P 24 hours in metformin group (P metformin group. Metformin alone or with add-on insulin is an effective and cheap treatment option for patients with type 2 diabetes in pregnancy. This trial is registered with clinical trial registration number: Clinical trials.gov NCT01855763.

  17. Modulation of gut microbiota by berberine and metformin during the treatment of high-fat diet-induced obesity in rats.

    Science.gov (United States)

    Zhang, Xu; Zhao, Yufeng; Xu, Jia; Xue, Zhengsheng; Zhang, Menghui; Pang, Xiaoyan; Zhang, Xiaojun; Zhao, Liping

    2015-09-23

    Accumulating evidence suggests that the gut microbiota is an important factor in mediating the development of obesity-related metabolic disorders, including type 2 diabetes. Metformin and berberine, two clinically effective drugs for treating diabetes, have recently been shown to exert their actions through modulating the gut microbiota. In this study, we demonstrated that metformin and berberine similarly shifted the overall structure of the gut microbiota in rats. Both drugs showed reverting effects on the high-fat diet-induced structural changes of gut microbiota. The diversity of gut microbiota was significantly reduced by both berberine- and metformin-treatments. Nearest shrunken centroids analysis identified 134 operational taxonomic units (OTUs) responding to the treatments, which showed close associations with the changes of obese phenotypes. Sixty out of the 134 OTUs were decreased by both drugs, while those belonging to putative short-chain fatty acids (SCFA)-producing bacteria, including Allobaculum, Bacteriodes, Blautia, Butyricoccus, and Phascolarctobacterium, were markedly increased by both berberine and, to a lesser extent, metformin. Taken together, our findings suggest that berberine and metformin showed similarity in modulating the gut microbiota, including the enrichment of SCFA-producing bacteria and reduction of microbial diversity, which may contribute to their beneficial effects to the host.

  18. Metformin Treatment in Type 2 Diabetes in Pregnancy: An Active Controlled, Parallel-Group, Randomized, Open Label Study in Patients with Type 2 Diabetes in Pregnancy

    Directory of Open Access Journals (Sweden)

    Jahan Ara Ainuddin

    2015-01-01

    Full Text Available Aims. To assess the effect of metformin and to compare it with insulin treatment in patients with type 2 diabetes in pregnancy in terms of perinatal outcome, maternal complications, additional insulin requirement, and treatment acceptability. Methods. In this randomized, open label study, 206 patients with type 2 diabetes in pregnancy who met the eligibility criteria were selected from the antenatal clinics. Insulin was added to metformin treatment when required, to maintain the target glycemic control. The patients were followed up till delivery. Maternal, and perinatal outcomes and pharmacotherapeutic characteristics were recorded on a proforma. Results. Maternal characteristics were comparable in metformin and insulin treated group. 84.9% patients in metformin group required add-on insulin therapy at mean gestational age of 26.58 ± 3.85 weeks. Less maternal weight gain (P24 hours in metformin group (P<0.01. Significant reduction in cost of treatment was found in metformin group. Conclusion. Metformin alone or with add-on insulin is an effective and cheap treatment option for patients with type 2 diabetes in pregnancy. This trial is registered with clinical trial registration number: Clinical trials.gov NCT01855763.

  19. Metformin versus insulin treatment in gestational diabetes in pregnancy in a developing country: a randomized control trial.

    Science.gov (United States)

    Ainuddin, Jahanara; Karim, Nasim; Hasan, Anjum Ara; Naqvi, Sanower Ali

    2015-02-01

    To compare treatment with metformin alone, metformin plus insulin and insulin alone in women with gestational diabetes (GDM). A total of 150 gestational diabetic patients who fulfilled the eligibility criteria were included in this prospective randomized control open labeled study. A risk factor based screening was done followed by a GCT and then local GTT criteria from antenatal clinics. They were initially divided into two groups with odd numbers assigned to metformin treatment and even numbers to insulin treatment. Metformin and/or insulin treatment was given and target blood sugar levels aimed at FBS ≤ 100 mg/dl and postprandial levels ≤ 126 mg/dl. Supplemental insulin was added to metformin treatment group to maintain the glycemic targets if required. Patients were followed until delivery and maternal fetal outcomes and pharmacotherapeutic characteristics were recorded on a performa. Less maternal weight gain was found in the metformin treated groups (9.8 ± 1.5 kg [metformin alone] vs. 9.8 ± 1.4 kg [metformin plus insulin] vs. 12.5 ± 1.1 kg [insulin alone] P metformin treated groups. There were no perinatal deaths in the study. Mean birth weight was significantly less in metformin treated groups (3.4 ± 0.4 kg vs. 3.3 ± 0.5 kg vs. 3.7 ± 0.5 kg P metformin groups. 42.7% of patients required supplemental insulin (mean dose of 13.6 ± 2 units) in the metformin group. Mean gestational age at which insulin was added was 31.8 ± 5.9 weeks. Metformin is an effective and cheap treatment option for women with gestational diabetes with or without supplemental insulin. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  20. Predictors of HbA1c levels in patients initiating metformin.

    Science.gov (United States)

    Martono, Doti P; Hak, Eelko; Lambers Heerspink, Hiddo; Wilffert, Bob; Denig, Petra

    2016-12-01

    The aim was to assess demographic and clinical factors as predictors of short (6 months) and long term (18 months) HbA1c levels in diabetes patients initiating metformin treatment. We conducted a cohort study including type 2 diabetes patients who received their first metformin prescription between 2007 and 2013 in the Groningen Initiative to Analyze Type 2 Diabetes Treatment (GIANTT) database. The primary outcome was HbA1c level at follow-up adjusted for baseline HbA1c; the secondary outcome was failing to achieve the target HbA1c level of 53 mmol/mol. Associations were analyzed by linear and logistic regression. Multiple imputation was used for missing data. Additional analyses stratified by dose and adherence level were conducted. The cohort included 6050 patients initiating metformin. Baseline HbA1c at target consistently predicted better HbA1c outcomes. Longer diabetes duration and lower total cholesterol level at baseline were predictors for higher HbA1c levels at 6 months. At 18 months, cholesterol level was not a predictor. Longer diabetes duration was also associated with not achieving the target HbA1c at follow-up. The association for longer diabetes duration was especially seen in patients starting on low dose treatment. No consistent associations were found for comorbidity and comedication. Diabetes duration was a relevant predictor of HbA1c levels after 6 and 18 months of follow-up in patients initiating metformin treatment. Given the study design, no causal inference can be made. Our study suggests that prompt treatment intensification may be needed in patients who have a longer diabetes duration at treatment initiation.

  1. Short-term treatment outcomes of children starting antiretroviral ...

    African Journals Online (AJOL)

    Short-term treatment outcomes of children starting antiretroviral therapy in the intensive care unit, general medical wards and outpatient HIV clinics at Red Cross War Memorial Children's Hospital, Cape Town, South Africa: A retrospective cohort study.

  2. Metformin ameliorates insulitis in STZ-induced diabetic mice

    Directory of Open Access Journals (Sweden)

    Guo-Jun Jiang

    2017-04-01

    Full Text Available Background & Aims Metformin is currently the most widely used first-line hypoglycemic agent for diabetes mellitus. Besides glucose-lowering action, there is increasingly interest in the potential anti-inflammatory action of this drug. In the present study, we investigated the actions of metformin on experimental insulitis using STZ-induced diabetic mice. Methods Mice with acute diabetes induced by STZ were administered metformin by gavage. Changes of blood glucose and body weight, and the daily amount of food and water intake were measured. Pancreatic tissues were collected for histologic analyses. Pathological assessment and immunohistochemistry analysis were used to determine the effect of metformin on insulitis. Inflammatory cytokines in the pancreas and insulin levels were measured through ELISA analysis. Results Metformin significantly reduced blood glucose levels and improved aberrant water intake behavior in experimental diabetic mice. No significant differences were observed in terms of body weight and food intake behavior in metformin-treated animals. In the STZ-induced model of diabetes, we found the appearance of pronounced insulitis. However, metformin administration reduced the severity of insulitis assessed by blind pathological scoring. In addition, metformin treatment improved insulin levels in experimental diabetic mice. ELISA assay revealed decreased levels of inflammatory response marker IL-1β and TNF-α in the pancreatic tissues following metformin treatment. Conclusion Metformin attenuated insulitis in the STZ-induced mice model of diabetes. This islet-protective effect might be partly correlated with the anti-inflammatory action of metformin.

  3. Cost-effectiveness of metformin plus vildagliptin compared with metformin plus sulphonylurea for the treatment of patients with type 2 diabetes mellitus: a Portuguese healthcare system perspective.

    Science.gov (United States)

    Viriato, Daniel; Calado, Frederico; Gruenberger, Jean-Bernard; Ong, Siew Hwa; Carvalho, Davide; Silva-Nunes, José; Johal, Sukhvinder; Viana, Ricardo

    2014-07-01

    To evaluate the cost-effectiveness of vildagliptin plus metformin vs generic sulphonylurea plus metformin in patients with type 2 diabetes mellitus, not controlled with metformin, from a Portuguese healthcare system perspective. A cost-effectiveness model was constructed using risk equations from the UK Prospective Diabetes Study Outcomes Model with a 10,000-patient cohort and a lifetime horizon. The model predicted microvascular and macrovascular complications and mortality in yearly cycles. Patients entered the model as metformin monotherapy failures and switched to alternative treatments (metformin plus basal-bolus insulin and subsequently metformin plus intensive insulin) when glycated hemoglobin A1c >7.5% was reached. Baseline patient characteristics and clinical variables were derived from a Portuguese epidemiological study. Cost estimates were based on direct medical costs only. One-way and probabilistic sensitivity analyses were conducted to test the robustness of the model. There were fewer non-fatal diabetes-related adverse events (AEs) in patients treated with metformin plus vildagliptin compared with patients treated with metformin plus sulphonylurea (6752 vs 6815). Addition of vildagliptin compared with sulphonylurea led to increased drug acquisition costs but reduced costs of AEs, managing morbidities, and monitoring patients. Treatment with metformin plus vildagliptin yielded a mean per-patient gain of 0.1279 quality-adjusted life years (QALYs) and a mean per-patient increase in total cost of €1161, giving an incremental cost-effectiveness ratio (ICER) of €9072 per QALY. Univariate analyses showed that ICER values were robust and ranged from €4195 to €16,052 per QALY when different parameters were varied. The model excluded several diabetes-related morbidities, such as peripheral neuropathy and ulceration, and did not model second events. Patients were presumed to enter the model with no diabetes-related complications. Treatment with

  4. Mechanisms involved in metformin action in the treatment of polycystic ovary syndrome.

    Science.gov (United States)

    Motta, A B

    2009-01-01

    The N, N' dimethyl-biguanide : Metformin is an antidiabetic drug that increases glucose utilization in insulin-sensitive tissues. As Polycystic Ovary Syndrome (PCOS) and diabetes share some altered parameters-such as abnormal glucose: insulin ratio, altered lipidic metabolism and insulin-resistance syndrome- the use of metformin has become increasingly accepted and widespread in the treatment of PCOS. Currently, metformin is used to induce ovulation and during early pregnancy in PCOS patients, however, a complete knowledge of the metformin action has not been achieved yet. This review describes beyond the classical reproductive action of metformin and explores other benefits of the drug. In addition, the present work discusses the molecular mechanisms involved further than the classical pathway that involves the AMP-activated protein kinase.

  5. Metformin as an adjunct therapy for the treatment of moderate to severe acne vulgaris.

    Science.gov (United States)

    Lee, John K; Smith, Andrew D

    2017-11-15

    The purpose of this literature review is to evaluate the use of metformin as an adjunct therapy in the treatment of moderate-to-severe acne in those not diagnosed with polycystic ovary syndrome (PCOS) or androgen excess. The authors conducted independent literature searches. Results were limited to clinical trials and randomized controlled trials. Studies with participants diagnosed with moderateto-severe acne vulgaris taking metformin versus placebo or other active treatment were included;studies with participants diagnosed with PCOS or androgen excess were excluded. The authors found three studies consistent with the search guidelines that evaluated the effects of metformin as adjunct therapy in moderate to severe acne vulgaris. In eachstudy, metformin was an effective adjunct therapy in the treatment of moderate-to-severe acne vulgaris.

  6. [Current role of metformin in treatment of diabetes mellitus type 2].

    Science.gov (United States)

    Janssen, J A

    2000-09-30

    Metformin-associated lactic acidosis is not necessarily due to metformin accumulation. It appears that mortality in patients receiving metformin who develop lactic acidosis is mostly linked to underlying disease. It has been suggested that metformin should be the first-line agent for the treatment of obese type 2 diabetic patients since metformin was associated with a significant decrease in macrovascular events and a reduction of all-cause mortality in the United Kingdom Prospective Diabetes Study (UKPDS) in a substudy. However, in this substudy no significant decrease in microvascular complications was observed in obese subjects with intensive metformin therapy. In addition, the use of metformin in combination with sulfonylurea seemed to be associated with excess risk of diabetes-related and all-cause mortality in obese subjects. Due to the discrepant and contradictory nature of the results in the obese patients and a lack of power the UKPDS offered no decision for any drug for initial therapy of type 2 diabetes. The main message of the UKPDS is that lowering of the blood glucose to the normal range is beneficial irrespective of the hypoglycaemic agent used. A rational approach to therapy in a type 2 diabetes patient who fails to sufficiently lower blood sugar with diet and weight loss is to begin therapy with a sulfonylurea or metformin and to add another oral agent if the desired glycaemic control is not achieved.

  7. Oral combination therapy: repaglinide plus metformin for treatment of type 2 diabetes.

    Science.gov (United States)

    Raskin, P

    2008-12-01

    Type 2 diabetes is characterized by decreases in insulin secretion and insulin sensitivity. Several classes of oral antidiabetic medications are currently approved for the treatment of type 2 diabetes. A stepwise treatment approach from monotherapy to combination therapy is traditionally used; however, the frequency of treatment failure with monotherapy has resulted in a move towards earlier treatment with combination therapies that target the two principal defects in glycaemic control. One such combination regimen is repaglinide (a prandial glucose regulator that increases insulin release) plus metformin (an insulin sensitizer that inhibits hepatic glucose output, increases peripheral glucose uptake and utilization and minimizes weight gain). Findings from several clinical trials have shown that combination therapy with repaglinide plus metformin is well tolerated and results in greater reductions of haemoglobin A(1c) and fasting plasma glucose values compared with either monotherapy. Repaglinide may also provide a more suitable alternative to combination therapy with sulphonylureas and metformin because of its reduced propensity for hypoglycaemia. The combination regimen of repaglinide plus metformin should therefore be considered as a valuable option in the management of patients with type 2 diabetes when monotherapy is no longer adequate.

  8. Short-term Treatment of Daumone Improves Hepatic Inflammation in Aged Mice.

    Science.gov (United States)

    Park, Jong Hee; Ha, Hunjoo

    2015-05-01

    Chronic inflammation has been proposed as one of the main molecular mechanisms of aging and age-related diseases. Although evidence in humans is limited, short-term calorie restriction (CR) has been shown to have anti-inflammatory effects in aged experimental animals. We reported on the long-term treatment of daumone, a synthetic pheromone secreted by Caenorhabditis elegans in an energy deficient environment, extends the life-span and attenuates liver injury in aged mice. The present study examined whether late onset short-term treatment of daumone exerts anti-inflammatory effects in the livers of aged mice. Daumone was administered orally at doses of 2 or 20 mg/kg/day for 5 weeks to 24-month-old male C57BL/6J mice. Increased liver macrophage infiltration and gene expression of proinflammatory cytokines in aged mice were significantly attenuated by daumone treatment, suggesting that short-term oral administration of daumone may have hepatoprotective effects. Daumone also dose-dependently suppressed tumor necrosis factor-α (TNF-α)-induced nuclear factor-κB (NF-κB) phosphorylation in HepG2 cells. The present data demonstrated that short-term treatment of daumone has anti-inflammatory effects in aged mouse livers possibly through suppression of NF-κB signaling and suggest that daumone may become a lead compound targeting aging and age-associated diseases.

  9. Metformin for olanzapine-induced weight gain: a systematic review and meta-analysis.

    Science.gov (United States)

    Praharaj, Samir Kumar; Jana, Amlan Kusum; Goyal, Nishant; Sinha, Vinod Kumar

    2011-03-01

    Olanzapine is an atypical antipsychotic that is useful in schizophrenia and bipolar affective disorder, but its use is associated with troublesome weight gain and metabolic syndrome. A variety of pharmacological agents has been studied in the efforts to reverse weight gain induced by olanzapine, but current evidence is insufficient to support any particular pharmacological approach. We conducted a systematic review and meta-analysis of randomized controlled trials of metformin for the treatment of olanzapine-induced weight gain. Systematic review of the literature revealed 12 studies that had assessed metformin for antipsychotic-induced weight gain. Of these, four studies (n= 105) met the review inclusion criteria and were included in the final analysis. Meta-analysis was performed to see the effect size of the treatment on body weight, waist circumference and body-mass index (BMI). Weighted mean difference (WMD) for body weight was 5.02 (95% CI 3.93, 6.10) kg lower with metformin as compared with placebo at 12 weeks. For waist circumference, the test for heterogeneity was significant (P= 0.00002, I(2) = 85.1%). Therefore, a random effects model was used to calculate WMD, which was 1.42 (95% CI 0.29, 3.13) cm lower with metformin as compared with placebo at 12 weeks. For BMI, WMD was 1.82 (95% CI 1.44, 2.19) kg m(-2) lower with metformin as compared with placebo at 12 weeks. Existing data suggest that short term modest weight loss is possible with metformin in patients with olanzapine-induced weight gain. © 2011 The Authors. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society.

  10. The effect of metformin treatment on ICSI in infertile polycystic ovary syndrome

    Directory of Open Access Journals (Sweden)

    Firoozeh Akbari Asbagh

    2010-03-01

    Full Text Available "n Normal 0 false false false EN-US X-NONE AR-SA MicrosoftInternetExplorer4 /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Table Normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-priority:99; mso-style-qformat:yes; mso-style-parent:""; mso-padding-alt:0in 5.4pt 0in 5.4pt; mso-para-margin:0in; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:11.0pt; font-family:"Calibri","sans-serif"; mso-ascii-font-family:Calibri; mso-ascii-theme-font:minor-latin; mso-fareast-font-family:"Times New Roman"; mso-fareast-theme-font:minor-fareast; mso-hansi-font-family:Calibri; mso-hansi-theme-font:minor-latin; mso-bidi-font-family:Arial; mso-bidi-theme-font:minor-bidi;} Background: Insulin resistance is common in women with Polycystic Ovary Syndrome (PCOS and can cause poor outcome of infertility treatment. The aim of our study was to assess the effect of treatment with metformin on outcome of Intra Cytoplasmic Sperm Injection (ICSI in infertile PCOS women."n"nMethods: A randomized clinical trial study was carried out in infertile women with PCOS, before ICSI, referred to infertility clinic of Mirza Koochackhan Hospital of Tehran University of Medical Science Tehran, Iran, between 2006 and 2008. The patients were randomized in two groups of metformin 500 mg Po, three times daily, six weeks before the ICSI cycle and placebo patients in each group were divided into BMI <28 kg/m2 and BMI ≥28 kg/m2."n"nResults: Of 52 study women 26(50% were in metformin group. mean age were 29.8±4.9 year in metformin group versus 29.4±5.9 year and placebo groups. Treatment with metformin, in subgroup of BMI <28 kg/m2, significantly increased number of mature follicle (p=0.01, embryo (p=0.04, oocytes (p=0.007 and mature oocytes (p=0.03 but in subgroup of BMI≥28 kg/m2, there was no significant difference in the metformin and placebo groups (p>0.05. Metformin treatment caused more chemical and clinical

  11. Novel combination treatment of type 2 diabetes DPP-4 inhibition + metformin

    Directory of Open Access Journals (Sweden)

    Bo Ahrén

    2008-04-01

    Full Text Available Bo AhrénDepartment of Clinical Sciences, Division of Medicine, Lund University, Lund, SwedenAbstract: Inhibition of dipeptidyl peptidase-4 (DPP-4 as a novel therapy for type 2 diabetes is based on prevention of the inactivation process of bioactive peptides, the most important in the context of treatment of diabetes of which is glucagon-like peptide-1 (GLP-1. Most clinical experience with DPP-4 inhibition is based on vildagliptin (GalvusR, Novartis and sitagliptin (JanuviaR, Merck. These compounds improve glycemic control both in monotherapy and in combination with other oral hyperglycemic agents. Both have also been shown to efficiently improve glycemic control when added to ongoing metformin therapy in patients with inadequate glycemic control. Under that condition, they reduce HbA1c levels by 0.65%–1.1% (baseline HbA1c 7.2–8.7% in studies up to 52 weeks of duration in combination versus continuous therapy with metformin alone. Sitagliptin has also been examined in initial combination therapy with metformin have; HbA1c was reduced by this combination by 2.1% (baseline HbA1c 8.8% after 24 weeks of treatment. Both fasting and prandial glucose are reduced by DPP-4 inhibition in combination with metformin in association with improvement of insulin secretion and insulin resistance and increase in concentrations of active GLP-1. The combination of DPP-4 inhibition and metformin has been shown to be highly tolerable with very low risk of hypoglycemia. Hence, DPP-4 inhibition in combination with metformin is an efficient, safe and tolerable combination therapy for type 2 diabetes.Keywords: DPP-4 inhibition, sitagliptin, vildagliptin, metformin, type 2 diabetes

  12. Two weeks of metformin treatment induces AMPK-dependent enhancement of insulin-stimulated glucose uptake in mouse soleus muscle

    Science.gov (United States)

    Kristensen, Jonas Møller; Treebak, Jonas T.; Schjerling, Peter; Goodyear, Laurie

    2014-01-01

    Metformin-induced activation of the 5′-AMP-activated protein kinase (AMPK) has been associated with enhanced glucose uptake in skeletal muscle, but so far no direct causality has been examined. We hypothesized that an effect of in vivo metformin treatment on glucose uptake in mouse skeletal muscles is dependent on AMPK signaling. Oral doses of metformin or saline treatment were given to muscle-specific kinase dead (KD) AMPKα2 mice and wild-type (WT) littermates either once or chronically for 2 wk. Soleus and extensor digitorum longus muscles were used for measurements of glucose transport and Western blot analyses. Chronic treatment with metformin enhanced insulin-stimulated glucose uptake in soleus muscles of WT (∼45%, P metformin treatment. Insulin signaling at the level of Akt and TBC1D4 protein expression as well as Akt Thr308/Ser473 and TBC1D4 Thr642/Ser711 phosphorylation were not changed by metformin treatment. Also, protein expressions of Rab4, GLUT4, and hexokinase II were unaltered after treatment. The acute metformin treatment did not affect glucose uptake in muscle of either of the genotypes. In conclusion, we provide novel evidence for a role of AMPK in potentiating the effect of insulin on glucose uptake in soleus muscle in response to chronic metformin treatment. PMID:24644243

  13. Carbohydrate-lipid profile and use of metformin with micronized fenofibrate in reducing metabolic consequences of craniopharyngioma treatment in children: single institution experience.

    Science.gov (United States)

    Kalina, Maria Aleksandra; Wilczek, Marta; Kalina-Faska, Barbara; Skała-Zamorowska, Eliza; Mandera, Marek; Małecka Tendera, Ewa

    2015-01-01

    To evaluate auxology and metabolic disturbances in children with craniopharyngioma, and to present observational results of treatment of metabolic sequels with metformin and micronized fenofibrate. The studied group comprised 22 children [median age at diagnosis 10.5 (0.17-16.75) years; median follow-up 5.1 years]. Assessment included height standard deviations (SDS), body mass index (BMI) SDS, concentrations of lipids, glucose and insulin (fasting or oral glucose tolerance test) and homeostatic model assessment of insulin resistance (HOMA-IR) index. Ten adolescents with hyperinsulinemia and dyslipidemia received therapy with metformin (500-1500 mg/daily) and micronized fenofibrate (160 mg/daily). At diagnosis, median hSDS was -1.66 (range: -4.08; +0.1). Nine (40.9%) children were growth hormone-treated. There was gradual increase of BMI SDS, 18 (81.8%) patients being overweight at the final assessment. Dyslipidaemia was found in 19 patients (86.4%), hyperinsulinaemia in 11 patients (50%) and elevated HOMA-IR in 15 patients (68.2%). Decrease of triglycerides [median 263.5 (171-362) mg/dL vs. 154 (102-183) mg/dL] and HOMA-IR [8.64 (5.08-12.65) vs. 4.68 (0.7-7.9)] was significant in the group treated with metformin and fenofibrate for 6 months. Significant auxologic changes and metabolic abnormalities were found in children treated for craniopharyngioma. The use of metformin and fenofibrate seemed to attenuate these disturbances in a short-term observation.

  14. Short-Term Treatment of Children With Encopresis

    Science.gov (United States)

    FIREMAN, GARY; KOPLEWICZ, HAROLD S.

    1992-01-01

    To examine the effectiveness of a short-term behavioral treatment of encopresis, 52 encopretic children were evaluated and treated according to a standardized protocol. The treatment was highly effective, with a significant decrease in soiling during the first month (P < 0.01). Of the children who began treatment, 84.6% successfully reached the criterion of 2 consecutive weeks with no soiling accidents in a mean time of 28 days, and 78.8% successfully completed an additional 7-week phaseout period. The evaluations provided rich descriptive information regarding the characteristics of encopretic children. In agreement with the literature, no specific pattern of behavioral pathology was apparent. PMID:22700057

  15. Lack of metformin effect on mouse embryo AMPK activity: implications for metformin treatment during pregnancy.

    Science.gov (United States)

    Lee, Hyung-Yul; Wei, Dan; Loeken, Mary R

    2014-01-01

    Adenosine monophosphate-activated protein kinase (AMPK) is stimulated in embryos during diabetic pregnancy by maternal hyperglycaemia-induced embryo oxidative stress. Stimulation of AMPK disrupts embryo gene expression and causes neural tube defects. Metformin, which may be taken during early pregnancy, has been reported to stimulate AMPK activity. Thus, the benefits of improved glycaemic control could be offset by stimulated embryo AMPK activity. Here, we investigated whether metformin can stimulate AMPK activity in mouse embryos and can adversely affect embryo gene expression and neural tube defects. Pregnant nondiabetic mice were administered metformin beginning on the first day of pregnancy. Activation of maternal and embryo AMPK [phospho-AMPK α (Thr172) relative to total AMPK], expression of Pax3, a gene required for neural tube closure, and neural tube defects were studied. Mouse embryonic stem cells were used as a cell culture model of embryonic neuroepithelium to study metformin effects on AMPK and Pax3 expression. Metformin had no effect on AMPK in embryos or maternal skeletal muscle but increased activated AMPK in maternal liver. Metformin did not inhibit Pax3 expression or increase neural tube defects. However, metformin increased activated AMPK and inhibited Pax3 expression by mouse embryonic stem cells. Mate1/Slc47a1 and Oct3/Slc22a, which encode metformin transporters, were expressed at barely detectable levels by embryos. Although metformin can have effects associated with diabetic embryopathy in vitro, the lack of effects on mouse embryos in vivo may be due to lack of metformin transporters and indicates that the benefits of metformin on glycaemic control are not counteracted by stimulation of embryo AMPK activity and consequent embryopathy. Copyright © 2013 John Wiley & Sons, Ltd.

  16. Metformin efficacy and safety for colorectal polyps: a double-blind randomized controlled trial

    International Nuclear Information System (INIS)

    Higurashi, Takuma; Fujisawa, Nobutaka; Uchiyama, Shiori; Ezuka, Akiko; Nagase, Hajime; Kessoku, Takaomi; Matsuhashi, Nobuyuki; Yamanaka, Shoji; Inayama, Yoshiaki; Morita, Satoshi; Nakajima, Atsushi; Takahashi, Hirokazu; Endo, Hiroki; Hosono, Kunihiro; Yamada, Eiji; Ohkubo, Hidenori; Sakai, Eiji; Uchiyama, Takashi; Hata, Yasuo

    2012-01-01

    Colorectal cancer is one of the major neoplasms and a leading cause of cancer death worldwide, and new preventive strategies are needed to lower the burden of this disease. Metformin, a biguanide, which is widely used for treating diabetes mellitus, has recently been suggestive to have a suppressive effect on tumorigenesis and cancer cell growth. In a previous study conducted in non-diabetic subjects, we showed that oral short-term low-dose metformin suppressed the development of colorectal aberrant crypt foci (ACF). ACF have been considered as a useful surrogate biomarker of CRC, although the biological significance of these lesions remains controversial. We devised a prospective randomized controlled trial to evaluate the chemopreventive effect of metformin against metachronous colorectal polyps and the safety of this drug in non-diabetic post-polypectomy patients. This study is a multi-center, double-blind, placebo-controlled, randomized controlled trial to be conducted in non-diabetic patients with a recent history of undergoing colorectal polypectomy. All adult patients visiting the Yokohama City University hospital or affiliated hospitals for polypectomy shall be recruited for the study. Eligible patients will then be allocated randomly into either one of two groups: the metformin group and the placebo group. Patients in the metformin group shall receive oral metformin at 250 mg per day, and those in the placebo group shall receive an oral placebo tablet. At the end of 1 year of administration of metformin/placebo, colonoscopy will be performed to evaluate the polyp formation. This is the first study proposed to explore the effect of metformin against colorectal polyp formation. Metformin activates AMPK, which inhibits the mammalian target of rapamycin (mTOR) pathway. The mTOR pathway plays an important role in the cellular protein translational machinery and cell proliferation. Patients with type 2 diabetes taking under treatment with metformin have been

  17. Metformin efficacy and safety for colorectal polyps: a double-blind randomized controlled trial

    Directory of Open Access Journals (Sweden)

    Higurashi Takuma

    2012-03-01

    Full Text Available Abstract Background Colorectal cancer is one of the major neoplasms and a leading cause of cancer death worldwide, and new preventive strategies are needed to lower the burden of this disease. Metformin, a biguanide, which is widely used for treating diabetes mellitus, has recently been suggestive to have a suppressive effect on tumorigenesis and cancer cell growth. In a previous study conducted in non-diabetic subjects, we showed that oral short-term low-dose metformin suppressed the development of colorectal aberrant crypt foci (ACF. ACF have been considered as a useful surrogate biomarker of CRC, although the biological significance of these lesions remains controversial. We devised a prospective randomized controlled trial to evaluate the chemopreventive effect of metformin against metachronous colorectal polyps and the safety of this drug in non-diabetic post-polypectomy patients. Methods/Design This study is a multi-center, double-blind, placebo-controlled, randomized controlled trial to be conducted in non-diabetic patients with a recent history of undergoing colorectal polypectomy. All adult patients visiting the Yokohama City University hospital or affiliated hospitals for polypectomy shall be recruited for the study. Eligible patients will then be allocated randomly into either one of two groups: the metformin group and the placebo group. Patients in the metformin group shall receive oral metformin at 250 mg per day, and those in the placebo group shall receive an oral placebo tablet. At the end of 1 year of administration of metformin/placebo, colonoscopy will be performed to evaluate the polyp formation. Discussion This is the first study proposed to explore the effect of metformin against colorectal polyp formation. Metformin activates AMPK, which inhibits the mammalian target of rapamycin (mTOR pathway. The mTOR pathway plays an important role in the cellular protein translational machinery and cell proliferation. Patients with

  18. Should metformin be included in fertility treatment of PCOS patients?

    Science.gov (United States)

    Haas, Jigal; Bentov, Yaakov

    2017-03-01

    Metformin, a drug developed for the treatment of patients with type II diabetes, has become commonly prescribed medication for PCOS patients. Initially, metformin was prescribed for patients with impaired glucose tolerance at the pre conception period, however more recently its use was expanded to many of the PCOS patients and for the whole duration of pregnancy. Several studies examining the effects of Metformin during pregnancy reported a lower pregnancy loss, reduced gestational diabetes and no increased risk for birth defects, however, several more recent studies also raised concerns about its safe use. The therapeutic effect of metformin stems from its ability to inhibit the action of the first complex of the electron transport resulting in reduced ATP production. At the initial stages of embryo development, the only source of ATP is the mitochondrial electron transport chain. Lowering ATP production at the critical stage of early embryo development may impair oocyte maturation and embryo development as well as reprogram the metabolic characteristics of the offspring. Copyright © 2017 Elsevier Ltd. All rights reserved.

  19. Metformin extended release treatment of adolescent obesity: a 48-week randomized, double-blind, placebo-controlled trial with 48-week follow-up.

    Science.gov (United States)

    Wilson, Darrell M; Abrams, Stephanie H; Aye, Tandy; Lee, Phillip D K; Lenders, Carine; Lustig, Robert H; Osganian, Stavroula V; Feldman, Henry A

    2010-02-01

    Metformin has been proffered as a therapy for adolescent obesity, although long-term controlled studies have not been reported. To test the hypothesis that 48 weeks of daily metformin hydrochloride extended release (XR) therapy will reduce body mass index (BMI) in obese adolescents, as compared with placebo. Multicenter, randomized, double-blind, placebo-controlled clinical trial. The 6 centers of the Glaser Pediatric Research Network from October 2003 to August 2007. Obese (BMI > or = 95th percentile) adolescents (aged 13-18 years) were randomly assigned to the intervention (n = 39) or placebo groups. Intervention Following a 1-month run-in period, subjects following a lifestyle intervention program were randomized 1:1 to 48 weeks' treatment with metformin hydrochloride XR, 2000 mg once daily, or an identical placebo. Subjects were monitored for an additional 48 weeks. Main Outcome Measure Change in BMI, adjusted for site, sex, race, ethnicity, and age and metformin vs placebo. After 48 weeks, mean (SE) adjusted BMI increased 0.2 (0.5) in the placebo group and decreased 0.9 (0.5) in the metformin XR group (P = .03). This difference persisted for 12 to 24 weeks after cessation of treatment. No significant effects of metformin on body composition, abdominal fat, or insulin indices were observed. Metformin XR caused a small but statistically significant decrease in BMI when added to a lifestyle intervention program. clinicaltrials.gov Identifiers: NCT00209482 and NCT00120146.

  20. Metformin Treatment Does Not Affect Testicular Size in Offspring Born to Mothers with Gestational Diabetes.

    Science.gov (United States)

    Tertti, Kristiina; Toppari, Jorma; Virtanen, Helena E; Sadov, Sergey; Rönnemaa, Tapani

    2016-01-01

    Studies in rodents suggest that metformin treatment during pregnancy may have harmful effects on testicular development in offspring. Our aim was to determine whether metformin treatment of gestational diabetes mellitus (GDM) affects testicular size in male offspring. We compared the testicular size in prepubertal boys born to mothers who participated in a randomized controlled trial (RCT) comparing metformin with insulin in the treatment of GDM. Twenty-five (42.4% of invited) and 27 (52.9% of invited) boys whose mothers had been treated with metformin or insulin, respectively, participated in the study. Testicular size was measured by a ruler, an orchidometer, and by ultrasonography at the age of 33 to 85 months. The mean age of the boys was 60 months at the time of examination, and did not differ between the metformin and insulin group (p = 0.88). There was no difference in testicular size between the boys in the two groups (p always ≥ 0.40), and there were no significant differences in height, weight, BMI, BMI z-score, or waist-to-hip ratio (WHR) between the boys in the groups. Prepubertal testicular size did not differ between offspring born to metformin-treated mothers and those born to insulin-treated mothers.

  1. Impact of Treatment with Metformin on Adipocytokines in Patients with Polycystic Ovary Syndrome: A Meta-Analysis.

    Science.gov (United States)

    Kong, Wen; Niu, Xun; Zeng, Tianshu; Lu, Meixia; Chen, Lulu

    2015-01-01

    Metformin is effective for the treatment of polycystic ovary syndrome, but conflicting results regarding its effect on adipocytokine levels (adiponectin, resistin, visfatin, and leptin) in patients with polycystic ovary syndrome receiving metformin treatment have been reported. To provide high-quality evidence about the effect of metformin treatment on adipocytokines in patients with polycystic ovary syndrome, relevant studies that assessed the levels of adipocytokines (adiponectin, resistin, visfatin, and leptin) in patients with polycystic ovary syndrome receiving treatment with metformin administration were reviewed and analyzed. A literature search was conducted in the SCI, PUBMED, EMBASE, and Elsevier databases, and personal contact was made with the authors. Standard mean differences and 95% confidence intervals were calculated and combined appropriately. To ensure synthesis of the best available evidence, sensitivity analyses were performed. A total of 34 data sets were included in 4 different outcomes, involving 744 women with polycystic ovary syndrome and adipocytokine levels measured both before and after metformin administration. Metformin treatment was associated with significantly elevated serum adiponectin concentrations (standard mean differences [95% confidence interval], -0.43 [-0.75 to -0.11]) and decreased serum leptin concentrations (0.65 [0.26 to 1.04]), whereas no significant difference in resistin level (-0.01 [-0.49 to 0.45]) or visfatin level (-0.04 [-1.55 to 1.46]) was found. Metformin administration was associated with increased serum adiponectin concentrations and decreased serum leptin levels. Further study is needed to elucidate whether this apparent effect decreases the incidence of type 2 diabetes and other metabolic diseases in patients with polycystic ovary syndrome later in life.

  2. The effect of metformin treatment in vivo on acute and long-term energy metabolism and progesterone production in vitro by granulosa cells from women with polycystic ovary syndrome.

    Science.gov (United States)

    Maruthini, D; Harris, S E; Barth, J H; Balen, A H; Campbell, B K; Picton, H M

    2014-10-10

    What are the consequences of polycystic ovary syndrome (PCOS) pathology and metformin-pretreatment in vivo in women with PCOS on the metabolism and steroid production of follicular phenotype- and long-term cultured-granulosa cells (GC)? PCOS pathology significantly compromised glucose metabolism and the progesterone synthetic capacity of follicular- and long-term cultured-GCs and the metabolic impact of PCOS on GC function was alleviated by metformin-pretreatment in vivo. Granulosa cells from women with PCOS have been shown to have an impaired insulin-stimulated glucose uptake and lactate production in vitro. However, these results were obtained by placing GCs in unphysiological conditions in culture medium containing high glucose and insulin concentrations. Moreover, existing data on insulin-responsive steroid production in vitro by PCOS GCs vary. Case-control experimental research comparing glucose uptake, pyruvate and lactate production and progesterone production in vitro by GCs from three aetiological groups, all undergoing IVF; healthy control women (Control, n = 12), women with PCOS treated with metformin in vivo (Metformin, n = 8) and women with PCOS not exposed to metformin (PCOS, n = 8). The study was conducted over a period of 3 years between 2007 and 2010. Rotterdam criteria were used for the diagnosis of PCOS; all subjects were matched for age, BMI and baseline FSH. Individual patient cultures were undertaken with cells incubated in a validated, physiological, serum-free culture medium containing doses of 0-6 mM glucose and 0-100 ng/ml insulin for 6 h and 144 h to quantify the impact of treatments on acute and long-term metabolism, respectively, and progesterone production. The metabolite content of spent media was measured using spectrophotometric plate reader assay. The progesterone content of spent media was measured by enzyme-linked immunosorbent assay. Viable GC number was quantified after 144 h of culture by the vital dye Neutral Red uptake assay

  3. Botulinum toxin type A in simple motor tics: short-term and long-term treatment-effects.

    Science.gov (United States)

    Rath, Judith J G; Tavy, Dénes L J; Wertenbroek, Agnes A A C M; van Woerkom, Theodoor C A M; de Bruijn, Sebastiaan F T M

    2010-08-01

    To determine the short-term and long-term treatment-effects of botulinum toxin type A in simple motor tics, we analyzed 15 consecutive patients (18 tics) with simple motor tics that were treated every 3 months with injections of BTX-A. Efficacy (rated on a 4-level scale) and duration of effect of the first 2 and last 2 (if treated 5 times or more) treatments were recorded, as well as latency of response, changes of premonitory urges (PMUs) and possible side effects. Total number of treatments for each tic varied from 2 to 50 (mean 11, median 6). In 16 of 18 tics (89%) short-term efficacy was reported successful (good or moderate). Long-term efficacy was reported in 12 tics of which 11 showed similar or even increased beneficial effects. Premonitory urge (PMU) was reported in 8 patients (53%). PMU, if present, lessened or disappeared after treatment with BTX-A. A permanent remission of the treated tic was seen in 3 patients with a maximum follow-up of 10 years. BTX-A appears a safe and effective treatment for simple motor tics and retains its efficacy after long-term treatment. BTX may also induce permanent remission of the treated tics and effects of BTX are not restricted to merely motor behaviour.

  4. Effect of adjunct metformin treatment on levels of plasma lipids in patients with type 1 diabetes

    DEFF Research Database (Denmark)

    Lund, S.S.; Tarnow, L.; Astrup, A.S.

    2009-01-01

    BACKGROUND: In addition to its glucose-lowering effect, metformin treatment has been suggested to improve lipidaemia in patients with type 2 diabetes. In contrast, in patients with type 1 diabetes (T1DM), information about the effect of metformin treatment on lipidaemia is limited. In this study......, we report the effect of a 1-year treatment with metformin vs. placebo on plasma lipids in T1DM patients and persistent poor glycaemic control. METHODS: One hundred T1DM patients with haemoglobinA(1c) (HbA(1c)) > or =8.5% during the year before enrolment entered a 1-month run-in period on placebo...... treatment. Thereafter, patients were randomized (baseline) to treatment with either metformin (1000 mg twice daily) or placebo for 12 months (double masked). Patients continued ongoing insulin therapy and their usual outpatient clinical care. Outcomes were assessed at baseline and after 1 year. RESULTS...

  5. Effect comparison of metformin with insulin treatment for gestational diabetes: a meta-analysis based on RCTs.

    Science.gov (United States)

    Li, Genxia; Zhao, Shujun; Cui, Shihong; Li, Lei; Xu, Yajuan; Li, Yuanyuan

    2015-07-01

    To compare the effects of metformin with insulin on maternal and neonatal outcomes in gestational diabetes mellitus (GDM). A literature search in PUBMED, EMBASE, Science Direct, Springer link, and Cochrane library was conducted using the following search terms: "Gestational Diabetes" or "GDM", and "insulin" and "metformin". Quality assessment of included studies was determined with Quality Assessment of Diagnostic Accuracy Studies. Review Manger 5.2 was used to analyze mean difference (MD)/risk ratio (RR) and 95 % confidence interval (CI) in random-effects model or fixed-effects model depending on the level of heterogeneity. A total of 11 studies were identified. There was no significant difference of the effect on maternal outcomes between the two treatments in glycohemoglobin A1c levels (P = 0.37), fasting blood glucose (P = 0.66), and the incidence of preeclampsia (P = 0.26); whereas, significantly reduced results were found in the metformin group in pregnancy-induced hypertension (PIH) rate (RR = 0.53, 95 % CI 0.31-0.90, P = 0.02), average weight gains after enrollment (MD = -1.28, 95 % CI -1.54 to -1.01, P metformin presented significantly lower average birth weights (MD = -44.35, 95 % CI -85.79 to -2.90, P = 0.04), incidence of hypoglycemia (RR = 0.69, 95 % CI 0.55-0.87, P = 0.001) and neonatal intensive care unit (NICU) (RR = 0.82, 95 % CI 0.67-0.99, P = 0.04). Metformin can significantly reduce several adverse maternal and neonatal outcomes including PIH rate, incidence of hypoglycemia and NICU, thus it may be an effective and safe alternative or additional treatment to insulin for GDM women.

  6. Prevention of mammary carcinogenesis by short-term estrogen and progestin treatments

    International Nuclear Information System (INIS)

    Rajkumar, Lakshmanaswamy; Guzman, Raphael C; Yang, Jason; Thordarson, Gudmundur; Talamantes, Frank; Nandi, Satyabrata

    2004-01-01

    Women who have undergone a full-term pregnancy before the age of 20 have one-half the risk of developing breast cancer compared with women who have never gone through a full-term pregnancy. This protective effect is observed universally among women of all ethnic groups. Parity in rats and mice also protects them against chemically induced mammary carcinogenesis. Seven-week-old virgin Lewis rats were given N-methyl-N-nitrosourea. Two weeks later the rats were treated with natural or synthetic estrogens and progestins for 7–21 days by subcutaneous implantation of silastic capsules. In our current experiment, we demonstrate that short-term sustained exposure to natural or synthetic estrogens along with progestins is effective in preventing mammary carcinogenesis in rats. Treatment with 30 mg estriol plus 30 mg progesterone for 3 weeks significantly reduced the incidence of mammary cancer. Short-term exposure to ethynyl estradiol plus megesterol acetate or norethindrone was effective in decreasing the incidence of mammary cancers. Tamoxifen plus progesterone treatment for 3 weeks was able to confer only a transient protection from mammary carcinogenesis, while 2-methoxy estradiol plus progesterone was effective in conferring protection against mammary cancers. The data obtained in the present study demonstrate that, in nulliparous rats, long-term protection against mammary carcinogenesis can be achieved by short-term treatments with natural or synthetic estrogen and progesterone combinations

  7. Effects of metformin on pregnancy outcomes in women with polycystic ovary syndrome

    Science.gov (United States)

    Zeng, Xian-Ling; Zhang, Ya-Fei; Tian, Quan; Xue, Yan; An, Rui-Fang

    2016-01-01

    Abstract Aim: The aim of the study is to evaluate the effects of metformin on pregnancy outcomes in women with polycystic ovary syndrome (PCOS). Methods: We searched electronic databases and bibliographies of relevant papers to identify studies comparing the pregnancy outcomes in the metformin group with those in the placebo or blank control group. Then, we did this meta-analysis based on the PRISMA guidelines. The primary outcomes included early pregnancy loss (EPL), preterm delivery, term delivery, and gestational diabetes mellitus (GDM). Secondary outcomes included pregnancy-induced hypertension (PIH), intrauterine growth restriction (IUGR), fetal malformation, vaginal delivery (VD), cesarean section (CS), and metformin's side effects, such as nausea or gastrointestinal discomfort. Certainly, data about neonatal death and macrosomia were analyzed if data available. Results: Finally, 13 studies including 5 randomized controlled trials (RCT) and 8 cohort studies involving 1606 pregnant women with PCOS were analyzed. The pooled OR of EPL was 0.19 with obvious statistical significance, manifesting that metformin help to lower the rate of EPL (95% CI 0.12–0.28, P metformin showed the advantage of reducing the prevalence of preterm delivery (OR 0.37, 95% CI 0.20–0.68, P = 0.002). In addition, metformin could promote term delivery greatly and the pooled OR was 5.23 with sharp statistical difference (95% CI 3.12–8.75, P Metformin treatment in women with PCOS throughout pregnancy could increase the possibility of term delivery, VD and reduce the risk of EPL, preterm labor, pregnancy complications such as GDM and PIH, with no serious side effects. Moreover, metformin was not teratogenic based on the limited data. So we may recommend metformin treatment for women with PCOS during the whole pregnancy period for it is quite beneficial and safe for both mothers and babies. PMID:27603343

  8. Metformin maintains the weight loss and metabolic benefits following rimonabant treatment in obese women with polycystic ovary syndrome (PCOS).

    Science.gov (United States)

    Sathyapalan, Thozhukat; Cho, Li Wei; Kilpatrick, Eric S; Coady, Anne-Marie; Atkin, Stephen L

    2009-01-01

    Rimonabant has been shown to reduce weight, free androgen index (FAI) and insulin resistance in obese patients with polycystic ovary syndrome (PCOS) compared to metformin. Studies have shown that significant weight regain occurs following the cessation of rimonabant therapy. This study was undertaken to determine if subsequent metformin treatment after rimonabant would maintain the improvement in weight, insulin resistance and hyperandrogenaemia in PCOS. An extension study for 3 months with the addition of metformin to the randomised open labelled parallel study of metformin and rimonabant in 20 patients with PCOS with a body mass index >or= 30 kg/m(2). Patients who were on 3 months of rimonabant were changed over to metformin for 3 months, whereas those on 3 months of metformin were continued on metformin for another 3 months. The primary end-point was a change in weight; secondary end-points were a change in FAI and insulin resistance. The mean weight loss of 6.2 kg associated with 3 months of rimonabant treatment was maintained by 3 months of metformin treatment (mean change +0.2 kg, P = 0.96). Therefore, the percentage reduction in weight remained significantly higher in the rimonabant/metformin group compared to metformin only subjects at 6 months compared to baseline (-6.0 +/- 0.1%vs. -2.8 +/- 0.1%, P = 0.04). The percentage change in testosterone and FAI from baseline to 6 months was also greater in the rimonabant/metformin group. [Testosterone (-45.0 +/- 5.0%vs. -16 +/- 2.0%, P = 0.02); FAI (-53.0 +/- 5.0%vs. -17.0 +/- 12.2%, P = 0.02)]. HOMA-IR continued to fall significantly in the rimonabant/metformin group between 0, 3 and 6 months (4.4 +/- 0.5 vs. 3.4 +/- 0.4 vs. 2.7 +/- 0.3, respectively, P weight loss and enhanced the metabolic and biochemical parameters achieved by treatment with rimonabant, compared to 6 months of metformin treatment alone.

  9. Relation between augmentation index and adiponectin during one-year metformin treatment for nonalcoholic steatohepatosis: effects beyond glucose lowering?

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    Shargorodsky Marina

    2012-06-01

    Full Text Available Abstract Background Insulin resistance (IR is the major driving force behind development and progression of atherosclerosis in patients with nonalcoholic fatty liver disease (NAFLD. Therefore, correction of IR is a relevant therapeutic target. We performed the current trial to evaluate whether 12- month metformin therapy improves vascular stiffness in patients with NAFLD and to assess if this improvement is associated with change in glucose control, insulin resistance or circulating adiponectin. Methods In randomized, placebo controlled study, 63 patients with NAFLD were assigned to one of two groups: Group 1 received daily metformin; Group 2 received placebo. Central aortic augmentation index (AI was performed using SphygmoCor (version 7.1, AtCor Medical, Sydney, Australia at baseline, at 4-and 12-month treatment period. Metabolic parameters, insulin resistance markers and serum adiponectin levels were determined. Results In placebo group: AI did not improve during the treatment period. Liver function and adiponectin levels did not change during the study. In multiple linear regression analysis, the independent predictors of arterial stiffness improvement were metformin treatment and increase in circulating adiponectin levels. Among metformin treated patients: AI decreased significantly during the study. ALP and ALT decreased during initial 4-month treatment period, however raised to the pretreatment levels after 12 months. Serum adiponectin level tended to increase during treatment period with metformin. Conclusions Metformin treatment was associated with significant decrease in AI during one year treatment in NAFLD patients. These beneficial vascular effects was associated with exposure to metformin per se as well as change in adiponectin levels suggesting that metformin may mediate its vascular effects via glicemic control-independent mechanisms. Trial registry no: NCT01084486

  10. Impact of Treatment with Metformin on Adipocytokines in Patients with Polycystic Ovary Syndrome: A Meta-Analysis

    Science.gov (United States)

    Kong, Wen; Niu, Xun; Zeng, Tianshu; Lu, Meixia; Chen, Lulu

    2015-01-01

    Background Metformin is effective for the treatment of polycystic ovary syndrome, but conflicting results regarding its effect on adipocytokine levels (adiponectin, resistin, visfatin, and leptin) in patients with polycystic ovary syndrome receiving metformin treatment have been reported. To provide high-quality evidence about the effect of metformin treatment on adipocytokines in patients with polycystic ovary syndrome, relevant studies that assessed the levels of adipocytokines (adiponectin, resistin, visfatin, and leptin) in patients with polycystic ovary syndrome receiving treatment with metformin administration were reviewed and analyzed. Methods A literature search was conducted in the SCI, PUBMED, EMBASE, and Elsevier databases, and personal contact was made with the authors. Standard mean differences and 95% confidence intervals were calculated and combined appropriately. To ensure synthesis of the best available evidence, sensitivity analyses were performed. Results A total of 34 data sets were included in 4 different outcomes, involving 744 women with polycystic ovary syndrome and adipocytokine levels measured both before and after metformin administration. Metformin treatment was associated with significantly elevated serum adiponectin concentrations (standard mean differences [95% confidence interval], −0.43 [−0.75 to −0.11]) and decreased serum leptin concentrations (0.65 [0.26 to 1.04]), whereas no significant difference in resistin level (−0.01 [−0.49 to 0.45]) or visfatin level (−0.04 [−1.55 to 1.46]) was found. Conclusions Metformin administration was associated with increased serum adiponectin concentrations and decreased serum leptin levels. Further study is needed to elucidate whether this apparent effect decreases the incidence of type 2 diabetes and other metabolic diseases in patients with polycystic ovary syndrome later in life. PMID:26473366

  11. Metformin alters the gut microbiome of individuals with treatment-naive type 2 diabetes, contributing to the therapeutic effects of the drug

    DEFF Research Database (Denmark)

    Wu, Hao; Esteve, Eduardo; Tremaroli, Valentina

    2017-01-01

    months and showed that metformin had strong effects on the gut microbiome. These results were verified in a subset of the placebo group that switched to metformin 6 months after the start of the trial. Transfer of fecal samples (obtained before and 4 months after treatment) from metformin-treated donors......Metformin is widely used in the treatment of type 2 diabetes (T2D), but its mechanism of action is poorly defined. Recent evidence implicates the gut microbiota as a site of metformin action. In a double-blind study, we randomized individuals with treatment-naive T2D to placebo or metformin for 4...... to germ-free mice showed that glucose tolerance was improved in mice that received metformin-altered microbiota. By directly investigating metformin-microbiota interactions in a gut simulator, we showed that metformin affected pathways with common biological functions in species from two different phyla...

  12. Comparison of costs and outcomes of dapagliflozin with other glucose-lowering therapy classes added to metformin using a short-term cost-effectiveness model in the US setting.

    Science.gov (United States)

    Chakravarty, Abhiroop; Rastogi, Mohini; Dhankhar, Praveen; Bell, Kelly F

    2018-05-01

    To compare 1-year costs and benefits of dapagliflozin (DAPA), a sodium-glucose cotransporter-2 (SGLT-2) inhibitor, with those of other treatments for type 2 diabetes (T2D), such as glucagon-like peptide-1 receptor agonists (GLP-1RAs), sulfonylureas (SUs), thiazolidinediones (TZDs), and dipeptidyl peptidase-4 inhibitors (DPP-4i), all combined with metformin. A short-term decision-analytic model with a 1-year time horizon was developed from a payer's perspective in the United States setting. Costs and benefits associated with four clinical end-points (glycated hemoglobin [A1C], body weight, systolic blood pressure [SBP], and risk of hypoglycemia) were evaluated in the analysis. The impact of DAPA and other glucose-lowering therapy classes on these clinical end-points was estimated from a network meta-analysis (NMA). Data for costs and quality-adjusted life-years (QALYs) associated with a per-unit change in these clinical end-points were taken from published literature. Drug prices were taken from an annual wholesale price list. All costs were inflation-adjusted to December 2016 costs using the medical care component of the consumer price index. Total costs (both medical and drug costs), total QALYs, and incremental cost-effectiveness ratios (ICERs) were estimated. Sensitivity analyses (SA) were performed to explore uncertainty in the inputs. To assess face validity, results from the short-term model were compared with long-term models published for these drugs. The total annual medical cost for DAPA was less than that for GLP-1RA ($186 less), DPP-4i ($1,142 less), SU ($2,474 less), and TZD ($1,640 less). Treatment with DAPA resulted in an average QALY gain of 0.0107, 0.0587, 0.1137, and 0.0715 per treated patient when compared with GLP-1RA, DPP-4i, SU, and TZD, respectively. ICERs for DAPA vs SU and TZD were $19,005 and $25,835, respectively. DAPA was a cost-saving option when compared with GLP-1RAs and DPP-4is. Among all four clinical end-points, change in weight

  13. Inhibition of glioblastoma tumorspheres by combined treatment with 2-deoxyglucose and metformin.

    Science.gov (United States)

    Kim, Eui Hyun; Lee, Ji-Hyun; Oh, Yoonjee; Koh, Ilkyoo; Shim, Jin-Kyoung; Park, Junseong; Choi, Junjeong; Yun, Mijin; Jeon, Jeong Yong; Huh, Yong Min; Chang, Jong Hee; Kim, Sun Ho; Kim, Kyung-Sup; Cheong, Jae-Ho; Kim, Pilnam; Kang, Seok-Gu

    2017-02-01

    Deprivation of tumor bioenergetics by inhibition of multiple energy pathways has been suggested as an effective therapeutic approach for various human tumors. However, this idea has not been evaluated in glioblastoma (GBM). We hypothesized that dual inhibition of glycolysis and oxidative phosphorylation could effectively suppress GBM tumorspheres (TS). Effects of 2-deoxyglucose (2DG) and metformin, alone and in combination, on GBM-TS were evaluated. Viability, cellular energy metabolism status, stemness, invasive properties, and GBM-TS transcriptomes were examined. In vivo efficacy was tested in a mouse orthotopic xenograft model. GBM-TS viability was decreased by the combination of 2DG and metformin. ATP assay and PET showed that cellular energy metabolism was also decreased by this combination. Sphere formation, expression of stemness-related proteins, and invasive capacity of GBM-TS were also significantly suppressed by combined treatment with 2DG and metformin. A transcriptome analysis showed that the expression levels of stemness- and epithelial mesenchymal transition-related genes were also significantly downregulated by combination of 2DG and metformin. Combination treatment also prolonged survival of tumor-bearing mice and decreased invasiveness of GBM-TS. The combination of 2DG and metformin effectively decreased the stemness and invasive properties of GBM-TS and showed a potential survival benefit in a mouse orthotopic xenograft model. Our findings suggest that targeting TS-forming cells by this dual inhibition of cellular bioenergetics warrants expedited clinical evaluation for the treatment of GBM. © The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com

  14. Comparative treatment between sitagliptin vs. metformin, alone or in combination, in patients with polycystic ovary syndrome. A clinical entity at high risk for developing diabetes mellitus and gestational diabetes: A pilot study

    Directory of Open Access Journals (Sweden)

    J.C. Paredes Palma

    2018-01-01

    Conclusion: Therapeutic effect of sitagliptin was observed in patients with PCOS comparable to metformin and the combination of metformin-sitagliptin is more effective in terms of ovulation than the other two treatments alone.

  15. Metformin use in patients undergoing in vitro fertilization treatment: results of a worldwide web-based survey.

    Science.gov (United States)

    Christianson, Mindy S; Wu, Harold; Zhao, Yulian; Yemini, Matan; Leong, Milton; Shoham, Zeev

    2015-03-01

    To identify trends regarding therapeutic approaches to metformin administration in patients undergoing in vitro fertilization (IVF) treatment worldwide. A retrospective evaluation utilizing the results of a web-based survey, IVFWorldwide ( www.IVF-worldwide.com/ ), was performed. Responses from 101 centers performing a total of 50,800 annual IVF cycles was performed. Of these cycles, 10.4% (n = 5,260) reported metformin use during IVF cycles. Indications for metformin use in IVF cycles included polycystic ovary syndrome (PCOS) patients who were habitual abortions (67%), had prior poor egg quality (61%), had high serum insulin levels (56%). Less reported was PCOS with obesity/anvoulation (29%), PCOS with multiple manifestations (23%) and glucose intolerance and insulin resistance (23%). Over half of cycles (54%) treated patients with metformin up to 3 months prior to starting IVF. A majority (82%) of IVF cycles utilized 1500-2000 mg/day of metformin. A nearly equal percentage of centers continued metformin up to a positive β-HCG test (35%) or to 12 weeks gestation (33%). 70% of IVF cycles reported increased pregnancy rates and decreased miscarriage rates due to the use of metformin. 75% reported the data in the literature is not sufficient for reaching a definitive conclusion concerning metformin treatment in patients undergoing IVF. While metformin is used worldwide as an adjunct to standard IVF protocols, there is much variation in its use and the majority of centers report lack of evidence supporting its use.

  16. Metformin and Pregnancy

    Science.gov (United States)

    ... include Glucophage®, Diformin®, Glumetza®, FORTAMET ® and Glycon®. I use metformin for the treatment of type 2 diabetes. Should ... chances of complications in their newborns. If I use metformin throughout pregnancy will it affect the baby? It ...

  17. [Metformin efficiency for the adolescent PCOS treatment].

    Science.gov (United States)

    Kedikova, S; Sirakov, M; Boyadzhieva, M

    2012-01-01

    PCOS is a polyglandular heterogenic metabolic condition, which frequency in adolescence is defined between 11-26%. There are some aspects of PCOS which can be seen in a regular puberty and vice versa. This makes the adolescent PCOS a condition which is rather complicated to diagnose as well as to treat. The pathophysiology of PCOS is not fully clarified, but is well established the fundamental role of the insulin resistance and the hyperinsulinemia. This fact explains the detailed investigations of the insulin sensitizers use for the PCOS treatment. Nevertheless there is insufficient experience with this medication group for the adolescent PCOS treatment in Bulgaria. To evaluate the Metformin efficiency for the adolescent PCOS treatment. This is a prospective study including 55 girls with menstrual irregularities aged between 13 and 18 years. None of the subjects had previously been diagnosed with any endocrine pathology or had received any hormonal treatment for at least three months prior to their evaluation. They have been evaluated according to the diagnostic criteria for PCOS in adolescence accepted in 2010. The incidence of PCOS in our research was 38.9%. In 66.7% of them the body mass index was higher than normal. Insulin resistance was diagnosed in 90.5%. The insulin resistance was improved in 80% of the PCOS patients after six months therapy with Metformin 2 x 850 mg/p.d. The menstrual function was regulated in 77.8% of the cases.

  18. A short course of metformin does not reduce OHSS in a GnRH antagonist cycle for women with PCOS undergoing IVF: a randomised placebo-controlled trial.

    Science.gov (United States)

    Jacob, S L; Brewer, C; Tang, T; Picton, H M; Barth, J H; Balen, A H

    2016-12-01

    Does 'metformin' reduce the incidence of ovarian hyperstimulation syndrome (OHSS) for women with polycystic ovary syndrome (PCOS) undergoing a GnRH antagonist assisted conception treatment cycle? A short course of metformin does not reduce the incidence of OHSS for women with PCOS undergoing a GnRH antagonist treatment cycle. Metformin does reduce the incidence of OHSS in a GnRH-agonist treatment cycle. A randomised placebo-controlled trial (RCT) using metformin or placebo. Randomisation was blinded to both patient and investigator, using a random permuted blocks method with a 50:50 allocation ratio. The study was completed over 5 years (2009-2014) with 153 randomised patients. A sample size calculation based on the incidence of OHSS was completed prospectively suggesting a minimum of 146 recruits was required for the trial with a power of 80% and a type 1 error of 0.05. All patients met the Rotterdam criteria for PCOS and were treated with a standard GnRH antagonist IVF/ICSI treatment cycle in a tertiary infertility clinic. The study medication was started prior to stimulation and continued to oocyte retrieval. Of the 153 patients, 77 received metformin and 76 placebo. There was no reduction in the incidence of moderate-severe OHSS (Placebo (PLA) 12.2%, metformin (MET) = 16%, 95% CI -0.08-0.16, P = 0.66). There was no difference in total gonadotrophin dose (PLA = 1200, MET = 1200, 95% CI -118.67-118.67, P = 0.75), oocytes retrieved (PLA = 15, MET = 14, 95% CI -2.37-4.37, P = 0.66) or fertilisation rate (PLA = 60.7%, MET = 53.3%, 95% CI -0.96-14.94, P = 0.07). However, using metformin resulted in a reduced clinical pregnancy rate (CPR) per cycle started (PLA = 48.7%, MET = 28.6%, 95% CI 0.04-0.35, P = 0.02) and live birth rate (PLA = 51.6%, MET = 27.6%, 95% CI 0.05-0.40, P = 0.02). Furthermore, when ethnicity was taken into account there was a significant reduction in pregnancy outcome for the South Asian population irrespective of metformin or

  19. Two weeks of metformin treatment induces AMPK dependent enhancement of insulin-stimulated glucose uptake in mouse soleus muscle

    DEFF Research Database (Denmark)

    Kristensen, Jonas Møller; Treebak, Jonas Thue; Schjerling, Peter

    2014-01-01

    signaling. Methods: Oral doses of metformin or saline treatment were given muscle-specific kinase α2 dead AMPK mice (KD) and wild type (WT) littermates either once or chronically for 2 weeks. Soleus and Extensor Digitorum Longus (EDL) muscles were used for measurements of glucose transport and Western blot......Background: Metformin-induced activation of AMPK has been associated with enhanced glucose uptake in skeletal muscle but so far no direct causality has been examined. We hypothesized that an effect of in vivo metformin treatment on glucose uptake in mouse skeletal muscles is dependent upon AMPK...... analyzes. Results: Chronic treatment with metformin enhanced insulin-stimulated glucose uptake in soleus muscles of WT (45%, P...

  20. Does metformin treatment during pregnancy modify future metabolic profile in women with PCOS?

    Science.gov (United States)

    Underdal, Maria Othelie; Stridsklev, Solhild; Oppen, Ingrid Hennum; Høgetveit, Kristin; Andersen, Marianne Skovsager; Vanky, Eszter

    2018-04-05

    Worldwide, metformin is prescribed in an attempt to improve pregnancy outcome in PCOS. Metformin may also benefit future health by modulating the increased metabolic stress during pregnancy. To investigate if metformin during pregnancy modified future metabolic health in women with PCOS. Follow-up study of a randomized controlled trial, which compared metformin to placebo in women with PCOS. Mean follow-up period was 8 years (5-11). Three university hospitals, seven local hospitals, and one gynecological specialist practice. Women with PCOS according to Rotterdam criteria, all former participants in the PregMet study. Metformin 2000 mg daily or placebo from 1st trimester to delivery in the original study. No intervention in the present follow-up study. Main outcome measure was weight-gain in the follow-up period. Weight, body mass index, waist and hip circumferences and blood pressure were registered. Body composition was assessed by bioelectrical impedance analysis, and fasting lipids, glucose and insulin were analysed. 131 out of 239 (55%) invited women participated in the follow-up. Weight gain was similar in women given metformin (2.1±10.5) and women given placebo (1.8±11.2) at 7.7 years follow-up after pregnancy (p-value=0.834). No difference was found between those treated with metformin and placebo during pregnancy in BMI, waist/hip ratio, blood pressure, body composition, lipids, glucose and insulin levels or prevalence of metabolic syndrome at follow-up. Metformin treatment during pregnancy did not influence the metabolic profile in women with PCOS at 7.7 years of follow-up.

  1. Metformin Alters Gut Microbiota of Healthy Mice: Implication for Its Potential Role in Gut Microbiota Homeostasis

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    Wei Ma

    2018-06-01

    Full Text Available In recent years, the first-line anti-diabetic drug metformin has been shown to be also useful for the treatment of other diseases like cancer. To date, few reports were about the impact of metformin on gut microbiota. To fully understand the mechanism of action of metformin in treating diseases other than diabetes, it is especially important to investigate the impact of long-term metformin treatment on the gut microbiome in non-diabetic status. In this study, we treated healthy mice with metformin for 30 days, and observed 46 significantly changed gut microbes by using the 16S rRNA-based microbiome profiling technique. We found that microbes from the Verrucomicrobiaceae and Prevotellaceae classes were enriched, while those from Lachnospiraceae and Rhodobacteraceae were depleted. We further compared the altered microbiome profile with the profiles under various disease conditions using our recently developed comparative microbiome tool known as MicroPattern. Interestingly, the treatment of diabetes patients with metformin positively correlates with colon cancer and type 1 diabetes, indicating a confounding effect on the gut microbiome in patients with diabetes. However, the treatment of healthy mice with metformin exhibits a negative correlation with multiple inflammatory diseases, indicating a protective anti-inflammatory role of metformin in non-diabetes status. This result underscores the potential effect of metformin on gut microbiome homeostasis, which may contribute to the treatment of non-diabetic diseases.

  2. Reappraisal of metformin efficacy in the treatment of type 2 diabetes: a meta-analysis of randomised controlled trials.

    Directory of Open Access Journals (Sweden)

    Rémy Boussageon

    Full Text Available BACKGROUND: The UK Prospective Diabetes Study showed that metformin decreases mortality compared to diet alone in overweight patients with type 2 diabetes mellitus. Since then, it has been the first-line treatment in overweight patients with type 2 diabetes. However, metformin-sulphonylurea bitherapy may increase mortality. METHODS AND FINDINGS: This meta-analysis of randomised controlled trials evaluated metformin efficacy (in studies of metformin versus diet alone, versus placebo, and versus no treatment; metformin as an add-on therapy; and metformin withdrawal against cardiovascular morbidity or mortality in patients with type 2 diabetes. We searched Medline, Embase, and the Cochrane database. Primary end points were all-cause mortality and cardiovascular death. Secondary end points included all myocardial infarctions, all strokes, congestive heart failure, peripheral vascular disease, leg amputations, and microvascular complications. Thirteen randomised controlled trials (13,110 patients were retrieved; 9,560 patients were given metformin, and 3,550 patients were given conventional treatment or placebo. Metformin did not significantly affect the primary outcomes all-cause mortality, risk ratio (RR=0.99 (95% CI: 0.75 to 1.31, and cardiovascular mortality, RR=1.05 (95% CI: 0.67 to 1.64. The secondary outcomes were also unaffected by metformin treatment: all myocardial infarctions, RR=0.90 (95% CI: 0.74 to 1.09; all strokes, RR=0.76 (95% CI: 0.51 to 1.14; heart failure, RR=1.03 (95% CI: 0.67 to 1.59; peripheral vascular disease, RR=0.90 (95% CI: 0.46 to 1.78; leg amputations, RR=1.04 (95% CI: 0.44 to 2.44; and microvascular complications, RR=0.83 (95% CI: 0.59 to 1.17. For all-cause mortality and cardiovascular mortality, there was significant heterogeneity when including the UK Prospective Diabetes Study subgroups (I(2=41% and 59%. There was significant interaction with sulphonylurea as a concomitant treatment for myocardial infarction (p=0

  3. Short-Term Intercultural Psychotherapy: Ethnographic Inquiry

    Science.gov (United States)

    Seeley, Karen M.

    2004-01-01

    This article examines the challenges specific to short-term intercultural treatments and recently developed approaches to intercultural treatments based on notions of cultural knowledge and cultural competence. The article introduces alternative approaches to short-term intercultural treatments based on ethnographic inquiry adapted for clinical…

  4. Randomized placebo control study of metformin in psoriasis patients with metabolic syndrome (systemic treatment cohort

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    Surjit Singh

    2017-01-01

    Full Text Available Background: Psoriasis has been found to be associated with obesity, metabolic syndrome (MS, diabetes, and cardiovascular risk factors. Metformin treatment showed improvement in cardiovascular risk factors and hyperinsulinemia. Objective: To evaluate the efficacy and safety of metformin in psoriasis patients with MS. Materials and Methods: This was a single-center, parallel-group, randomized, open-label study with blinded end point assessment of metformin (1000 mg once daily for 12 weeks; n = 20 and placebo (n = 18 in psoriasis patients with MS. Total sample size was 38 participants. Results: Statistically significant improvement was observed in mean percentage change in erythema, scaling, and induration (ESI (P = 0.048 in metformin as compared to placebo while mean percentage change in psoriasis area and severity index (PASI and physician global assessment (PGA scores was not significant (PASI - P = 0.215, PGA - P = 0.070. There was a statistically significant difference in percentage of parameters of MS improved following 12 weeks of treatment in metformin (19% as compared to placebo (8.9% group (P = 0.046. Statistically significant difference in percentage of patients achieving 75% reduction in ESI scores (P = 0.024. Significant improvement was observed in mean weight, body mass index (BMI, total cholesterol, and low-density lipoprotein (LDL cholesterol in metformin group as compared to placebo. Improvement in BMI, fasting plasma glucose, serum triglycerides, high-density lipoprotein, LDL, systolic blood pressure, diastolic blood pressure, and total cholesterol was statistically significant in metformin group over the period of 12 weeks. There was no significant difference in adverse events in two groups except weight gain. Conclusion: Metformin has shown improvement in psoriasis and parameters of MS, hence can be used for the benefit of psoriasis patients having MS. Large, controlled studies are needed to confirm.

  5. Genomic Characterization of Metformin Hepatic Response.

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    Marcelo R Luizon

    2016-11-01

    Full Text Available Metformin is used as a first-line therapy for type 2 diabetes (T2D and prescribed for numerous other diseases. However, its mechanism of action in the liver has yet to be characterized in a systematic manner. To comprehensively identify genes and regulatory elements associated with metformin treatment, we carried out RNA-seq and ChIP-seq (H3K27ac, H3K27me3 on primary human hepatocytes from the same donor treated with vehicle control, metformin or metformin and compound C, an AMP-activated protein kinase (AMPK inhibitor (allowing to identify AMPK-independent pathways. We identified thousands of metformin responsive AMPK-dependent and AMPK-independent differentially expressed genes and regulatory elements. We functionally validated several elements for metformin-induced promoter and enhancer activity. These include an enhancer in an ataxia telangiectasia mutated (ATM intron that has SNPs in linkage disequilibrium with a metformin treatment response GWAS lead SNP (rs11212617 that showed increased enhancer activity for the associated haplotype. Expression quantitative trait locus (eQTL liver analysis and CRISPR activation suggest that this enhancer could be regulating ATM, which has a known role in AMPK activation, and potentially also EXPH5 and DDX10, its neighboring genes. Using ChIP-seq and siRNA knockdown, we further show that activating transcription factor 3 (ATF3, our top metformin upregulated AMPK-dependent gene, could have an important role in gluconeogenesis repression. Our findings provide a genome-wide representation of metformin hepatic response, highlight important sequences that could be associated with interindividual variability in glycemic response to metformin and identify novel T2D treatment candidates.

  6. Effects of metformin on pregnancy outcomes in women with polycystic ovary syndrome: A meta-analysis.

    Science.gov (United States)

    Zeng, Xian-Ling; Zhang, Ya-Fei; Tian, Quan; Xue, Yan; An, Rui-Fang

    2016-09-01

    The aim of the study is to evaluate the effects of metformin on pregnancy outcomes in women with polycystic ovary syndrome (PCOS). We searched electronic databases and bibliographies of relevant papers to identify studies comparing the pregnancy outcomes in the metformin group with those in the placebo or blank control group. Then, we did this meta-analysis based on the PRISMA guidelines. The primary outcomes included early pregnancy loss (EPL), preterm delivery, term delivery, and gestational diabetes mellitus (GDM). Secondary outcomes included pregnancy-induced hypertension (PIH), intrauterine growth restriction (IUGR), fetal malformation, vaginal delivery (VD), cesarean section (CS), and metformin's side effects, such as nausea or gastrointestinal discomfort. Certainly, data about neonatal death and macrosomia were analyzed if data available. Finally, 13 studies including 5 randomized controlled trials (RCT) and 8 cohort studies involving 1606 pregnant women with PCOS were analyzed. The pooled OR of EPL was 0.19 with obvious statistical significance, manifesting that metformin help to lower the rate of EPL (95% CI 0.12-0.28, P metformin showed the advantage of reducing the prevalence of preterm delivery (OR 0.37, 95% CI 0.20-0.68, P = 0.002). In addition, metformin could promote term delivery greatly and the pooled OR was 5.23 with sharp statistical difference (95% CI 3.12-8.75, P Metformin treatment in women with PCOS throughout pregnancy could increase the possibility of term delivery, VD and reduce the risk of EPL, preterm labor, pregnancy complications such as GDM and PIH, with no serious side effects. Moreover, metformin was not teratogenic based on the limited data. So we may recommend metformin treatment for women with PCOS during the whole pregnancy period for it is quite beneficial and safe for both mothers and babies.

  7. Effects of metformin treatment on serum levels of C-reactive protein and interleukin-6 in women with polycystic ovary syndrome: a meta-analysis

    Science.gov (United States)

    Wang, Jiao; Zhu, Lingyan; Hu, Kaixiang; Tang, Yunliang; Zeng, Xiangxia; Liu, Jianying; Xu, Jixiong

    2017-01-01

    BMI in the CRP and IL-6 related studies (SMD = −0.45, 95% CI: −0.68 to −0.23; SMD = −0.44, 95% CI: −0.73 to −0.16). Conclusion: This meta-analysis showed a significant decrease of serum CRP levels, especially in obese women, but no significant changes in IL-6 levels after metformin treatment in women with PCOS. In general, the data support that early metformin therapy may ameliorate the state of chronic inflammation in women with PCOS. Considering the obvious heterogeneity reported in the literature, further well-designed investigations with larger samples are needed to ascertain the long-term effects of metformin on chronic inflammation in PCOS. PMID:28953677

  8. The Pharmacogenetics of Metformin in Women with PCOS

    DEFF Research Database (Denmark)

    Pedersen, Andreas J T; Stage, Tore Bjerregaard; Glintborg, Dorte

    2018-01-01

    Polycystic ovary syndrome (PCOS) is the most common endocrine disorder affecting women of reproductive age. PCOS is associated with obesity, dyslipidaemia and insulin resistance, and metformin treatment may improve such metabolic features. The effect of genetic variants in key metformin transport......Polycystic ovary syndrome (PCOS) is the most common endocrine disorder affecting women of reproductive age. PCOS is associated with obesity, dyslipidaemia and insulin resistance, and metformin treatment may improve such metabolic features. The effect of genetic variants in key metformin...... transporters, their transcriptional regulators or in metformin target genes on metformin response in women with PCOS is unclear. Associations between pharmacodynamic responses to metformin (changes in weight, lipid profile, insulin sensitivity evaluated by oral glucose tolerance testing) and polymorphisms...... in OCT1 (rs12208357 and rs72552763), HNF1A (rs1169288 and rs2464196), MATE1 (rs2289669 and rs2252281), MATE2-K (rs12943590) and ATM (rs11212617) were studied in 40 women with PCOS randomized to 12 months of treatment with metformin 1000 mg twice daily ± oral contraceptive pills (150 mg desogestrel + 30...

  9. Comparison between metformin and insulin in treatment of gestational diabetes mellitus and effect on neonatal hypoglycaemia

    International Nuclear Information System (INIS)

    Ayub, S.; Jaffar, S.R.

    2015-01-01

    To compare the efficacy of metformin in the treatment of gestational diabetes mellitus (GDM) with insulin and to compare the frequency of hypoglycaemia in neonates of the mothers treated with metformin and insulin. Study Design: Randomized control trial to compare the efficacy of metformin with insulin in the treatment of GDM. Place and Duration of Study: Outpatient department and labour ward of Obstetric and Gynaecology department of Benazir Bhutto Hospital Rawalpindi from August 2012 to January 2013. Patients and Method: A total of 110 pregnant ladies with GDM diagnosed after 20 weeks of gestation were included and divided into group A and group B with 55 patients in each group. Group A patients were treated with insulin and group B with metformin. Plasma fasting glucose and two hours postprandial glucose levels were determined on weekly basis for four weeks after starting the treatment to determine the efficacy of insulin and metformin. At birth plasma glucose levels of all the neonates were carried out two hourly, and more frequently depending upon the requirement, during first 24 hours in both the groups to determine neonatal hypoglycaemia. Results: Fasting plasma glucose in group A and B were calculated as 5.96 ± 0.58 and 5.76 ± 0.46 mmol/L respectively (p=0.280), while two hours post-prandial plasma glucose levels were 7.34 ± 0.48 and 7.28 ± 0.58 mmol/L respectively (p=0.650). Efficacy in group A was 78.18% and in group B was 70.91% (p=0.381) while frequency of neonatal hypoglycaemia was calculated as 61.54% in group A and 41% in group B (p=0.113). Conclusion: The efficacy of metformin in treatment of gestational diabetes mellitus is similar as with insulin and the frequency of hypoglycemia in neonates of the mother treated with metformin and insulin is also similar. (author)

  10. Metformin in cancer.

    Science.gov (United States)

    Mallik, Ritwika; Chowdhury, Tahseen A

    2018-05-26

    Metformin is a lipophilic biguanide which inhibits hepatic gluconeogenesis and improves peripheral utilization of glucose. It is the first line pharmacotherapy for glucose control in patients with Type 2 diabetes due to its safety, efficacy and tolerability. Metformin exhibits pleotropic effects, which may have beneficial effects on a variety of tissues independent of glucose control. A potential anti-tumourigenic effect of metformin may be mediated by its role in activating AMP-kinase, which in turn inhibits mammalian target of rapamycin (mTOR). Non-AMPK dependent protective pathways may include reduction of insulin, insulin-like growth factor-1, leptin, inflammatory pathways and potentiation of adiponectin, all of which may have a role in tumourigenesis. A role in inhibiting cancer stem cells is also postulated. A number of large scale observational and cohort studies suggest metformin is associated with a reduced risk of a number of cancers, although the data is not conclusive. Recent randomised studies reporting use of metformin in treatment of cancer have revealed mixed results, and the results of much larger randomised trials of metformin as an adjuvant therapy in breast and colorectal cancers are awaited. Copyright © 2018 Elsevier B.V. All rights reserved.

  11. Evaluation of the effect of metformin and insulin in hyperglycemia treatment after coronary artery bypass surgery in nondiabetic patients

    Directory of Open Access Journals (Sweden)

    Kamran Ghods

    2017-01-01

    Full Text Available Introduction: Insulin therapy is the most commonly used treatment for controlling hyperglycemia after coronary artery bypass surgery in both diabetic and nondiabetic patients. Metformin has been indicated for critically ill patients as an alternate for the treatment of hyperglycemia. This study evaluated the effect of metformin and insulin in hyperglycemia treatment after coronary artery bypass surgery in nondiabetic patients. Settings and Design: This study was a clinical trial comprising nondiabetic patients who had undergone coronary artery bypass surgery. Patients were randomly divided into the insulin group and the metformin group. Methods: Patients in the insulin group received continuous infusion of insulin while those in the metformin group received 500 mg metformin tablets twice daily. All the patients were followed up for 3 days after stabilization of blood glucose levels. Statistical Analysis: Data were analyzed using Chi-square test and Mann–Whitney U-test. Results: This study included a total of 56 patients. During the study period, the mean blood glucose levels decreased from 225.24 to 112.36 mg/dl (↓112.88 mg/dl in the insulin group and from 221.80 to 121.92 mg/dl in the metformin group (↓99.88 mg/dl. There was no significant difference in the blood glucose levels of the patients between the two groups at any measurement times (P > 0.05. Conclusion: Using 500 mg metformin twice daily is similar to using insulin in nondiabetic patients undergoing coronary artery bypass graft. Therefore, the use of metformin can be considered as a treatment strategy for controlling hyperglycemia in this group of patients.

  12. Exercise but not metformin improves health-related quality of life and mood states in older adults with type 2 diabetes.

    Science.gov (United States)

    Baptista, Liliana C; Machado-Rodrigues, Aristides M; Martins, Raul A

    2017-07-01

    The aim of this cohort study is to analyse the effect of three types of treatment: (i) exercise training with multicomponent exercise (E); (ii) pharmacologic treatment with oral hypoglycaemic drug - metformin (M); and (iii) a combined therapy - exercise and metformin (E + M) on health-related quality of life (HRQoL) and mood states in older adults with type 2 diabetes (T2D) with comorbidity in an early stage of the disease. Participants (n = 284) underwent 1 of the following 3 conditions: (i) E (n = 59) trained three times/week; (ii) M (n = 30) used 850 mg of metformin twice daily; and (iii) E + M (n = 195) combined exercise and metformin. Furthermore, participants completed baseline and 2-year follow-up evaluations including a Shortform Health Survey 36, Profile of Mood States - Short-form, the health history questionnaires, anthropometric, and blood biochemistry. E and E + M revealed improved mood states, with large effect size on the vigour domain, and moderate effect size in the anger and total mood disturbance (TMD) domains (P  0.05). Metformin had no significant effect on the self-referred HRQoL in T2D participants aged above 60 years, in an early stage of the disease. The E and E + M were the most effective long-term therapies to improve mood states and HRQoL in older adults with T2D.

  13. Effects of fructose-induced metabolic syndrome on rat skeletal cells and tissue, and their responses to metformin treatment.

    Science.gov (United States)

    Felice, Juan Ignacio; Schurman, León; McCarthy, Antonio Desmond; Sedlinsky, Claudia; Aguirre, José Ignacio; Cortizo, Ana María

    2017-04-01

    Deleterious effects of metabolic syndrome (MS) on bone are still controversial. In this study we evaluated the effects of a fructose-induced MS, and/or an oral treatment with metformin on the osteogenic potential of bone marrow mesenchymal stromal cells (MSC), as well as on bone formation and architecture. 32 male 8week-old Wistar rats were assigned to four groups: control (C), control plus oral metformin (CM), rats receiving 10% fructose in drinking water (FRD), and FRD plus metformin (FRDM). Samples were collected to measure blood parameters, and to perform pQCT analysis and static and dynamic histomorphometry. MSC were isolated to determine their osteogenic potential. Metformin improved blood parameters in FRDM rats. pQCT and static and dynamic histomorphometry showed no significant differences in trabecular and cortical bone parameters among groups. FRD reduced TRAP expression and osteocyte density in trabecular bone and metformin only normalized osteocyte density. FRD decreased the osteogenic potential of MSC and metformin administration could revert some of these parameters. FRD-induced MS shows reduction in MSC osteogenic potential, in osteocyte density and in TRAP activity. Oral metformin treatment was able to prevent trabecular osteocyte loss and the reduction in extracellular mineralization induced by FRD-induced MS. Copyright © 2017 Elsevier B.V. All rights reserved.

  14. Effect of metformin treatment during pregnancy on women with PCOS: a systematic review and meta-analysis.

    Science.gov (United States)

    Tan, Xingrong; Li, Shengbing; Chang, Ying; Fang, Chao; Liu, Hua; Zhang, Xingping; Wang, Yi

    2016-09-11

    Some previous studies have found that continued metformin use is beneficial in the management of polycystic ovary syndrome (PCOS) in pregnant women. A systemic review and meta-analysis were needed to more fully assess the effects of metformin on pregnant PCOS patients. The literature was fully searched using MEDLINE, EMBASE, SCOPUS, and COCHRANE for continued metformin use during pregnancy in women with PCOS. A systematic review and meta-analysis were performed to evaluate the comprehensive effects of continued metformin treatment on pregnancy-related outcomes in these women. Eleven eligible studies out of 127 relevant publications were included in meta-analysis. The rates of early pregnancy loss and preterm delivery were found to be significantly decreased in metformin-treated PCOS women. A non-significant difference was found in fetal abnormality and fetal birth weight between the metformin-treated and the non-treated groups. The incidence of gestational diabetes mellitus (GDM) and hypertension/preeclampsia were not significantly different in the two groups, probably because of inconsistent results in the subgroup analysis. Our results showed that continued use during of metformin, during pregnancy in women with PCOS, had no effect on incidence of fetal abnormalities or fetal birth weight. The effects of metformin on GDM and hypertension/preeclampsia should be determined through high-quality randomized controlled trials.

  15. Use of metformin and vildagliptin for treatment of type 2 diabetes in the elderly.

    Science.gov (United States)

    Sicras-Mainar, Antoni; Navarro-Artieda, Ruth

    2014-01-01

    The aim of this study was to describe the clinical (treatment adherence, metabolic control, hypoglycemia, and macrovascular complications) and economic (resource use and costs) consequences of using a combination of metformin + vildagliptin to treat type 2 diabetes in elderly patients seen in daily clinical practice. We conducted a multicenter, retrospective, observational study that included patients aged ≥65 years treated with metformin who started a second oral antidiabetic therapy during the years 2008-2009. There were two groups of patients: a study group receiving metformin + vildagliptin and a reference group receiving metformin + other oral antidiabetics (sulfonylureas or glitazones). The main measures were comorbidity, compliance/persistence, metabolic control (glycosylated hemoglobin vildagliptin group and 717 (72.6%) in the reference group. Vildagliptin-treated patients had significantly (Pvildagliptin showed better adherence and metabolic control and lower rates of hypoglycemia, resulting in lower health care costs for the national health system.

  16. Extreme lactic acidosis type B associated with metformin treatment

    Science.gov (United States)

    Vernersson, Einar; Frid, Anders; Sterner, Gunnar

    2011-01-01

    The elimination of metformin is exclusively through the kidneys and elevated plasma concentrations can cause lactic acidosis. We report a case of severe lactic acidosis (pH 6.60) occuring with ostensibly normal therapeutic doses of metformin in the setting of acute renal failure. Continuous veno-venous haemodiafiltration decreased plasma metformin concentrations from 266 lmol/L at presentation to 68 lmol/L, 21 h later. The patient improved rapidly. PMID:25984205

  17. Metformin improves glucose effectiveness, not insulin sensitivity: predicting treatment response in women with polycystic ovary syndrome in an open-label, interventional study.

    Science.gov (United States)

    Pau, Cindy T; Keefe, Candace; Duran, Jessica; Welt, Corrine K

    2014-05-01

    Although metformin is widely used to improve insulin resistance in women with polycystic ovary syndrome (PCOS), its mechanism of action is complex, with inconsistent effects on insulin sensitivity and variability in treatment response. The aim of the study was to delineate the effect of metformin on glucose and insulin parameters, determine additional treatment outcomes, and predict patients with PCOS who will respond to treatment. We conducted an open-label, interventional study at an academic medical center. Women with PCOS (n = 36) diagnosed by the National Institutes of Health criteria participated in the study. Subjects underwent fasting blood sampling, an IV glucose tolerance test, dual-energy x-ray absorptiometry scan, transvaginal ultrasound, and measurement of human chorionic gonadotropin-stimulated androgen levels before and after 12 weeks of treatment with metformin extended release 1500 mg/d. Interval visits were performed to monitor anthropometric measurements and menstrual cycle parameters. Changes in glucose and insulin parameters, androgen levels, anthropometric measurements, and ovulatory menstrual cycles were evaluated. Insulin sensitivity did not change despite weight loss. Glucose effectiveness (P = .002) and the acute insulin response to glucose (P = .002) increased, and basal glucose levels (P = .001) decreased after metformin treatment. T levels also decreased. Women with improved ovulatory function (61%) had lower baseline T levels and lower baseline and stimulated T and androstenedione levels after metformin treatment (all P effectiveness and insulin sensitivity, metformin does not improve insulin sensitivity in women with PCOS but does improve glucose effectiveness. The improvement in glucose effectiveness may be partially mediated by decreased glucose levels. T levels also decreased with metformin treatment. Ovulation during metformin treatment was associated with lower baseline T levels and greater T and androstenedione decreases during

  18. Short-term preoperative octreotide treatment for TSH-secreting pituitary adenoma.

    Science.gov (United States)

    Fukuhara, Noriaki; Horiguchi, Kentaro; Nishioka, Hiroshi; Suzuki, Hisanori; Takeshita, Akira; Takeuchi, Yasuhiro; Inoshita, Naoko; Yamada, Shozo

    2015-01-01

    Preoperative control of hyperthyroidism in patients with TSH-secreting pituitary adenomas (TSHoma) may avoid perioperative thyroid storm. Perioperative administration of octreotide may control hyperthyroidism, as well as shrink tumor size. The effects of preoperative octreotide treatment were assessed in a large number of patients with TSHomas. Of 81 patients who underwent surgery for TSHoma at Toranomon Hospital between January 2001 and May 2013, 44 received preoperative short-term octreotide. After excluding one patient because of side effects, 19 received octreotide as a subcutaneous injection, and 24 as a long-acting release (LAR) injection. Median duration between initiation of octreotide treatment and surgery was 33.5 days. Octreotide normalized free T4 in 36 of 43 patients (84%) and shrank tumors in 23 of 38 (61%). Length of octreotide treatment did not differ significantly in patients with and without hormonal normalization (p=0.09) and with and without tumor shrinkage (p=0.84). Serum TSH and free T4 concentrations, duration of treatment, incidence of growth hormone (GH) co-secretion, results of octreotide loading tests, form of administration (subcutaneous injection or LAR), tumor volume, and tumor consistency did not differ significantly in patients with and without hormonal normalization and with and without tumor shrinkage. Short-term preoperative octreotide administration was highly effective for TSHoma shrinkage and normalization of excess hormone concentrations, with tolerable side effects.

  19. Short-term azithromycin treatment promotes cornea allograft survival in the rat.

    Science.gov (United States)

    Wacker, Katrin; Denker, Sophy; Hildebrand, Antonia; Eberwein, Philipp; Reinhard, Thomas; Schwartzkopff, Johannes

    2013-01-01

    Any inflammatory response following corneal transplantation may induce rejection and irreversible graft failure. The purpose of this study is to analyze the anti-inflammatory effect of azithromycin (AZM) following experimental keratoplasty in rats. Corneal transplants were performed between Fisher-donor and Lewis-recipient rats. Recipients were postoperatively treated three times daily with AZM, miglyol, ofloxacin or dexamethasone eye drops. As an additional control, AZM was applied following syngeneic keratoplasty. Furthermore, short-term treatments with AZM for seven days perioperatively or with AZM only three days prior to the transplantation were compared to appropriate controls. All transplants were monitored clinically for opacity, edema, and vascularization. Infiltrating CD45(+), CD4(+), CD8(+), CD25(+), CD161(+) and CD163(+) cells were quantified via immunohistochemistry. AZM significantly promoted corneal graft survival compared with miglyol or ofloxacin treatment. This effect was comparable to topical dexamethasone. No adverse AZM effect was observed. Histology confirmed a significant reduction of infiltrating leukocytes. The short-term application of AZM for three days prior to transplantation or for seven days perioperatively reduced corneal graft rejection significantly compared with the controls. Along with antibiotic properties, topical AZM has a strong anti-inflammatory effect. Following keratoplasty, this effect is comparable to topical dexamethasone without the risk of steroid-induced adverse effects. Short-term treatment with AZM three days prior to the transplantation was sufficient to promote graft survival in the rat keratoplasty model. We therefore suggest further assessing the anti-inflammatory function of topical AZM following keratoplasty in humans.

  20. Short-term azithromycin treatment promotes cornea allograft survival in the rat.

    Directory of Open Access Journals (Sweden)

    Katrin Wacker

    Full Text Available Any inflammatory response following corneal transplantation may induce rejection and irreversible graft failure. The purpose of this study is to analyze the anti-inflammatory effect of azithromycin (AZM following experimental keratoplasty in rats.Corneal transplants were performed between Fisher-donor and Lewis-recipient rats. Recipients were postoperatively treated three times daily with AZM, miglyol, ofloxacin or dexamethasone eye drops. As an additional control, AZM was applied following syngeneic keratoplasty. Furthermore, short-term treatments with AZM for seven days perioperatively or with AZM only three days prior to the transplantation were compared to appropriate controls. All transplants were monitored clinically for opacity, edema, and vascularization. Infiltrating CD45(+, CD4(+, CD8(+, CD25(+, CD161(+ and CD163(+ cells were quantified via immunohistochemistry.AZM significantly promoted corneal graft survival compared with miglyol or ofloxacin treatment. This effect was comparable to topical dexamethasone. No adverse AZM effect was observed. Histology confirmed a significant reduction of infiltrating leukocytes. The short-term application of AZM for three days prior to transplantation or for seven days perioperatively reduced corneal graft rejection significantly compared with the controls.Along with antibiotic properties, topical AZM has a strong anti-inflammatory effect. Following keratoplasty, this effect is comparable to topical dexamethasone without the risk of steroid-induced adverse effects. Short-term treatment with AZM three days prior to the transplantation was sufficient to promote graft survival in the rat keratoplasty model. We therefore suggest further assessing the anti-inflammatory function of topical AZM following keratoplasty in humans.

  1. Study of Blood Leptin Levels before and After Treatment with Metformin in Diabetes Type Ii Patients

    Directory of Open Access Journals (Sweden)

    R Didehdar

    2005-04-01

    Full Text Available Introduction: Leptin is a fat tissue hormone that has 176 amino acids with a molecular weight of 16 KD . Leptin has effects on the hypothalamus and peripheral tissues resulting in decreased food absorption and increased energy consumption that finally reduces the body weight and BMI. The aim of this research was to investigate the blood levels of leptin before and after treatment with Metformin in type II diabetic patients. Methods: 25 type II diabetic patients without any previous drug treatment history were investigated. This study was a clinical trail before and after treatment with Metformin. Results: There was no particular difference in BMI, average body weight, fat mass and free fat mass before and after treatment. Similarly, the difference in concentration levels of blood glucose, cholesterol, tri-glycerides and LDL-cholesterol before and after treatment was not statistically significant. Also, there was no difference in the average concentration of leptin and insulin before and after treatment Conclusion: This result showed that although metformin decreased glucose and lipid levels during the treatment period, (1 month it did not have an effect on leptin, Insulin and other related factors during treatment.;

  2. Renoprotective effects of metformin.

    Science.gov (United States)

    Nasri, Running Hamid

    2013-05-16

    Metformin as a biguanid drug entered to the market 50 years ago and now is generally recommended as the first-line treatment in type 2 diabetes, especially in overweight patients, however in recent years new indications for its use have emerged . It improves peripheral and liver sensitivity to insulin, reduces basal hepatic glucose production, increases insulin-stimulated uptake and utilization of glucose by peripheral tissues, decreases hunger and causes weight reduction.Recently, much attention has been made toward the possible kidney protective efficacy of metformin. Recent studies have proven that metformin, possesses antioxidant properties, too.

  3. Long-term efficacy and safety of sodium-glucose cotransporter-2 inhibitors as add-on to metformin treatment in the management of type 2 diabetes mellitus

    Science.gov (United States)

    Li, Jian; Gong, Yanping; Li, Chunlin; Lu, Yanhui; Liu, Yu; Shao, Yinghong

    2017-01-01

    Abstract Background: Drug intensification is often required for patients with type 2 diabetes mellitus on stable metformin therapy. Among the potential candidates for a combination therapy, sodium-glucose transporter-2 (SGLT2) inhibitors have shown promising outcomes. This meta-analysis was performed to compare the efficacy and safety of SGLT2 inhibitors with non-SGLT2 combinations as add-on treatment to metformin. Methods: Literature search was carried out in multiple electronic databases for the acquisition of relevant randomized controlled trials (RCTs) by following a priori eligibility criteria. After the assessment of quality of the included RCTs, meta-analyses of mean differences or odds ratios (OR) were performed to achieve overall effect sizes of the changes from baseline in selected efficacy and safety endpoints reported in the individual studies. Between-studies heterogeneity was estimated with between-studies statistical heterogeneity (I2) index. Results: Six RCTs fulfilled the eligibility criteria. SGLT2 inhibitors as add-on to metformin treatment reduced % HbA1c significantly more than non-SGLT2 combinations after 52 weeks (P = .002) as well as after 104 weeks (P SGLT2 inhibitors also reduced fasting plasma glucose levels, body weight, systolic, and diastolic blood pressures after 52 weeks and 104 weeks significantly (P SGLT2 combinations. Incidence of hypoglycemia was significantly lower (P = .02) but incidence of suspected or confirmed genital tract infections was significantly higher (P SGLT2 inhibitors treated in comparison with non-SGLT2 combinations. Conclusion: As add-on to metformin treatment, SGLT2 inhibitors are found significantly more efficacious than non-SGLT2 inhibitor combinations in the management of type 2 diabetes mellitus, although, SGLT2 inhibitor therapy is associated with significantly higher incidence of suspected or confirmed genital tract infections. PMID:28682870

  4. Metformin Decouples Phospholipid Metabolism in Breast Cancer Cells.

    Directory of Open Access Journals (Sweden)

    Tim A D Smith

    Full Text Available The antidiabetic drug metformin, currently undergoing trials for cancer treatment, modulates lipid and glucose metabolism both crucial in phospholipid synthesis. Here the effect of treatment of breast tumour cells with metformin on phosphatidylcholine (PtdCho metabolism which plays a key role in membrane synthesis and intracellular signalling has been examined.MDA-MB-468, BT474 and SKBr3 breast cancer cell lines were treated with metformin and [3H-methyl]choline and [14C(U]glucose incorporation and lipid accumulation determined in the presence and absence of lipase inhibitors. Activities of choline kinase (CK, CTP:phosphocholine cytidylyl transferase (CCT and PtdCho-phospholipase C (PLC were also measured. [3H] Radiolabelled metabolites were determined using thin layer chromatography.Metformin-treated cells exhibited decreased formation of [3H]phosphocholine but increased accumulation of [3H]choline by PtdCho. CK and PLC activities were decreased and CCT activity increased by metformin-treatment. [14C] incorporation into fatty acids was decreased and into glycerol was increased in breast cancer cells treated with metformin incubated with [14C(U]glucose.This is the first study to show that treatment of breast cancer cells with metformin induces profound changes in phospholipid metabolism.

  5. Ethinyl estradiol-drospirenone vs ethinyl estradiol-drospirenone plus metformin in the treatment of lean women with polycystic ovary syndrome.

    Science.gov (United States)

    Cinar, Nese; Harmanci, Ayla; Bayraktar, Miyase; Yildiz, Bulent O

    2013-03-01

    Oral contraceptive use might be associated with cardiometabolic risk in PCOS. We aimed to compare the effects of ethinyl estradiol-drospirenone (EE/DRSP) alone vs EE/DRSP plus metformin on clinical and cardiometabolic parameters in PCOS. Prospective observational study. Forty-five lean patients with PCOS who received EE/DRSP (30 μg/3 mg) (n = 25) or EE/DRSP plus metformin (1700 mg/day) (n = 20) and 45 BMI-matched healthy controls. BMI, waist-to-hip ratio (WHR), hirsutism scores, androgens, lipids, glucose and insulin levels during an OGTT were measured before and after 6 months of treatment in patients and compared to controls. At baseline, patients with PCOS showed similar glucose, insulin and lipids but increased 2 h glucose values compared to controls. Hirsutism scores and free androgen index decreased in both treatment groups. BMI and WHR did not show any change in the EE/DRSP group, while metformin addition resulted in a decrease in BMI. Lipid levels increased in both groups. Glucose and insulin parameters did not change in any group, but metformin addition compared to EE/DRSP alone significantly decreased waist circumference, fasting insulin and HOMA-IR. After-treatment values for both EE/DRSP alone and in combination with metformin compared to the control group showed increased 2 h glucose and increased lipids in patients with PCOS. EE/DRSP alone or in combination with metformin improves clinical and biochemical hyperandrogenism in lean PCOS. Both treatments similarly alter lipid profile. EE/DRSP alone does not affect insulin sensitivity, whereas combining EE/DRSP with metformin might improve it. © 2012 Blackwell Publishing Ltd.

  6. Metformin Use and Endometrial Cancer Survival

    Science.gov (United States)

    Nevadunsky, Nicole S.; Van Arsdale, Anne; Strickler, Howard D.; Moadel, Alyson; Kaur, Gurpreet; Frimer, Marina; Conroy, Erin; Goldberg, Gary L.; Einstein, Mark H.

    2013-01-01

    Objective Impaired glucose tolerance and diabetes are risk factors for the development of uterine cancer. Although greater progression free survival among diabetic patients with ovarian and breast cancer using metformin have been reported, no studies have assessed the association of metformin use with survival in women with endometrial cancer (EC). Methods We conducted a single-institution retrospective cohort study of all patients treated for uterine cancer from January 1999 through December 2009. Demographic, medical, social, and survival data were abstracted from medical records and the national death registry. Overall survival (OS) was estimated using Kaplan-Meier methods. Cox models were utilized for multivariate analysis. All statistical tests were two-sided. Results Of 985 patients, 114 (12%) had diabetes and were treated with metformin, 136 (14%) were diabetic but did not use metformin, and 735 (74%) had not been diagnosed with diabetes. Greater OS was observed in diabetics with non-endometrioid EC who used metformin than in diabetic cases not using metformin and non-endometrioid EC cases without diabetes (log rank test (p=0.02)). This association remained significant (hazard ratio = 0.54, 95% CI: 0.30–0.97, p<0.04) after adjusting for age, clinical stage, grade, chemotherapy treatment, radiation treatment and presence of hyperlipidemia in multivariate analysis. No association between metformin use and OS in diabetics with endometrioid histology was observed. Conclusion Diabetic EC patients with non-endometrioid tumors who used metformin had lower risk of death than women with EC who did not use metformin. These data suggest that metformin might be useful as adjuvant therapy for non-endometrioid EC. PMID:24189334

  7. Metformin for Clozapine Associated Obesity: A Systematic Review and Meta-Analysis.

    Directory of Open Access Journals (Sweden)

    Dan J Siskind

    Full Text Available Although clozapine is the gold-standard for treatment refractory schizophrenia, it has the worst metabolic profile of all antipsychotics. This is partly mediated by clozapine's impact on glucagon-like peptide (GLP-1. There is an absence of robust evidence for effective treatments for clozapine associated weight gain and metabolic syndrome. Metformin, with its role in increasing GLP-1 may aid weight loss among people on clozapine.We conducted a systematic-review and meta-analysis of metformin versus placebo for change in weight and metabolic syndrome for people on clozapine without diabetes mellitus. We searched the Cochrane Schizophrenia Group's trial register, Pubmed and Embase, as well as the following Chinese databases: the Chinese Biomedical Literature Service System and China Knowledge Resource Integrated Database. This was supplemented by hand searches of key papers.Eight studies, of which three were from Chinese databases, with 478 participants were included. We found that metformin was superior to placebo in terms of weight loss (-3.12kg, 95%CI -4.88kg to -1.37kg and BMI (-1.18kg/m2, 95%CI -1.76kg/m2 to -0.61kg/m2. Metformin significantly improved three of the five components of metabolic syndrome; waist circumference, fasting glucose and triglycerides. Sensitivity analysis on study quality and duration did not greatly impact results.Metformin led to clinically meaningful weight loss among people on clozapine, and may reduce the rates of metabolic syndrome. Inclusion of metformin into the treatment protocols of people on clozapine, as tolerated, should be considered.PROSPERO registration number: CRD42015029723.

  8. Metformin for Clozapine Associated Obesity: A Systematic Review and Meta-Analysis.

    Science.gov (United States)

    Siskind, Dan J; Leung, Janni; Russell, Anthony W; Wysoczanski, Daniel; Kisely, Steve

    2016-01-01

    Although clozapine is the gold-standard for treatment refractory schizophrenia, it has the worst metabolic profile of all antipsychotics. This is partly mediated by clozapine's impact on glucagon-like peptide (GLP-1). There is an absence of robust evidence for effective treatments for clozapine associated weight gain and metabolic syndrome. Metformin, with its role in increasing GLP-1 may aid weight loss among people on clozapine. We conducted a systematic-review and meta-analysis of metformin versus placebo for change in weight and metabolic syndrome for people on clozapine without diabetes mellitus. We searched the Cochrane Schizophrenia Group's trial register, Pubmed and Embase, as well as the following Chinese databases: the Chinese Biomedical Literature Service System and China Knowledge Resource Integrated Database. This was supplemented by hand searches of key papers. Eight studies, of which three were from Chinese databases, with 478 participants were included. We found that metformin was superior to placebo in terms of weight loss (-3.12kg, 95%CI -4.88kg to -1.37kg) and BMI (-1.18kg/m2, 95%CI -1.76kg/m2 to -0.61kg/m2). Metformin significantly improved three of the five components of metabolic syndrome; waist circumference, fasting glucose and triglycerides. Sensitivity analysis on study quality and duration did not greatly impact results. Metformin led to clinically meaningful weight loss among people on clozapine, and may reduce the rates of metabolic syndrome. Inclusion of metformin into the treatment protocols of people on clozapine, as tolerated, should be considered. PROSPERO registration number: CRD42015029723.

  9. The efficacy of short-term clobetasol lotion in the treatment of scalp psoriasis.

    Science.gov (United States)

    Rajabi-Estarabadi, Ali; Hasanzadeh, Hournaz; Taheri, Arash; Feldman, Steven R; Firooz, Alireza

    2018-03-01

    Scalp psoriasis can have a considerable impact on patients' quality of life and is considered difficult to treat. Treatment failure may, however, be due to poor adherence, as application of topical treatments to hair bearing areas is difficult and time consuming and also poor communication between physician and patient. To assess the efficacy of short-term treatment of scalp psoriasis with topical clobetasol lotion. Twelve patients with mild to severe scalp psoriasis were recruited for this study. Patients applied clobetasol 0.05% lotion twice daily for seven days. They were followed up with phone calls three days after starting the treatment. Skin hydration, transepidermal water loss (TEWL) and skin erythema were assessed noninvasively at baseline and end of study. One week after treatment, median PSI score decreased significantly (p = .002). There was also a significant decrease in median TEWL (p = .012) and increase in skin hydration one week after treatment (p = .010). Eighty three percent of patients were satisfied with treatment result and felt convenient with applying clobetasol lotion. Lack of a long-term follow-up. Psoriasis is a long-term disease, and improving adherence in the short time could improve patient's adherence to treatment in long time.

  10. A review of the evidence for the use of metformin in the treatment of metabolic syndrome caused by antipsychotics.

    Science.gov (United States)

    Jesus, Cátia; Jesus, Inês; Agius, Mark

    2015-09-01

    Psychiatric patients requiring therapy with antipsychotics have a greater incidence of becoming overweight or obese compared with the general population. Many of these patients are often treated with second-generation (atypical) antipsychotics (SGAs), which are associated with weight gain, dyslipidaemia, and other metabolic derangements. The most important and first line of treatment for the metabolic syndrome is lifestyle changes including diet and exercise. However, other approaches like the use of medication (e.g. Metformin) have been also used, mainly when the lifestyle changes are difficult to achieve. Therefore, the treatment of antipsychotic-induced weight gain with metformin may be an option after the lifestyle and dietary changes fail. The use of metformin is still experimental and off license regarding the treatment of metabolic syndrome in Psychiatric patients, however we wished to assess the evidence for its use. Our study is a literature based research. For our research we reviewed 12 Pubmed published articles from 2006 to 2013. Metformin have been reported to counteract effectively antipsychotic-induced body weight gain and has been demonstrated to improve glycaemic control and promote a moderate weight loss in both diabetic and non-diabetic subjects. Metformin use appears to be a benefit when started early in the course of treatment and mostly in young adults newly exposed to antipsychotic drugs.

  11. Treatment Compliance with Fixed-Dose Combination of Vildagliptin/Metformin in Patients with Type 2 Diabetes Mellitus Inadequately Controlled with Metformin Monotherapy: A 24-Week Observational Study

    Directory of Open Access Journals (Sweden)

    Grigorios Rombopoulos

    2015-01-01

    Full Text Available Objective. To evaluate the differences in treatment compliance with vildagliptin/metformin fixed-dose versus free-dose combination therapy in patients with type 2 diabetes mellitus (T2DM in Greece. Design. Adult patients with T2DM, inadequately controlled with metformin monotherapy, (850 mg bid, participated in this 24-week, multicenter, observational study. Patients were enrolled in two cohorts: vildagliptin/metformin fixed-dose combination (group A and vildagliptin metformin free-dose combination (group B. Results. 659 patients were enrolled, 360 were male, with mean BMI 30.1, mean T2DM duration 59.6 months, and mean HbA1c at baseline 8%; 366 patients were assigned to group A and 293 to group B; data for 3 patients was missing. In group A, 98.9% of patients were compliant with their treatment compared to 84.6% of group B. The odds ratio for compliance in group A versus B was (OR 18.9 (95% CI: 6.2, 57.7; P<0.001. In group A mean HbA1c decreased from 8.1% at baseline to 6.9% (P<0.001 at the study end and from 7.9% to 6.8% (P<0.001 in group B. Conclusions. Patients in group A were more compliant than patients in group B. These results are in accordance with international literature suggesting that fixed-dose combination therapies lead to increased compliance to treatment.

  12. Hyperglycemia-induced metabolic compensation inhibits metformin sensitivity in ovarian cancer

    Science.gov (United States)

    Litchfield, Lacey M.; Mukherjee, Abir; Eckert, Mark A.; Johnson, Alyssa; Mills, Kathryn A.; Pan, Shawn; Shridhar, Viji; Lengyel, Ernst; Romero, Iris L.

    2015-01-01

    Increasing interest in repurposing the diabetic medication metformin for cancer treatment has raised important questions about the translation of promising preclinical findings to therapeutic efficacy, especially in non-diabetic patients. A significant limitation of the findings to date is the use of supraphysiologic metformin doses and hyperglycemic conditions in vitro. Our goals were to determine the impact of hyperglycemia on metformin response and to address the applicability of metformin as a cancer therapeutic in non-diabetic patients. In normoglycemic conditions, lower concentrations of metformin were required to inhibit cell viability, while metformin treatment in hyperglycemic conditions resulted in increased glucose uptake and glycolytic flux, contributing to cell survival. Mechanistically, maintenance of c-Myc expression under conditions of hyperglycemia or via gene amplification facilitated metabolic escape from the effects of metformin. In vivo, treatment of an ovarian cancer mouse model with metformin resulted in greater tumor weight reduction in normoglycemic vs. hyperglycemic mice, with increased c-Myc expression observed in metformin-treated hyperglycemic mice. These findings indicate that hyperglycemia inhibits the anti-cancer effects of metformin in vitro and in vivo. Furthermore, our results suggest that metformin may elicit stronger responses in normoglycemic vs. hyperglycemic patients, highlighting the need for prospective clinical testing in patients without diabetes. PMID:26172303

  13. A follow-up of a randomised study of metformin and insulin in gestational diabetes mellitus: growth and development of the children at the age of 18 months.

    Science.gov (United States)

    Ijäs, H; Vääräsmäki, M; Saarela, T; Keravuo, R; Raudaskoski, T

    2015-06-01

    To compare the growth and development of children born to mothers with gestational diabetes mellitus (GDM) requiring pharmacological treatment, and randomised to treatment with metformin or insulin. Follow-up of a randomised controlled trial (RCT) comparing metformin and insulin treatment of GDM. Data were gathered during routine visits to child welfare clinics at the ages of 6, 12, and 18 months, including weight and height measurements, and assessment of motor, social, and linguistic development. The children of mothers with GDM randomised to metformin (n = 47) or insulin (n = 50) treatment during pregnancy. Data were collected from the structured questionnaire filled in at the child welfare clinics. The growth and development of the children until the age of 18 months. Children exposed to metformin were significantly heavier (10.47 versus 9.85 kg, 95% CI 0.04-1.20) at the age of 12 months and taller and heavier (83.9 vs 82.2 cm, 95% CI 0.23-3.03, 12.05 vs 11.32 kg, 95% CI 0.04-1.43) at the age of 18 months. The mean ponderal index (PI) did not differ significantly. The motor, social, or linguistic development evaluated at the age of 18 months did not differ between the groups. Children prenatally exposed to metformin were heavier at the 12 months measurements and taller and heavier at the 18 months measurements than those exposed to insulin, but their body composition defined by PI did not differ. Over the short term, metformin does not seem to be harmful with regards to early motor, linguistic, or social development. © 2014 Royal College of Obstetricians and Gynaecologists.

  14. Metformin in dermatology: an overview.

    Science.gov (United States)

    Badr, D; Kurban, M; Abbas, O

    2013-11-01

    For several decades, metformin has been used as an oral hypoglycaemic agent, where it is the first line of treatment in overweight and obese type 2 diabetic patients. This is because it decreases the hepatic glucose output and acts as an insulin sensitizer by increasing the glucose utilization by muscles and adipocytes. As a result of the improvement in glycaemic control, serum insulin concentrations decline slightly, thus improving hyperinsulinaemia and its signs. In addition, it has been shown that metformin has platelet anti-aggregating and antioxidant effects. These pharmacological properties have allowed metformin to be effective in non-diabetic situations including cutaneous conditions. This is an evidence-based review on the use of metformin in the treatment of skin disorders such as hirsutism, acne, hidradenitis suppurativa, acanthosis nigricans, psoriasis, skin cancer, among others. In addition, cutaneous side-effects such as leukocytoclastic vasculitis, bullous pemphigoid, psoriasiform drug eruption, lichen planus and acute alopecia have been associated with metformin use and are discussed in the article. © 2013 The Authors Journal of the European Academy of Dermatology and Venereology © 2013 European Academy of Dermatology and Venereology.

  15. Randomized clinical trial evaluating metformin versus oral contraceptive pills in the treatment of adolescents with polycystic ovarian syndrome.

    Science.gov (United States)

    Al-Zubeidi, Hiba; Klein, Karen O

    2015-07-01

    Polycystic ovarian syndrome (PCOS) is characterized by irregular menses, elevated androgens, and insulin resistance. Little information is published about the treatment of adolescent PCOS. The aim of this study was to evaluate metformin versus oral contraceptive pills (OCP) in treating adolescent PCOS. Twenty-two girls were randomized to either treatment for 6 months. The outcomes variables included body mass index (BMI) and free testosterone (FT). BMI decreased in all patients (metformin p=0.004, OCP p=0.045). FT decreased significantly only with OCP. Insulin resistance measures decreased in all patients but did not reach significance. The only significant difference in any of the variables between the two groups was number of menses. BMI and FT remained less than baseline for 3 months off treatment. Metformin and OCP have a positive effect on BMI, which persists after treatment is discontinued. FT decreased with both treatments, but only reached significance with OCP.

  16. Two weeks of metformin treatment enhances mitochondrial respiration in skeletal muscle of AMPK kinase dead but not wild type mice

    DEFF Research Database (Denmark)

    Kristensen, Jonas Møller; Larsen, Steen; Helge, Jørn Wulff

    2013-01-01

    signaling. We investigated this by two weeks of oral metformin treatment of muscle specific kinase dead a(2) (KD) AMPK mice and wild type (WT) littermates. We measured mitochondrial respiration and protein activity and expressions of key enzymes involved in mitochondrial carbohydrate and fat metabolism...... and oxidative phosphorylation. Mitochondrial respiration, HAD and CS activity, PDH and complex I-V and cytochrome c protein expression were all reduced in AMPK KD compared to WT tibialis anterior muscles. Surprisingly, metformin treatment only enhanced respiration in AMPK KD mice and thereby rescued...... the respiration defect compared to the WT mice. Metformin did not influence protein activities or expressions in either WT or AMPK KD mice.We conclude that two weeks of in vivo metformin treatment enhances mitochondrial respiration in the mitochondrial deficient AMPK KD but not WT mice. The improvement seems...

  17. Metformin inhibits glutaminase activity and protects against hepatic encephalopathy.

    Directory of Open Access Journals (Sweden)

    Javier Ampuero

    Full Text Available AIM: To investigate the influence of metformin use on liver dysfunction and hepatic encephalopathy in a retrospective cohort of diabetic cirrhotic patients. To analyze the impact of metformin on glutaminase activity and ammonia production in vitro. METHODS: Eighty-two cirrhotic patients with type 2 diabetes were included. Forty-one patients were classified as insulin sensitizers experienced (metformin and 41 as controls (cirrhotic patients with type 2 diabetes mellitus without metformin treatment. Baseline analysis included: insulin, glucose, glucagon, leptin, adiponectin, TNFr2, AST, ALT. HOMA-IR was calculated. Baseline HE risk was calculated according to minimal hepatic encephalopathy, oral glutamine challenge and mutations in glutaminase gene. We performed an experimental study in vitro including an enzymatic activity assay where glutaminase inhibition was measured according to different metformin concentrations. In Caco2 cells, glutaminase activity inhibition was evaluated by ammonia production at 24, 48 and 72 hours after metformina treatment. RESULTS: Hepatic encephalopathy was diagnosed during follow-up in 23.2% (19/82: 4.9% (2/41 in patients receiving metformin and 41.5% (17/41 in patients without metformin treatment (logRank 9.81; p=0.002. In multivariate analysis, metformin use [H.R.11.4 (95% CI: 1.2-108.8; p=0.034], age at diagnosis [H.R.1.12 (95% CI: 1.04-1.2; p=0.002], female sex [H.R.10.4 (95% CI: 1.5-71.6; p=0.017] and HE risk [H.R.21.3 (95% CI: 2.8-163.4; p=0.003] were found independently associated with hepatic encephalopathy. In the enzymatic assay, glutaminase activity inhibition reached 68% with metformin 100 mM. In Caco2 cells, metformin (20 mM decreased glutaminase activity up to 24% at 72 hours post-treatment (p<0.05. CONCLUSIONS: Metformin was found independently related to overt hepatic encephalopathy in patients with type 2 diabetes mellitus and high risk of hepatic encephalopathy. Metformin inhibits glutaminase

  18. Metformin treatment modulates the tumour-induced wasting effects in muscle protein metabolism minimising the cachexia in tumour-bearing rats

    International Nuclear Information System (INIS)

    Oliveira, André G.; Gomes-Marcondes, Maria Cristina C.

    2016-01-01

    Cancer-cachexia state frequently induces both fat and protein wasting, leading to death. In this way, the knowledge of the mechanism of drugs and their side effects can be a new feature to treat and to have success, contributing to a better life quality for these patients. Metformin is an oral drug used in type 2 diabetes mellitus, showing inhibitory effect on proliferation in some neoplastic cells. For this reason, we evaluated its modulatory effect on Walker-256 tumour evolution and also on protein metabolism in gastrocnemius muscle and body composition. Wistar rats received or not tumour implant and metformin treatment and were distributed into four groups, as followed: control (C), Walker 256 tumour-bearing (W), metformin-treated (M) and tumour-bearing treated with metformin (WM). Animals were weighed three times a week, and after cachexia state has been detected, the rats were euthanised and muscle and tumour excised and analysed by biochemical and molecular assays. Tumour growth promoted some deleterious effects on chemical body composition, increasing water and decreasing fat percentage, and reducing lean body mass. In muscle tissue, tumour led to a decreased protein synthesis and an increased proteolysis, showing the higher activity of the ubiquitin-proteasome pathway. On the other hand, the metformin treatment likely minimised the tumour-induced wasting state; in this way, this treatment ameliorated chemical body composition, reduced the higher activities of proteolytic enzymes and decreased the protein waste. Metformin treatment not only decreases the tumour growth but also improves the protein metabolism in gastrocnemius muscle in tumour-bearing rats

  19. Combined metformin and insulin treatment reverses metabolically impaired omental adipogenesis and accumulation of 4-hydroxynonenal in obese diabetic patients

    Directory of Open Access Journals (Sweden)

    Morana Jaganjac

    2017-08-01

    Full Text Available Objective: Obesity-associated impaired fat accumulation in the visceral adipose tissue can lead to ectopic fat deposition and increased risk of insulin resistance and type 2 diabetes mellitus (T2DM. This study investigated whether impaired adipogenesis of omental (OM adipose tissues and elevated 4-hydroxynonenal (4-HNE accumulation contribute to this process, and if combined metformin and insulin treatment in T2DM patients could rescue this phenotype. Methods: OM adipose tissues were obtained from forty clinically well characterized obese individuals during weight reduction surgery. Levels of 4-HNE protein adducts, adipocyte size and number of macrophages were determined within these tissues by immunohistochemistry. Adipogenic capacity and gene expression profiles were assessed in preadipocytes derived from these tissues in relation to insulin resistance and in response to 4-HNE, metformin or combined metformin and insulin treatment. Results: Preadipocytes isolated from insulin resistant (IR and T2DM individuals exhibited lower adipogenesis, marked by upregulation of anti-adipogenic genes, compared to preadipocytes derived from insulin sensitive (IS individuals. Impaired adipogenesis was also associated with increased 4-HNE levels, smaller adipocytes and greater macrophage presence in the adipose tissues. Within the T2DM group, preadipocytes from combined metformin and insulin treated subset showed better in vitro adipogenesis compared to metformin alone, which was associated with less presence of macrophages and 4-HNE in the adipose tissues. Treatment of preadipocytes in vitro with 4-HNE reduced their adipogenesis and increased proliferation, even in the presence of metformin, which was partially rescued by the presence of insulin. Conclusion: This study reveals involvement of 4-HNE in the impaired OM adipogenesis-associated with insulin resistance and T2DM and provides a proof of concept that this impairment can be reversed by the synergistic

  20. All-Cause and Cardiovascular Mortality following Treatment with Metformin or Glyburide in Patients with Type 2 Diabetes Mellitus.

    Science.gov (United States)

    Raee, Mohammad Reza; Nargesi, Arash Aghajani; Heidari, Behnam; Mansournia, Mohammad Ali; Larry, Mehrdad; Rabizadeh, Soghra; Zarifkar, Mitra; Esteghamati, Alireza; Nakhjavani, Manouchehr

    2017-03-01

    Both metformin and sulfonylurea (SU) drugs are among the most widely-used anti-hyperglycemic medications in patients with type 2 diabetes mellitus (T2DM). Previous studies have shown that treatment with SUs might be associated with decreased survival compared with metformin. This study aimed to evaluate all-cause and cardiovascular mortality rates between glyburide and metformin in patients diagnosed with T2DM. This was a cohort study on 717 patients with T2DM (271 undergoing monotherapy with glyburide and 446 with metformin). Data were gathered from 2001 to 2014. All-cause and cardiovascular mortality were end-points. During the follow-up, 24 deaths were identified, of which 13 were cardiovascular in nature. The group with glyburide monotherapy had greater all-cause mortality (17 (6.3%) in glyburide vs. 7 (1.6%) in metformin, P = 0.001) and cardiovascular mortality (11 (4.1%) in glyburide vs. 2 (0.4%) in metformin; P = 0.001). Metformin was more protective than glyburide for both all-cause (HR: 0.27 [0.10 - 0.73] P-value = 0.01) and cardiovascular mortality (HR: 0.12 [0.20 - 0.66], P-value = 0.01) after multiple adjustments for cardiovascular risk factors. Among adverse cardiovascular events, non-fatal MI was higher in glyburide compared to metformin monotherapy group (3.2% vs. 0.8%; P-value = 0.03), but not coronary artery bypass grafting (P-value = 0.85), stenting (P-value = 0.69), need for angiography (P-value = 0.24), CCU admission (P-value = 0.34) or cerebrovascular accident (P-value = 0.10). Treatment with glyburide is associated with increased all-cause and cardiovascular mortality in patients with T2DM.

  1. Metformin versus insulin for gestational diabetes mellitus: a meta-analysis.

    Science.gov (United States)

    Zhao, Li-Ping; Sheng, Xiao-Yan; Zhou, Shuang; Yang, Ting; Ma, Ling-Yue; Zhou, Ying; Cui, Yi-Min

    2015-11-01

    The aim of the present meta-analysis was to determine the efficacy and safety of metformin for the treatment of women with gestational diabetes mellitus (GDM). We searched databases, including PubMed, Embase and the Cochrane Central Register of Controlled Trials, for randomized controlled trials (RCTs) comparing metformin and insulin treatments in women with GDM. We carried out statistical analyses using RevMan 2011 and used the Grading of Recommendations, Assessment, Development, and Evaluations profiler to rate the quality of evidence of the primary outcomes. We analysed eight studies involving 1592 subjects. Meta-analysis of the RCTs showed that metformin had statistically significant effects on pregnancy-induced hypertension [PIH; risk ratio (RR) 0.54; 95% confidence interval (CI) 0.31, 0.91]. However, its effects on neonatal hypoglycaemia (RR 0.80; 95% CI 0.62, 1.02), rate of large-for-gestational age infants (RR 0.77; 95% CI 0.55, 1.08), respiratory distress syndrome (RR 1.26; 95% CI 0.67, 2.37), phototherapy (RR 0.94; 95% CI 0.67, 1.31) and perinatal death (RR 1.01; 95% CI 0.11, 9.53) were not significant. Our analyses suggest that there is no clinically relevant difference in efficacy or safety between metformin and insulin; however, metformin may be a good choice for GDM because of the lower risk of PIH. The advantages of metformin in terms of glycaemic control, PIH incidence and gestational age at birth are unclear, and should be verified in further trials. © 2015 The British Pharmacological Society.

  2. The use of metformin is associated with decreased lumbar radiculopathy pain

    Directory of Open Access Journals (Sweden)

    Taylor A

    2013-12-01

    Full Text Available Amber Taylor,1 Anton H Westveld,2,6 Magdalena Szkudlinska,1 Prathima Guruguri,1 Emil Annabi,3 Amol Patwardhan,3 Theodore J Price,4 Hussein N Yassine51Department of Medicine, University of Arizona, Tucson, AZ, USA; 2Statistics Laboratory, Bio5 Institute, Statistics GIDP, University of Arizona, Tucson, AZ, USA; 3Department of Anesthesia, University of Arizona, Tucson, AZ, USA; 4Department of Pharmacology, University of Arizona, Tucson, AZ, USA; 5Department of Medicine, University of Southern California, LA, CA, USA; 6Faculty of ESTeM, University of Canberra, Canberra, ACT, AustraliaAbstract: Lumbar radiculopathy pain represents a major public health problem, with few effective long-term treatments. Preclinical neuropathic and postsurgical pain studies implicate the kinase adenosine monophosphate activated kinase (AMPK as a potential pharmacological target for the treatment of chronic pain conditions. Metformin, which acts via AMPK, is a safe and clinically available drug used in the treatment of diabetes. Despite the strong preclinical rationale, the utility of metformin as a potential pain therapeutic has not yet been studied in humans. Our objective was to assess whether metformin is associated with decreased lumbar radiculopathy pain, in a retrospective chart review. We completed a retrospective chart review of patients who sought care from a university pain specialist for lumbar radiculopathy between 2008 and 2011. Patients on metformin at the time of visit to a university pain specialist were compared with patients who were not on metformin. We compared the pain outcomes in 46 patients on metformin and 94 patients not taking metformin therapy. The major finding was that metformin use was associated with a decrease in the mean of “pain now,” by −1.85 (confidence interval: −3.6 to −0.08 on a 0–10 visual analog scale, using a matched propensity scoring analysis and confirmed using a Bayesian analysis, with a significant mean decrease

  3. Metformin increases plasma ghrelin in Type 2 diabetes.

    Science.gov (United States)

    Doogue, Matthew P; Begg, Evan J; Moore, M Peter; Lunt, Helen; Pemberton, Chris J; Zhang, Mei

    2009-12-01

    * Metformin, unlike the other major antihyperglycaemic drugs, is not associated with weight gain. * Ghrelin is an appetite-stimulating hormone whose concentrations vary in relation to food, obesity and diabetes control. * Reports are conflicting about how metformin affects ghrelin concentrations, and this study was aimed at resolving this issue in patients with Type 2 diabetes. * In this study an increase in ghrelin concentrations was seen in response to metformin treatment in patients with Type 2 diabetes. * This effect was opposite to what might be expected if the effect of metformin on weight control was mediated via suppression of ghrelin. * It is likely that the ghrelin response was secondary to improved glycaemic control. * Meal time changes in appetite and satiety did not correlate with changes in ghrelin, which suggests ghrelin may not be important in meal initiation. Metformin treatment of Type 2 diabetes is not usually associated with weight gain, and may assist with weight reduction. Plasma ghrelin concentrations are inversely associated with obesity and food intake. Metformin might therefore affect ghrelin concentrations, although previous studies have shown variable results in this regard. The primary aim of this study was to determine the effect of metformin on plasma ghrelin, appetite and satiety in patients with Type 2 diabetes. Eighteen patients with Type 2 diabetes were studied before and after 6 weeks of metformin treatment, which was titrated to 1 g b.d. On the study days patients were fed standard meals of 390 kcal at 08.00 and 12.30 h, plasma samples were collected at 15- and 30-min intervals, and appetite and satiety were measured on visual analogue scales. Changes in the area under the concentration-time curves (AUCs) of plasma ghrelin, insulin, glucose, appetite and satiety were assessed and examined for correlations with metformin AUCs. Changes in fasting adiponectin and leptin were also measured. Treatment with metformin increased the

  4. Metformin effectiveness and safety in the management of overweight/obese nondiabetic children and adolescents: metabolic benefits of the continuous exposure to metformin at 12 and 24 months.

    Science.gov (United States)

    Marques, Pedro; Limbert, Catarina; Oliveira, Laura; Santos, Maria Inês; Lopes, Lurdes

    2016-02-19

    Childhood obesity prevalence is rising and new therapeutical approaches are needed. Metformin is likely beneficial in obese and/or insulin-resistant children/adolescents, but its role in this setting is still unclear. We aimed to evaluate the effectiveness, in terms of weight loss and insulin resistance, and safety of metformin in nondiabetic overweight/obese children and adolescents. We retrospectively reviewed clinical records of 78 nondiabetic obese/overweight [body mass index (BMI)≥85th/95th percentile for age and sex] children and adolescents. Anthropometric and metabolic outcomes of 39 patients treated with metformin (mean daily dose: 1.3±0.5 g) were analyzed and compared to lifestyle intervention alone at different follow-up times (12 and 24 months). The mean age of the 78 patients was 13.3 years, 41 were females and mean BMI and BMI-SDS were 32.8 kg/m2 and 3.1, respectively. There was a decrease in mean BMI-SDS within each treatment group in all periods, except at 24 months for lifestyle intervention. However, the change in BMI-SDS was not significantly superior in the metformin group when compared to lifestyle intervention. Metformin had greater effectiveness over lifestyle intervention alone in reducing fasting insulin levels and homeostasis model assessment for insulin-resistance index (HOMA-IR) at both 12 and 24 months. Five patients had gastrointestinal adverse effects (12.8%), four requiring dose reduction, but metformin could be resumed in all. Metformin for nondiabetic obese/overweight children and adolescents resulted in a noteworthy insulin resistance improvement, without significant BMI advantage when compared to lifestyle intervention. Metformin metabolic and anthropometric effects appear to be beneficial up to 24 months, without relevant adverse effects, highlighting its potential long-term benefits.

  5. Short-term Treatment of Daumone Improves Hepatic Inflammation in Aged Mice

    OpenAIRE

    Park, Jong Hee; Ha, Hunjoo

    2015-01-01

    Chronic inflammation has been proposed as one of the main molecular mechanisms of aging and age-related diseases. Although evidence in humans is limited, short-term calorie restriction (CR) has been shown to have anti-inflammatory effects in aged experimental animals. We reported on the long-term treatment of daumone, a synthetic pheromone secreted by Caenorhabditis elegans in an energy deficient environment, extends the life-span and attenuates liver injury in aged mice. The present study ex...

  6. Metformin in gestational diabetes mellitus: predictors of poor response.

    Science.gov (United States)

    Gante, Inês; Melo, Luís; Dores, Jorge; Ruas, Luísa; Almeida, Maria do Céu

    2018-01-01

    Metformin can be regarded as a first-line treatment in gestational diabetes mellitus (GDM) due to its safety and effectiveness. However, a proportion of women do not achieve adequate glycemic control with metformin alone. We aim to identify predictors of this poor response to metformin. Retrospective multicentre cohort study of women with GDM who started metformin as first-line treatment. The assessed cohort was divided into a metformin group and metformin plus insulin group. Biometric and demographic characteristics, glycemic control data, obstetric, neonatal and postpartum outcomes were compared between groups and analysed in order to identify predictors of poor response to metformin. Data were analysed using STATA, version 13.1. Of the 388 women enrolled in the study, 135 (34.8%) required additional insulin therapy to achieve the glycemic targets. Higher age (aOR: 1.08 (1.03-1.13), P  = 0.003), higher pre-pregnancy body mass index (BMI) (1.06 (1.02-1.10), P  = 0.003) and earlier introduction of metformin (0.89 (0.85-0.94), P  metformin, insulin supplementation was not associated with poor neonatal outcomes. Higher age, higher pre-pregnancy BMI and earlier introduction of metformin could be used as predictors of poor response to metformin. © 2018 European Society of Endocrinology.

  7. Metformin treatment in different phenotypes of polycystic ovary syndrome.

    Science.gov (United States)

    Hosseini, Marzieh Agha; Alleyassin, Ashraf; Sarvi, Fatemeh; Safdarian, Leila; Kokab, Abas; Fanisalek, Mehran

    2013-11-01

    The aim of this study was to evaluate the effectiveness of Metformin on ovulation and eventual clinical pregnancy in different phenotypes of polycystic ovary syndrome (PCOS). A total of 359 subjects who had proven PCOS according to Rotterdam criteria were prospectively selected. Patients' PCOS phenotypes were determined and recorded. All patients were younger than 35 years. Clinical and biochemical assays in all patients were initially obtained. Then patients were divided into two separate groups. One group received both 1,500 mg of Metformin and 1 mg of folic acid per day and the other group received only 1 mg of folic acid for a total of 2 months. Subsequently, all patients underwent ovulation stimulation with 5 mg of Letrozole per day for 5 days followed by an intra-uterine insemination. Finally, ovulation and pregnancy rates were evaluated for all four PCOS phenotypes. Effect of Metformin therapy was evaluated for each group and each phenotype. The pregnancy rate in Metformin and non-Metformin groups were, respectively, as follows: in phenotype A (39.2 vs. 33.7 %, p = 0.270), phenotype B (43.8 vs. 20 %, p = 0.210), phenotype C (44 vs. 20 %, p = 0.064), and phenotype D (36.5 vs. 28.6 %, p = 0.279). Although there was a little improvement in ovulation and pregnancy rates among patients with B and C phenotypes, there was not a statistically significant difference between the two groups. Based on our study, Metformin therapy does not change the ovulation and pregnancy rate.

  8. Cinnamon Bark, Water Soluble Cinnamon Extract, and Metformin as Initial Treatment for Type 2 Diabetes Mellitus: A Randomized, Controlled Trial

    Science.gov (United States)

    2016-12-14

    Cinnamon Extract, and Metformin as Initial Treatment for Type 2 Diabetes Mellitus : A Randomized, Controlled Trial. Paul Crawford, MD Clinical Investigation...Title: “Cinnamon Bark, Water-Soluble Cinnamon Extract, and Metformin as Initial Treatment for Type 2 Diabetes Mellitus : A Randomized, Controlled...as initial treatment for Type 2 diabetes mellitus : A randomized, controlled trial. IRB #: FWH20110004H Principal Investigator (PI) Rank / Civ

  9. Application of induced short-term hyperglycemia in comprehensive treatment of locally disseminated cancer of mammary gland

    International Nuclear Information System (INIS)

    Letyagin, V.P.; Poddubnyj, I.K.; Sokolova, I.G.; Ermilova, V.D.; Ajtakova, T.I.

    1984-01-01

    The paper deals with an analysis of the results of treatment of 12 patients with mammary gland cancer receiving preoperative radiation and chemotherapy and in whom short-term hyperglycemia was simultaneously induced. The peculiarities of the said modality and advantages offered by its application are discussed. The cases given the same treatment unaccompanied by hyperglycemia were in control. Since short-term hyperglycemia as a component of comprehensive treatment of mammary gland cancer resulted in a higher effectiveness of the latter, it merits attention and further studies

  10. Efficacy and safety of metformin or oral contraceptives, or both in polycystic ovary syndrome

    Directory of Open Access Journals (Sweden)

    Yang YM

    2015-09-01

    contraceptives are at least patient convenient, efficacious, and safe for the treatment of PCOS. However, well-designed, prospective, long-term, large-scale, randomized clinical trials are necessary to elucidate the efficacy and safety of metformin, oral contraceptives, or both in the treatment of PCOS, and to elucidate their individual roles in the treatment of this condition. Keywords: polycystic ovary syndrome, metformin, oral contraceptive pill, ovulatory dysfunction, hyperandrogenism, efficacy, safety

  11. Metformin in prevention and treatment of antipsychotic induced weight gain: a systematic review and meta-analysis.

    Science.gov (United States)

    de Silva, Varuni Asanka; Suraweera, Chathurie; Ratnatunga, Suhashini S; Dayabandara, Madhubashinee; Wanniarachchi, Nimali; Hanwella, Raveen

    2016-10-03

    Most antipsychotics are associated with weight gain and other metabolic complications. Several randomized trials have shown metformin to be effective, but this still hasn't been included in clinical guidelines on managing antipsychotic induced weight gain. All double blind placebo controlled trials assessing the efficacy of metformin in the treatment of antipsychotic induced weight gain were included. Cochrane Central Register of Controlled Trials (CENTRAL) and MEDLINE were searched for the period January 2000-December 2015. Meta-analysis was carried out using the random effects model. Meta analysis of 12 published studies with a total of 743 patients found that in patients treated with antipsychotics, metformin treatment resulted in significantly better anthropometric and metabolic parameters than placebo. The mean change in weight was -3.27 kg (95 % CI -4.66 to -1.89) (Z = 4.64, p resistance index [-1.49 (95 % CI -2.40 to -0.59)] but not fasting blood sugar [-2.48 mg/dl (95 % CI -5.54 to 0.57]. This meta-analysis confirms that metformin is effective in treating antipsychotic induced weight gain in patients with schizophrenia or schizoaffective disorder.

  12. Effect of vildagliptin add-on treatment to metformin on plasma asymmetric dimethylarginine in type 2 diabetes mellitus patients.

    Science.gov (United States)

    Cakirca, Mustafa; Karatoprak, Cumali; Zorlu, Mehmet; Kiskac, Muharrem; Kanat, Mustafa; Cikrikcioglu, Mehmet Ali; Soysal, Pinar; Hursitoglu, Mehmet; Camli, Ahmet Adil; Erkoc, Reha; Abdul-Ghani, Muhammad

    2014-01-01

    A close association has been demonstrated between increased cardiovascular risk and high asymmetric dimethylarginine (ADMA) levels in type 2 diabetes mellitus (DM) patients. We planned to measure serum ADMA levels in type 2 DM patients using vildagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor. A total of 68 type 2 DM patients who were on metformin were enrolled in the study. Based on the glycemic levels of patients, vildagliptin was added on to treatment in 33 patients. Patients were followed for 6 months. Serum ADMA, C-reactive protein, and fibrinogen levels were compared in groups of patients using metformin or metformin + vildagliptin, after 6 months. Serum ADMA levels were found to be significantly lower in the group using vildagliptin compared to the group using metformin + vildagliptin (Pvildagliptin treatment was observed to lower serum ADMA levels in type 2 DM patients. Our findings notwithstanding, large-scale prospective randomized controlled studies are warranted to conclude that vildagliptin provides cardiovascular protection along with diabetes regulation.

  13. The effects of long- and short-term interdisciplinary treatment approaches in women with fibromyalgia: a randomized controlled trial.

    Science.gov (United States)

    Saral, Ilknur; Sindel, Dilsad; Esmaeilzadeh, Sina; Sertel-Berk, Hanife Ozlem; Oral, Aydan

    2016-10-01

    We investigated the effects of long- and short-term interdisciplinary treatment approaches for reducing symptoms and improving health-related quality of life (HRQoL) and physical functions of patients with fibromyalgia and compared the effects of two different interdisciplinary treatment approaches. We conducted a prospective, randomized, controlled trial involving 66 women with fibromyalgia eligible for the study at a university hospital setting. The patients were randomized into three groups (allocation ratio 1:1:1) using a computer-generated random numbers: a long-term interdisciplinary treatment group (LG, n = 22) that participated in 10 sessions (3-h once-weekly session for 10 weeks) of cognitive behavioral therapy (CBT) together with exercise training and other fibromyalgia related educational programs (two full days); a short-term interdisciplinary treatment group (SG, n = 22) that received two full days of educational, exercise, and CBT programs; and a control group (CG, n = 22). The patients were evaluated at baseline and 6 months after treatment using the visual analog scale (pain, fatigue, and sleep), Fibromyalgia Impact Questionnaire, Beck Depression Inventory, Short Form-36, tender point numbers, and pressure algometry as primary outcomes. The statistical analysis was confined to the 'per-protocol' set. No blinding was performed. The number of patients analyzed was 21 in the LG, 19 in the SG, and 19 in the CG. The intensity of pain (p treatment approaches when compared with controls; the long-term treatment was found more effective in reducing pain than the short-term. Both, long- and short-term interdisciplinary treatments were effective in reducing the severity of some symptoms and disease activity in patients with fibromyalgia. The short-term program well meets the needs of women with fibromyalgia particularly in relation to pain and health status as measured using FIQ; however, a long-term program may be beneficial in reducing fatigue and

  14. The effect of exercise and metformin treatment on circulating free DNA in pregnancy.

    Science.gov (United States)

    Christiansen, S C; Vanky, E; Klungland, H; Stafne, S N; Mørkved, S; Salvesen, K Å; Sæther, M; Carlsen, S M

    2014-12-01

    Some pregnancy complications are characterized by increased levels of cell-free fetal (cffDNA) and maternal DNA (cfmDNA), the latter may also be elevated during physical strain. This study aims at assessing the impact of exercise and metformin intervention in pregnancy, and to compare the levels of cell free DNA in pregnant women with or without PCOS diagnosis. Consecutive women from two previous randomized controlled trials in pregnancy were included. Women came from a trial with organized exercise vs. standard antenatal care in pregnancy and a trial of metformin vs. placebo in PCOS women. Levels of cffDNA, cfmDNA and cell-free total DNA (cftDNA) were measured by qPCR. Training in pregnancy did not affect the levels of cffDNA, cfmDNA or cftDNA. PCOS-women treated with metformin had lower levels of cfmDNA and cftDNA at week 32 (mean ± SD: 301 ± 162 versus 570 ± 337, p = 0.012, 345 ± 173 versus 635 ± 370, p = 0.019); otherwise the levels were comparable to PCOS-controls. Metformin-treated PCOS-women had higher cffDNA at inclusion, in the 1st trimester; later on in pregnancy the levels in the metformin and placebo groups were equal. A comparison of pregnant women in the exercise study (TRIP) to placebo-treated pregnant PCOS-women, showed the levels of cffDNA, cfmDNA or cftDNA during mid-pregnancy (weeks 18-36) to be equal. Training during pregnancy was not associated with altered levels of cffDNA cfmDNA or cftDNA, but metformin treatment may reduce cfmDNA and cftDNA in pregnant PCOS women. Copyright © 2014 Elsevier Ltd. All rights reserved.

  15. Serum vascular endothelial growth factor B is elevated in women with polycystic ovary syndrome and can be decreased with metformin treatment.

    Science.gov (United States)

    Cheng, Feifei; Zhao, Lu; Wu, Yuanyuan; Huang, Tiantian; Yang, Gangyi; Zhang, Zhanyu; Wu, Yijia; Jia, Fang; Wu, Jinlin; Chen, Chen; Liu, Dongfang

    2016-03-01

    To determine serum vascular endothelial growth factor B (VEGF-B) levels in polycystic ovary syndrome, their association with insulin resistance and β-cell dysfunction, and the effect of metformin on serum VEGF-B levels. A cross-sectional, interventional study. We recruited 103 women with polycystic ovary syndrome and 96 age-matched healthy controls. Serum VEGF-B levels were determined in all participants, and 44 polycystic ovary syndrome patients randomly received metformin. We measured VEGF-B levels in healthy controls and women with polycystic ovary syndrome before and after metformin treatment. Women with polycystic ovary syndrome had higher serum VEGF-B levels, which decreased with metformin treatment. In the lean and overweight/obese groups, patients with polycystic ovary syndrome had higher plasma VEGF-B levels than did healthy controls (P polycystic ovary syndrome. Serum VEGF-B is significantly higher in women with polycystic ovary syndrome and is closely and positively related to insulin resistance. Metformin treatment reduces VEGF-B levels and ameliorates insulin resistance. © 2015 John Wiley & Sons Ltd.

  16. Metformin in prevention and treatment of antipsychotic induced weight gain: a systematic review and meta-analysis

    Directory of Open Access Journals (Sweden)

    Varuni Asanka de Silva

    2016-10-01

    Full Text Available Abstract Background Most antipsychotics are associated with weight gain and other metabolic complications. Several randomized trials have shown metformin to be effective, but this still hasn’t been included in clinical guidelines on managing antipsychotic induced weight gain. Methods All double blind placebo controlled trials assessing the efficacy of metformin in the treatment of antipsychotic induced weight gain were included. Cochrane Central Register of Controlled Trials (CENTRAL and MEDLINE were searched for the period January 2000-December 2015. Meta-analysis was carried out using the random effects model. Results Meta analysis of 12 published studies with a total of 743 patients found that in patients treated with antipsychotics, metformin treatment resulted in significantly better anthropometric and metabolic parameters than placebo. The mean change in weight was −3.27 kg (95 % CI −4.66 to −1.89 (Z = 4.64, p < 0.001. Metformin compared to placebo resulted in significant reduction in BMI [−1.13 kg/m2 (95 % CI −1.61 to −0.66] and insulin resistance index [−1.49 (95 % CI −2.40 to −0.59] but not fasting blood sugar [−2.48 mg/dl (95 % CI −5.54 to 0.57]. Conclusion This meta-analysis confirms that metformin is effective in treating antipsychotic induced weight gain in patients with schizophrenia or schizoaffective disorder.

  17. Loss of Eyebrows and Eyelashes During Concomitant Treatment with Sitagliptin and Metformin.

    Science.gov (United States)

    Succurro, Elena; Palleria, Caterina; Ruffo, Mariafrancesca; Serra, Raffaele; Arturi, Franco; Gallelli, Luca

    2017-01-01

    The fixed dose combination of sitagliptin 50 mg and metformin 850 mg (Janumet ®), is indicated for the treatment of type 2 diabetes mellitus in addition to diet and exercise to improve glycemic control in patients treated with metformin alone. We report a 69-year-old man with type 2 diabetes that developed sudden loss of eyebrows and eyelashes about 4 months after the beginning of Janumet®. Clinical and laboratory findings excluded the presence of systemic or skin diseases able to induce these manifestations, while the Naranjo probability scale documented a possible association between the drug and the adverse drug reaction. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  18. Impact of metformin treatment and swimming exercise on visfatin levels in high-fat-induced obesity rats.

    Science.gov (United States)

    Gao, Ya; Wang, Changjiang; Pan, Tianrong; Luo, Li

    2014-02-01

    Visfatin is a recently discovered adipocytokine that contributes to glucose and obesity-related conditions. Until now, its responses to the insulin-sensitizing agent metformin and to exercise are largely unknown. We aim to investigate the impact of metformin treatment and/or swimming exercise on serum visfatin and visfatin levels in subcutaneous adipose tissue (SAT), peri-renal adipose tissue (PAT) and skeletal muscle (SM) of high-fat-induced obesity rats. Sprague-Dawley rats were fed a normal diet or a high-fat diet for 16 weeks to develop obesity model. The high-fat-induced obesity model rats were then randomized to metformin (MET), swimming exercise (SWI), or adjunctive therapy of metformin and swimming exercise (MAS), besides high-fat obesity control group and a normal control group, all with 10 rats per group. Zoometric and glycemic parameters, lipid profile, and serum visfatin levels were assessed at baseline and after 6 weeks of therapy. Visfatin levels in SAT, PAT and SM were determined by Western Blot. Metformin and swimming exercise improved lipid profile, and increased insulin sensitivity and body weight reduction were observed. Both metformin and swimming exercise down-regulated visfatin levels in SAT and PAT, while the adjunctive therapy conferred greater benefits, but no changes of visfatin levels were observed in SM. Our results indicate that visfatin down-regulation in SAT and PAT may be one of the mechanisms by which metformin and swimming exercise inhibit obesity.

  19. Effect of adjunct metformin treatment in patients with type-1 diabetes and persistent inadequate glycaemic control. A randomized study

    DEFF Research Database (Denmark)

    Lund, S.S.; Tarnow, L.; Astrup, A.S.

    2008-01-01

    BACKGROUND: Despite intensive insulin treatment, many patients with type-1 diabetes (T1DM) have longstanding inadequate glycaemic control. Metformin is an oral hypoglycaemic agent that improves insulin action in patients with type-2 diabetes. We investigated the effect of a one-year treatment...... with metformin versus placebo in patients with T1DM and persistent poor glycaemic control. METHODOLOGY/PRINCIPAL FINDINGS: One hundred patients with T1DM, preserved hypoglycaemic awareness and HaemoglobinA(1c) (HbA(1c)) > or = 8.5% during the year before enrolment entered a one-month run-in on placebo treatment....... Thereafter, patients were randomized (baseline) to treatment with either metformin (1 g twice daily) or placebo for 12 months (double-masked). Patients continued ongoing insulin therapy and their usual outpatient clinical care. The primary outcome measure was change in HbA(1c) after one year of treatment...

  20. Short-Term Group Treatment for Adult Children of Alcoholics.

    Science.gov (United States)

    Cooper, Alvin; McCormack, WIlliam A.

    1992-01-01

    Adult children of alcoholics (n=24) were tested on measures of loneliness, anxiety, hostility, depression, and interpersonal dependency before and after participation in short-term group therapy. Highly significant test score changes supported effectiveness of individual therapy in short-term groups. (Author/NB)

  1. Short-term treatment with flumazenil restores long-term object memory in a mouse model of Down syndrome.

    Science.gov (United States)

    Colas, Damien; Chuluun, Bayarsaikhan; Garner, Craig C; Heller, H Craig

    2017-04-01

    Down syndrome (DS) is a common genetic cause of intellectual disability yet no pro-cognitive drug therapies are approved for human use. Mechanistic studies in a mouse model of DS (Ts65Dn mice) demonstrate that impaired cognitive function is due to excessive neuronal inhibitory tone. These deficits are normalized by chronic, short-term low doses of GABA A receptor (GABA A R) antagonists in adult animals, but none of the compounds investigated are approved for human use. We explored the therapeutic potential of flumazenil (FLUM), a GABA A R antagonist working at the benzodiazepine binding site that has FDA approval. Long-term memory was assessed by the Novel Object Recognition (NOR) testing in Ts65Dn mice after acute or short-term chronic treatment with FLUM. Short-term, low, chronic dose regimens of FLUM elicit long-lasting (>1week) normalization of cognitive function in both young and aged mice. FLUM at low dosages produces long lasting cognitive improvements and has the potential of fulfilling an unmet therapeutic need in DS. Copyright © 2017. Published by Elsevier Inc.

  2. Effect of metformin on exercise capacity in metabolic syndrome.

    Science.gov (United States)

    Paul, Abi Albon; Dkhar, Steven Aibor; Kamalanathan, Sadishkumar; Thabah, Molly Mary; George, Melvin; Chandrasekaran, Indumathi; Gunaseelan, Vikneswaran; Selvarajan, Sandhiya

    2017-11-01

    Metabolic syndrome is a constellation of risk factors with increased predilection towards occurrence of cardiovascular diseases. Currently physical exercise and management with metformin are the prevailing treatment modalities for metabolic syndrome. Patients with metabolic syndrome have been found to have reduced exercise capacity over a period of time. Likewise metformin has been shown to decrease exercise capacity among healthy volunteers. Hence this study aims to evaluate the effect of metformin on the exercise capacity of patients with metabolic syndrome. Prospective study with 6 weeks follow up. Newly diagnosed patients with metabolic syndrome and to be started on Table Metformin 500mg twice a day were recruited for the study after obtaining written informed consent. Cardiopulmonary Exercise Testing (CPET) was done at baseline before the subjects were started on metformin and after 6 weeks of treatment using cardiopulmonary exercise testing apparatus (ZAN600). Fifteen treatment naïve patients with metabolic syndrome completed six weeks of therapy with metformin. In these patients oxygen uptake [VO2] showed statistically significant decrease from 1.10±0.44 at baseline to 0.9±0.39 (l/min) after six weeks of treatment with metformin [mean difference of -0.20 (-0.31 to -0.09); P=0.001]. Similarly oxygen uptake/kg body weight [VO2/Kg] showed a significant decrease from 14.10±4.73 to 11.44±3.81 (mlkg -1 min -1 ) at the end of six weeks of treatment [mean difference of -2.66 (-4.06 to -1.26); P=0.001]. Six weeks of treatment with metformin significantly decreases exercise capacity in newly diagnosed patients with metabolic syndrome. Copyright © 2017 Diabetes India. Published by Elsevier Ltd. All rights reserved.

  3. Efficacy of metformin in the treatment of NIDDM. Meta-analysis

    DEFF Research Database (Denmark)

    Johansen, K

    1999-01-01

    OBJECTIVE: The results differ concerning randomized controlled trials of the effects of metformin on blood glucose regulation and body weight. To get a systematic overview, a meta-analysis of the efficacy of metformin was performed by comparing metformin with placebo and sulfonylurea. RESEARCH...... DESIGN AND METHODS: All randomized controlled trials published since 1957 were selected by searching the Current List of Medical Literature, Cumulated Index Medicus, Medline, and Embase, Meta-analysis was performed calculating weighted mean difference (WMD) of fasting blood glucose, glycosylated...

  4. Metformin Pharmacogenomics: Current Status and Future Directions

    Science.gov (United States)

    Pawlyk, Aaron C.; Giacomini, Kathleen M.; McKeon, Catherine; Shuldiner, Alan R.

    2014-01-01

    The incidence of type 2 diabetes (T2D) and its costs to the health care system continue to rise. Despite the availability of at least 10 drug classes for the treatment of T2D, metformin remains the most widely used first-line pharmacotherapy for its treatment; however, marked interindividual variability in response and few clinical or biomarker predictors of response reduce its optimal use. As clinical care moves toward precision medicine, a variety of broad discovery-based “omics” approaches will be required. Technical innovation, decreasing sequencing cost, and routine sample storage and processing has made pharmacogenomics the most widely applied discovery-based approach to date. This opens up the opportunity to understand the genetics underlying the interindividual variation in metformin responses in order for clinicians to prescribe specific treatments to given individuals for better efficacy and safety: metformin for those predicted to respond and alternative therapies for those predicted to be nonresponders or who are at increased risk for adverse side effects. Furthermore, understanding of the genetic determinants of metformin response may lead to the identification of novel targets and development of more effective agents for diabetes treatment. The goals of this workshop sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases were to review the state of research on metformin pharmacogenomics, discuss the scientific and clinical hurdles to furthering our knowledge of the variability in patient responses to metformin, and consider how to effectively use this increased understanding to improve patient outcomes. PMID:25060887

  5. Sulfonylurea versus metformin monotherapy in patients with type 2 diabetes

    DEFF Research Database (Denmark)

    Hemmingsen, Bianca; Schroll, Jeppe B; Wetterslev, Jørn

    2014-01-01

    BACKGROUND: Guidelines recommend metformin as the first-line oral treatment for type 2 diabetes. We conducted a systematic review to assess whether the use of second- and third-generation sulfonylurea agents is associated with benefits and harms in terms of patient-important outcomes compared...... with metformin. METHODS: We searched several electronic databases and other sources for randomized clinical trials published to August 2011. We included trials that compared sulfonylurea versus metformin monotherapy among patients 18 years or older with type 2 diabetes and that had an intervention period...... of at least 24 weeks. We assessed risk of bias and extracted data related to interventions and outcomes. The risk of random errors was assessed by trial sequential analysis. RESULTS: We included 14 trials (4560 participants). All trials were judged to be at high risk of bias. Data on patient...

  6. Metformin and male reproduction: effects on Sertoli cell metabolism

    Directory of Open Access Journals (Sweden)

    2014-08-01

    Full Text Available Metformin, widely used for the treatment of type 2 diabetes, is increasingly becoming the subject of research in other areas of medicine. Apart form antihyperglycemic effect of metformin has an inhibitory effect on the proliferation of various tumor cells both in vivo and in vitro. Metformin is well established in the treatment of anovulatory infertility in polycystic ovary syndrome, while its influence male reproductive function are poorly understood.

  7. Effect of combined gliclazide/metformin treatment on oxidative stress, lipid profile, and hepatorenal functions in type 2 diabetic patients.

    Science.gov (United States)

    Alsharidah, Mansour; Algeffari, Metab; Abdel-Moneim, Abdel-Moneim Hafez; Lutfi, Mohamed Faisal; Alshelowi, Haila

    2018-01-01

    Type 2 diabetes is a chronic condition that requires pharmacotherapy interventions. Metformin and gliclazide are widely used drugs in monotherapy. However, their complementary action made utilization of the combination of these drugs an appealing approach. The study compared major therapeutic potentials of combined metformin/gliclazide treatment over metformin monotherapy based on the following parameters: oxidative stress, lipid profile, and hepatorenal functions. This is a comparative study was conducted from March 2015 to March 2016. The study screened 80 type 2 diabetic patients, of which 40 patients underwent combined metformin + gliclazide therapy (500 mg BD + 80 mg OD, respectively). The other 40 were matched for age and duration of diabetes mellitus with the previous group and received metformin monotherapy (500 mg BD). The levels of fasting blood glucose (FBG), total glycated hemoglobin (HbA1c), lipid peroxidation, total antioxidant capacity, serum creatinine, aspartate and alanine transaminases, total cholesterol, triglycerides, high-density lipoproteins, and low-density lipoproteins were measured according to the standard methods. Oxidative stress, lipid profile, and hepatorenal functions were comparable in patients of both groups. However, patients on metformin treatment showed significantly lower levels of FBG [7.61 (6.70-8.89) mmol/L vs. 9.00 (7.30-10.68) mmol/L; P = .022] and HBA1c [7.00 (6.40-7.65)% vs. 8.20 (7.20-9.75)%; P metformin/gliclazide therapy and compared to those metformin alone. In contrast, glycemic control was poor in the diabetic patients undergoing combined therapy.

  8. Impact of short-term treatment with telmisartan on cerebral arterial remodeling in SHR.

    Directory of Open Access Journals (Sweden)

    Sébastien Foulquier

    Full Text Available Chronic hypertension decreases internal diameter of cerebral arteries and arterioles. We recently showed that short-term treatment with the angiotensin II receptor blocker telmisartan restored baseline internal diameter of small cerebral arterioles in spontaneously hypertensive rats (SHR, via reversal of structural remodeling and inhibition of the angiotensin II vasoconstrictor response. As larger arteries also participate in the regulation of cerebral circulation, we evaluated whether similar short-term treatment affects middle cerebral arteries of SHR.Baseline internal diameters of pressurised middle cerebral arteries from SHR and their respective controls, Wistar Kyoto rats (WKY and responses to angiotensin II were studied in a small vessel arteriograph. Pressure myogenic curves and passive internal diameters were measured following EDTA deactivation, and elastic modulus from stress-strain relationships.Active baseline internal diameter was 23% lower in SHR compared to WKY, passive internal diameter (EDTA 28% lower and elastic modulus unchanged. Pressure myogenic curves were shifted to higher pressure values in SHR. Telmisartan lowered blood pressure but had no effect on baseline internal diameter nor on structural remodeling (passive internal diameter and elastic modulus remained unchanged compared to SHR. Telmisartan shifted the pressure myogenic curve to lower pressure values than SHR.In the middle cerebral arteries of SHR, short-term treatment with telmisartan had no effect on structural remodeling and did not restore baseline internal diameter, but allowed myogenic tone to adapt towards lower pressure values.

  9. Metformin and berberine prevent olanzapine-induced weight gain in rats.

    Directory of Open Access Journals (Sweden)

    Yueshan Hu

    Full Text Available Olanzapine is a first line medication for the treatment of schizophrenia, but it is also one of the atypical antipsychotics carrying the highest risk of weight gain. Metformin was reported to produce significant attenuation of antipsychotic-induced weight gain in patients, while the study of preventing olanzapine-induced weight gain in an animal model is absent. Berberine, an herbal alkaloid, was shown in our previous studies to prevent fat accumulation in vitro and in vivo. Utilizing a well-replicated rat model of olanzapine-induced weight gain, here we demonstrated that two weeks of metformin or berberine treatment significantly prevented the olanzapine-induced weight gain and white fat accumulation. Neither metformin nor berberine treatment demonstrated a significant inhibition of olanzapine-increased food intake. But interestingly, a significant loss of brown adipose tissue caused by olanzapine treatment was prevented by the addition of metformin or berberine. Our gene expression analysis also demonstrated that the weight gain prevention efficacy of metformin or berberine treatment was associated with changes in the expression of multiple key genes controlling energy expenditure. This study not only demonstrates a significant preventive efficacy of metformin and berberine treatment on olanzapine-induced weight gain in rats, but also suggests a potential mechanism of action for preventing olanzapine-reduced energy expenditure.

  10. Multivitamin Use and Serum Vitamin B12 Concentrations in Older-Adult Metformin Users in REGARDS, 2003-2007.

    Science.gov (United States)

    Kancherla, Vijaya; Garn, Joshua V; Zakai, Neil A; Williamson, Rebecca S; Cashion, Winn T; Odewole, Oluwaseun; Judd, Suzanne E; Oakley, Godfrey P

    2016-01-01

    Metformin, an insulin-sensitizing drug, is a first line treatment for type 2 diabetes. Long-term use of metformin has been associated with subsequent reductions in vitamin B12 concentrations. The objective of our study was to determine whether metformin use is associated with lower serum vitamin B12 concentrations in older adults, and whether concurrent use of multivitamins modifies this association. We examined 2,510 participants aged 50 years and over, participating in the national population-based Reasons for Geographic And Racial Differences in Stroke (REGARDS) Study. Multivariable linear and logistic regression models were used to assess associations between multivitamin use and serum vitamin B12 concentrations. We estimated adjusted odds ratios (aOR)s and confidence intervals (CI)s. Results were stratified by three metformin/diabetes sub-groups: 1) participants with diabetes who were metformin users; 2) participants with diabetes who were not metformin users; and 3) participants without diabetes. We found that diabetic metformin users had significantly lower geometric mean serum B12 concentrations (409 pmol/L) than the group with diabetes not taking metformin (485 pmol/L; PL; P = 0.02). The geometric mean serum B12 concentrations were greater for multivitamin users (509 pmol/L) compared to those who did not use multivitamins (376 pmol/L; pvitamin B12 concentrations that were 50% (or 161 pmol/L) higher, compared to those not using multivitamins. Among metformin users, multivitamin use was associated with lower prevalence of combined low and borderline vitamin B12 concentrations (aOR = 0.14; 95% CI = 0.04, 0.54) compared to those not using multivitamins. In conclusion, metformin use was associated with lower geometric mean serum vitamin B12 concentrations among diabetic older adults compared to their counterparts. Concurrent multivitamin use may potentially protect against low or borderline vitamin B12 concentrations in long-term metformin users. Additional

  11. Effect of combined gliclazide/metformin treatment on oxidative stress, lipid profile, and hepatorenal functions in type 2 diabetic patients

    Directory of Open Access Journals (Sweden)

    Mansour Alsharidah

    2018-01-01

    Full Text Available Background: Type 2 diabetes is a chronic condition that requires pharmacotherapy interventions. Metformin and gliclazide are widely used drugs in monotherapy. However, their complementary action made utilization of the combination of these drugs an appealing approach. Aims: The study compared major therapeutic potentials of combined metformin/gliclazide treatment over metformin monotherapy based on the following parameters: oxidative stress, lipid profile, and hepatorenal functions. Subjects and methods: This is a comparative study was conducted from March 2015 to March 2016. The study screened 80 type 2 diabetic patients, of which 40 patients underwent combined metformin + gliclazide therapy (500 mg BD + 80 mg OD, respectively. The other 40 were matched for age and duration of diabetes mellitus with the previous group and received metformin monotherapy (500 mg BD. The levels of fasting blood glucose (FBG, total glycated hemoglobin (HbA1c, lipid peroxidation, total antioxidant capacity, serum creatinine, aspartate and alanine transaminases, total cholesterol, triglycerides, high-density lipoproteins, and low-density lipoproteins were measured according to the standard methods. Results: Oxidative stress, lipid profile, and hepatorenal functions were comparable in patients of both groups. However, patients on metformin treatment showed significantly lower levels of FBG [7.61 (6.70–8.89 mmol/L vs. 9.00 (7.30–10.68 mmol/L; P = .022] and HBA1c [7.00 (6.40–7.65% vs. 8.20 (7.20–9.75%; P < .001] compared to those on combined therapy. Conclusion: Oxidative stress, lipids profile, and hepatorenal functions were not different in patients who were on combined metformin/gliclazide therapy and compared to those metformin alone. In contrast, glycemic control was poor in the diabetic patients undergoing combined therapy. Keywords: Diabetes mellitus, Gliclazide, Glucose, Lipids, Metformin, Oxidative stress

  12. Exenatide with Metformin Ameliorated Visceral Adiposity and Insulin Resistance

    Directory of Open Access Journals (Sweden)

    Xuan Du

    2018-01-01

    Full Text Available Background. To study the effectiveness of exenatide with metformin and sequential treatment with exenatide and glargine added to metformin and their influence on insulin sensitivity and adipose distribution. Methods. 20 newly diagnosed obese type 2 diabetic patients were enrolled, and 2-month washout treatment of metformin, 6-month exenatide treatment, and 6-month glargine treatment were administrated sequentially accompanied with previous metformin. Glucolipid metabolic parameters were compared among groups. Adipose distribution was quantified with computerized tomography according to anatomy, dividing into visceral adipose tissue (VAT and subcutaneous adipose tissue (SAT, adding up to total adipose tissue (TAT. Results. The 6-month exenatide treatment dramatically ameliorated the glucose and lipid profile, improved insulin sensitivity, and mainly decreased VAT and also the ratio of VAT/SAT (RVS. The following 6-month glargine treatment increased VAT. The whole 12-month sequential treatment with exenatide and glargine added to metformin basically improved the insulin sensitivity and glucolipid control though VAT rebounded at the end, however without deteriorating the other parameters. Conclusion. Exenatide is an ideal treatment for obese type 2 diabetic patients in the aspect of adipose tissue distribution. Sequential treatment of exenatide and glargine could be an alternative for low-income patients who cannot afford GLP-1 agonist for long time. This trial is registered with ChiCTR-OOC-17013679.

  13. Metformin Impairs Spatial Memory and Visual Acuity in Old Male Mice.

    Science.gov (United States)

    Thangthaeng, Nopporn; Rutledge, Margaret; Wong, Jessica M; Vann, Philip H; Forster, Michael J; Sumien, Nathalie

    2017-02-01

    Metformin is an oral anti-diabetic used as first-line therapy for type 2 diabetes. Because benefits of metformin extend beyond diabetes to other age-related pathology, and because its effect on gene expression profiles resembles that of caloric restriction, metformin has a potential as an anti-aging intervention and may soon be assessed as an intervention to extend healthspan. However, beneficial actions of metformin in the central nervous system have not been clearly established. The current study examined the effect of chronic oral metformin treatment on motor and cognitive function when initiated in young, middle-aged, or old male mice. C57BL/6 mice aged 4, 11, or 22 months were randomly assigned to either a metformin group (2 mg/ml in drinking water) or a control group. The mice were monitored weekly for body weight, as well as food and water intake and a battery of behavioral tests for motor, cognitive and visual function was initiated after the first month of treatment. Liver, hippocampus and cortex were collected at the end of the study to assess redox homeostasis. Overall, metformin supplementation in male mice failed to affect blood glucose, body weights and redox homeostasis at any age. It also had no beneficial effect on age-related declines in psychomotor, cognitive or sensory functions. However, metformin treatment had a deleterious effect on spatial memory and visual acuity, and reduced SOD activity in brain regions. These data confirm that metformin treatment may be associated with deleterious effect resulting from the action of metformin on the central nervous system.

  14. Pharmacoeconomic analysis of clinical efficiency of combined metformin (Siofor - insulin therapy in patients with type 2 diabetes mellitus

    Directory of Open Access Journals (Sweden)

    I Yu Demidova

    2009-06-01

    Full Text Available Aim. To assess expedience of metformin combination with long-acting insulin, determine optimal doses of metformin for patients with type 2 diabetesmellitus (DM2, and accomplish pharmacoeconomic analysis of clinical efficiency of various therapeutic modalities. Materials and methods. Patients with decompensated DM2 (n=126 were under observation for 1 year during which they received rational hypoglycemictherapy with metformin and long-acting insulin (LAI at bedtime, with the dose being titrated until the desired level of glycemic control wasachieved. The patients were randomly allocated to the following 3 groups: group 1 (sulponylurea derivatives (SUD, LAI, and metformin at a doseof 1000 mg b.i.d., group 2 (SUD, LAI, and metformin at 500 mg b.i.d., group 3 (SUD and LAI. In case of postprandial glycemia >9 mmol/l at amaximum dose of SUD, it was replaced by short-acting insulin. Cost-effectiveness analysis of different therapeutic regimes was performed. Results. The cost of examination and treatment of patients given SUD and LAI in combination with metformin at a daily dose of 2000 mg to achievethe desired quality of glycemic control was lower compared with two other groups. Moreover, this therapy was most efficacious and ensured the desiredlevel of glycemic control in a greater number of patients. Cost-effectiveness analysis confirmed advantages of this treatment. Conclusion. Combined hypoglycemic therapy with SUD, LAI, and metformin (200 mg daily has the advantage of lowest cost and maximum efficiencycompared with other modalities.

  15. Effect of metformin alone compared with metformin plus simvastatin on polycystic ovarian syndrome in Pakistan women

    International Nuclear Information System (INIS)

    Malik, M.; Tasnim, N.; Mahmud, G.

    2018-01-01

    To determine the efficacy of metformin alone versus metformin plus simvastatin for treatment of polycystic ovarian syndrome (PCOS). Study Design:Randomized controlled trial. Place and Duration of Study:Maternal and Child Health Centre, Unit II, Pakistan Institute of Medical Sciences (PIMS), from November 2014 to April 2015. Methodology:One hundred and eight patients (108) were randomly divided into metformin group (n=54) and metformin plus simvastatin group (n=54), detailed clinical history, including menstrual details, was taken with thorough examination performed. Baseline ultrasound was performed to evaluate ovarian size and these were considered enlarged with volume >10cc or with >12 follicles in any one ovary. Blood samples were taken at baseline and after three months of therapy to determine the LH/FSH ratio and lipid profile. Efficacy was defined as >15% decrease in the baseline values. Results:The mean age of patients was 28.82 +- 7.18 years. Mean BMI of the patients was 22.41 +-1.55 Kg/m2 . Efficacy was achieved in 66.7% patients with metformin alone, while in 92.6% with combination medication (p=0.001). Conclusion:The combination of metformin plus simvastatin is more efficacious as compared to metformin alone for management of females with PCOS. (author)

  16. Does continuous use of metformin throughout pregnancy improve pregnancy outcomes in women with polycystic ovarian syndrome?

    Science.gov (United States)

    Nawaz, Fauzia Haq; Khalid, Roha; Naru, Tahira; Rizvi, Javed

    2008-10-01

    Polycystic ovarian syndrome (PCOS) is one of the most common endocrinopathies in women of reproductive age. It is associated with hyperinsulinemia and insulin resistance which is further aggravated during pregnancy. This mechanism has a pivotal role in the development of various complications during pregnancy. In the past few years, metformin, an insulin sensitizer, has been extensively evaluated for induction of ovulation. Its therapeutic use during pregnancy is, however, a recent strategy and is a debatable issue. At present, evidence is inadequate to support the long-term use of insulin-sensitizing agents during pregnancy. It is a challenge for both clinicians and researchers to provide good evidence of the safety of metformin for long-term use and during pregnancy. This study aimed to evaluate pregnancy outcomes in women with PCOS who conceived while on metformin treatment, and continued the medication for a variable length of time during pregnancy. This case-control study was conducted from January 2005 to December 2006 at the antenatal clinics of the Department of Obstetrics and Gynecology, Aga Khan University, Karachi, Pakistan. The sample included 137 infertile women with PCOS; of these, 105 conceived while taking metformin (cases), while 32 conceived spontaneously without metformin (controls). Outcomes were measured in three groups of cases which were formed according to the duration of use of metformin during pregnancy. Comparison was made between these groups and women with PCOS who conceived spontaneously. All 137 women in this study had a confirmed diagnosis of PCOS (Rotterdam criteria). These women were followed up during their course of pregnancy; data forms were completed once they had delivered. Cases were divided into three groups: group A, 40 women who stopped metformin between 4-16 weeks of pregnancy; group B, 20 women who received metformin up until 32 weeks of gestation; and group C; 45 women who continued metformin throughout pregnancy. All

  17. Proinsulin, adiponectin and hsCRP in reproductive age women with polycystic ovary syndrome (PCOS)--the effect of metformin treatment.

    Science.gov (United States)

    Kruszyńska, Aleksandra; Słowińska-Srzednicka, Jadwiga; Jeske, Wojciech; Zgliczyński, Wojciech

    2014-01-01

    Women with polycystic ovary syndrome (PCOS) often suffer from obesity and insulin resistance. The role of proinsulin, which is known to be an indicator of fertility outcomes in PCOS women, and that of adiponectin, in the pathogenesis of PCOS is not well elucidated. Our objective was to determine proinsulin, adiponectin, hsCRP and other hormonal and metabolic parameters in PCOS women before and after metformin treatment. Two PCOS groups of patients of reproductive age (90 lean and 88 obese or overweight) with two control groups, adjusted for body mass index (BMI), were compared at baseline. 32 PCOS women were studied at baseline, after three and six months of metformin (1,000 mg/day) treatment. Clinical, anthropometric, biochemical and hormonal parameters were assessed. Proinsulin and hsCRP levels were the highest in obese PCOS women and were statistically different than in lean PCOS women (proinsulin: 11.4 v. 6.9 pmol/L; hsCRP 2.46 v. 0.47 mg/L, p treatment only in obese PCOS women. PCOS, when accompanied by obesity, is associated with elevated proinsulin concentrations, which correlates with higher hsCRP and increased FAI. Proinsulin level decreases due to metformin treatment. Our results suggest that obese or overweight PCOS and lean PCOS are characterised by different hormonal and metabolic parameters and have a different response to metformin treatment.

  18. Use of metformin and vildagliptin for treatment of type 2 diabetes in the elderly

    Directory of Open Access Journals (Sweden)

    Sicras-Mainar A

    2014-06-01

    Full Text Available Antoni Sicras-Mainar,1 Ruth Navarro-Artieda2 1Dirección de Planificación, Badalona Serveis Assistencials SA, 2Documentación Médica, Hospital Germans Trias i Pujol, Badalona, Barcelona, Spain Background: The aim of this study was to describe the clinical (treatment adherence, metabolic control, hypoglycemia, and macrovascular complications and economic (resource use and costs consequences of using a combination of metformin + vildagliptin to treat type 2 diabetes in elderly patients seen in daily clinical practice. Methods: We conducted a multicenter, retrospective, observational study that included patients aged ≥65 years treated with metformin who started a second oral antidiabetic therapy during the years 2008–2009. There were two groups of patients: a study group receiving metformin + vildagliptin and a reference group receiving metformin + other oral antidiabetics (sulfonylureas or glitazones. The main measures were comorbidity, compliance/persistence, metabolic control (glycosylated hemoglobin <7%, complications (hypoglycemic, macrovascular, and total costs. The patients were followed for 2 years. Results: We recruited 987 patients (49.1% male of mean age 74.2 years. There were 270 (27.4% patients in the metformin + vildagliptin group and 717 (72.6% in the reference group. Vildagliptin-treated patients had significantly (P<0.05 improved compliance (68.3% versus 62.5%, respectively, persistence (61.5% versus 55.1%, and metabolic control (63.3% versus 57.6%. They also had lower rates of hypoglycemia (17.4% versus 42.8% and cardiovascular events (4.4% versus 8.6% and lower total costs (€2,544 versus €2,699, P<0.05. Conclusion: Patients treated with metformin and vildagliptin showed better adherence and metabolic control and lower rates of hypoglycemia, resulting in lower health care costs for the national health system. Keywords: vildagliptin, diabetes, metabolic control, hypoglycemia, cardiovascular events, health costs

  19. Metformin and metabolic diseases: a focus on hepatic aspects

    Science.gov (United States)

    Woo, Shih-Lung; Hu, Xiang; Botchlett, Rachel; Chen, Lulu; Huo, Yuqing

    2015-01-01

    Metformin has been widely used as a first-line anti-diabetic medicine for the treatment of type 2 diabetes (T2D). As a drug that primarily targets the liver, metformin suppresses hepatic glucose production (HGP), serving as the main mechanism by which metformin improves hyperglycemia of T2D. Biochemically, metformin suppresses gluconeogenesis and stimulates glycolysis. Metformin also inhibits glycogenolysis, which is a pathway that critically contributes to elevated HGP. While generating beneficial effects on hyperglycemia, metformin also improves insulin resistance and corrects dyslipidemia in patients with T2D. These beneficial effects of metformin implicate a role for metformin in managing non-alcoholic fatty liver disease. As supported by the results from both human and animal studies, metformin improves hepatic steatosis and suppresses liver inflammation. Mechanistically, the beneficial effects of metformin on hepatic aspects are mediated through both adenosine monophosphate-activated protein kinase (AMPK)-dependent and AMPK-independent pathways. In addition, metformin is generally safe and may also benefit patients with other chronic liver diseases. PMID:25676019

  20. Long-term use of metformin and the molecular subtype in invasive breast carcinoma patients – a retrospective study of clinical and tumor characteristics

    International Nuclear Information System (INIS)

    Besic, Nikola; Satej, Nika; Ratosa, Ivica; Horvat, Andreja Gojkovic; Marinko, Tanja; Gazic, Barbara; Petric, Rok

    2014-01-01

    Metformin may exhibit inhibitory effects on cancer cells by inhibiting mTOR signaling pathway. The aim of our retrospective study was to examine if patients with breast carcinoma (BC) and diabetes mellitus (DM) receiving metformin have a lower stage of carcinoma in comparison to patients not receiving metformin, and if the use of metformin correlates with the molecular subtype of BC. A chart review of 253 patients with invasive BC and DM (128 on metformin and 125 not on metformin) was performed. Control group consisted of 320 consecutive patients with invasive BC without DM. BC subtypes were classified by immunohistochemical surrogates as luminal A (estrogen receptor [ER] + and/or progesterone receptor [PR]+, HER-2-), luminal B (ER + and/or PR+, HER-2+), HER-2 (ER-, PR-, HER-2+), triple-negative/basal (ER-, PR-, HER-2-). Patients on metformin had a lower proportion of T3 or T4 tumors than patients who were not receiving metformin (16% vs. 26%; p = 0.035). No statistical difference was found between the two study groups in N stage. Patients with DM on metformin, with DM not on metformin and the control group had different molecular subtypes of BC (p = 0.01): the luminal A subtype was found in 78%, 83% and 71%, the luminal B in 12.6%, 9% and 11%, HER-2 in 0.8%, 1.6% and 8%, and the triple-negative/basal-like subtype in 8.6%, 6.4% and 10%, respectively. Our data indicate that long-term use of metformin use correlates with molecular subtype of BC in diabetics on metformin in comparison to diabetics not on metformin and patients without DM. However, most likely, different distribution of the molecular subtypes of BC in these three groups of patients was caused by other risk factors for breast carcinoma, such as age of patients or obesity

  1. Long-term Metformin Use and Vitamin B12 Deficiency in the Diabetes Prevention Program Outcomes Study

    OpenAIRE

    Aroda, Vanita R.; Edelstein, Sharon L.; Goldberg, Ronald B.; Knowler, William C.; Marcovina, Santica M.; Orchard, Trevor J.; Bray, George A.; Schade, David S.; Temprosa, Marinella G.; White, Neil H.; Crandall, Jill P.

    2016-01-01

    Participants from DPP/DPPOS were assigned to placebo (n=1082) or metformin (n=1073) for 3.2 years, followed by metformin in the metformin group for 9 years. Metformin use was associated with increased risk of vitamin B12 deficiency.

  2. The effect of lansoprazole, an OCT inhibitor, on metformin pharmacokinetics in healthy subjects.

    Science.gov (United States)

    Ding, Yi; Jia, YanYan; Song, Ying; Lu, ChengTao; Li, YuWen; Chen, MinChun; Wang, MingMing; Wen, AiDong

    2014-02-01

    Gastro-esophageal reflux disease is common in patients with type 2 diabetes. A common treatment is the co-administration of proton-pump inhibitors (PPIs) and metformin. To date, however, the effects of co-administration of PPIs, which inhibit organic cation transporter (OCT) activity, on the action of metformin (a well-known substrate of OCTs) have not been clearly demonstrated. This was a randomized, double-blind, two-way crossover, placebo-controlled trial. Healthy male volunteers (n = 20) received metformin (single dose 1,000 mg on day 1 and single dose 750 mg on day 2, with a 12-h interval) co-administered with placebo or with lansoprazole (30 mg). Plasma concentrations of metformin were measured up to 24 h after the second dose. The glucose-lowering effects of metformin were evaluated by the oral glucose tolerance test before and after each single dose of metformin within the 2-day period. Lansoprazole increased the mean metformin maximum plasma concentration and area under the plasma concentration-time curve from zero to 24 h after the second dosing by 15 and 17 %, respectively (P lansoprazole prolonged the metformin elimination half-life from 3.9 to 4.5 h and decreased its renal clearance by 13 % (P lansoprazole had no effect on the maximum glucose level and the area under the serum glucose concentration-time curve of metformin. Collectively, we found a modest pharmacokinetic drug interaction between lansoprazole and metformin, which suggests that the concomitant use of these drugs should be appropriately monitored. Further studies are warranted to assess changes in metformin pharmacokinetics in patients with diabetes receiving long-term lansoprazole therapy.

  3. Unlicensed use of metformin in children and adolescents in the UK.

    Science.gov (United States)

    Hsia, Yingfen; Dawoud, Dalia; Sutcliffe, Alastair G; Viner, Russell M; Kinra, Sanjay; Wong, Ian C K

    2012-01-01

    Metformin is the most commonly prescribed oral anti-diabetic drug in young people. It is also prescribed for polycystic ovarian syndrome (PCOS) and obesity treatment in adults in an unlicensed fashion. Little is known as to the extent metformin has been used in young people. We investigated the use of metformin in children and adolescents aged 0-18 years in the UK. Population-based prescribing data were obtained from the UK IMS Disease Analyzer between January 2000 and December 2010. A total of 2674 metformin prescriptions were issued to 337 patients (80% female) between 2000 and 2010. The prevalence of metformin prescribing increased from 0.03 per 1000 person-years [95% confidence interval (CI) 0.02, 0.05] to 0.16 per 1000 person-years (95% CI 0.12, 0.20) (P= 0.001). There was a steady increase in metformin prescribing in girls aged 16-18 years. There were 290 metformin treated patients (81% female; n= 235) who had at least one diagnosis of diabetes, PCOS or obesity. Among these patients, PCOS was the most common indication for metformin prescribing in girls (n= 120) followed by diabetes. There were 22 patients (7.6%) who received metformin for obesity treatment only. Prescribing of metformin increased between 2000 and 2010, in particular amongst girls aged 16-18 years. The main indication for metformin prescribing was PCOS. At present, metformin is not licensed for PCOS and obesity treatment in adults or children. As there is a steady increase in the prescribing of metformin in young people, further studies are required to investigate the efficacy and safety of these prescriptions. © 2011 The Authors. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society.

  4. METFORMIN: A REVIEW OF THE LITERATURE

    OpenAIRE

    Rodrigues Neto, Edilson Martins; Universidade Federal do Ceará- Dep Fisiologia e Farmacologia/ Faculdade Católica Rainha do Sertão; Marques, Lidia Audrey Rocha Valadas; Universidade Federal do Ceará - Dep Clínica Odontológica; Ferreira, Maria Augusta Drago; Universidade Federal do Ceará - Dep Farmácia; Lobo, Patricia Leal Dantas; Universidade Federal do Ceará- Curso de Odontologia Campus Sobral; Girão Junior, Francisco Josimar; Faculdade Católica Rainha do Sertão; Camarão, Gisela Costa; Universidade Federal do Ceará- Dep. Fisiologia e Farmacologia; Moraes, Maria Elisabete Amaral de; Universidade Federal do Ceará- Dep. Fisiologia e Farmacologia

    2015-01-01

    Metformin, commercialized under several trademarks and also as a generic medicine, is an oral anti-diabetic drug, belonging to the biguanide class. It is actually the first choice in the treatment of Type 2 diabetes mellitus (DM2) due to its toxicity and clinical efficaciousness. It extensive use requires a constant discussion on its characteristics and applications. Current paper is a bibliographical review comprising the application of metformin in DM2 treatment as its chemical, physical-ch...

  5. Metabolic and other effects of pioglitazone as an add-on therapy to metformin in the treatment of polycystic ovary syndrome (PCOS).

    Science.gov (United States)

    Valsamakis, Georgios; Lois, Kostas; Kumar, Sudhesh; Mastorakos, George

    2013-01-01

    Insulin resistance is a key pathogenic defect of the clustered metabolic disturbances seen in polycystic ovary syndrome (PCOS). Metformin is an insulin sensitizer acting in the liver and the peripheral tissues that ameliorates the metabolic and reproductive defects in PCOS. In addition, pioglitazone is an insulin sensitizer used in diabetes mellitus type 2 (T2DM), improving insulin resistance (IR) in adipose tissue and muscles. In T2DM, these drugs are also used as a combined treatment due to their "add-on effect" on insulin resistance. Although the beneficial role of troglitazone (a member of the thiazolidinediones (TZDs) family) in PCOS has been shown in the past, currently only pioglitazone is available in the market. A few small randomized controlled trials have directly compared the effectiveness of pioglitazone in women with PCOS, while there are a limited number of small studies that support the beneficial metabolic add-on effect of pioglitazone on metformin-treated PCOS women as compared to metformin or pioglitazone monotherapy. These findings suggest a potentially promising role for combined pioglitazone/metformin treatment in the management of PCOS in metformin-resistant patients. In view of recent concerns regarding pioglitazone usage and its associated health risk, we aim to compare the pros and cons of each drug regarding their metabolic and other hormonal effects in women with PCOS and to explore the possible beneficial effect of combined therapy in certain cases, taking into consideration the teratogenic effect of pioglitazone. Finally, we discuss the need for a randomized controlled trial that will evaluate the metabolic and other hormonal effects of combined metformin/pioglitazone treatment in PCOS with selective treatment targets.

  6. A review of thiazolidinediones and metformin in the treatment of type 2 diabetes with focus on cardiovascular complications

    Science.gov (United States)

    Behzad, Molavi; Negah, Rassouli; Suveer, Bagwe; Neda, Rasouli

    2007-01-01

    The rising incidence of obesity and insulin resistance to epidemic proportions has closely paralleled the surge in the prevalence of diabetes and outpaced therapeutic advances in diabetes prevention and treatment. Current evidence points to obesity induced oxidative stress and chronic inflammation as the common denominators in the evolution of insulin resistance and diabetes. Of all the hypoglycemic agents in the pharmacological arsenal against diabetes, thiazolidinediones, in particular pioglitazone, as well as metformin appear to have additional effects in ameliorating oxidative stress and inflammation; rendering them attractive tools for prevention of insulin resistance and diabetes. In addition to their hypoglycemic and lipid modifying properties, pioglitazone and metformin have been shown to exert anti-oxidative and anti-inflammatory effects in vascular beds, potentially slowing the accelerated atherosclerosis in diabetes, which is the major cause of morbidity and mortality in the affected population. The combination of pioglitazone and metformin would thus appear to be an effective pharmacological intervention in prevention and treatment of diabetes. Finally, this review will address the currently available evidence on diabetic cardiomyopathy and the potential role of combination therapy with pioglitazone and metformin. PMID:18200815

  7. Pivmecillinam versus sulfamethizole for short-term treatment of uncomplicated acute cystitis in general practice

    DEFF Research Database (Denmark)

    Bjerrum, Lars; Gahrn-Hansen, Bente; Grinsted, Per

    2009-01-01

    Objective. To investigate whether short-term treatment with pivmecillinam was more effective than sulfamethizole in patients with acute uncomplicated urinary tract infection (UTI). Design. Randomized controlled trial. Setting. General practice, Denmark. Subjects. Patients (n =167) with uncomplica......Objective. To investigate whether short-term treatment with pivmecillinam was more effective than sulfamethizole in patients with acute uncomplicated urinary tract infection (UTI). Design. Randomized controlled trial. Setting. General practice, Denmark. Subjects. Patients (n =167......) with uncomplicated UTI confirmed by positive urine phase-contrast microscopy. Main outcome measures. Drug efficacy based on clinical and bacteriological cure. Results. Urinary symptoms disappeared first in patients treated with pivmecillinam, but after five days there was no significant difference in clinical cure...... in 68.8% of patients randomized to pivmecillinam and in 77.9% randomized to sulfamethizole (difference -9.2%, CI -24.7%; 6.3%). Some 26.8% of patients randomized to pivmecillinam experienced a new UTI within 6 months after treatment compared with 18.4% of patients randomized to sulfamethizole...

  8. Short-term progestagen treatment in ewes during the breeding season

    OpenAIRE

    Almeida, José Carlos; Simões, João; Valentim, Ramiro; Mascarenhas, R.; Fontes, Paulo; Azevedo, Jorge

    2006-01-01

    To characterize the efficiency of oestrus synchronization with short-term progestagen treatment (stFGA), 20 Ile de France (IF) and 19 Churra da Terra Quente (CTQ) ewes were used during the mid-breeding season. At day 0 (D0), a 40 mg FGA sponge was inserted in all animals and 120 µg cloprostenol was injected. Five days later (D5), all sponges were removed and ewes were divided into two groups: group A (10 IF and 10 CTQ), treated with eCG (250 UI) at sponge withdrawal and group II (10 IF and 9 ...

  9. Phase II study of medroxyprogesterone acetate plus metformin as a fertility-sparing treatment for atypical endometrial hyperplasia and endometrial cancer.

    Science.gov (United States)

    Mitsuhashi, A; Sato, Y; Kiyokawa, T; Koshizaka, M; Hanaoka, H; Shozu, M

    2016-02-01

    Metformin, widely used in the treatment of type 2 diabetes mellitus, reduces the risk of cancer and relapse after treatment. Fertility-sparing treatment for endometrial cancer (EC) with progestin is associated with a high chance of disease regression, and the high relapse rate continues to be a problem. We assessed the efficacy of metformin in preventing recurrence after medroxyprogesterone acetate (MPA) as fertility-sparing treatment for atypical endometrial hyperplasia (AEH) and EC. This phase II study enrolled 17 patients with AEH and 19 patients with EC limited to the endometrium (age, 20-40 years). MPA (400 mg/day) and metformin (750-2250 mg/day) were administered for 24-36 weeks to achieve a complete response (CR). Metformin was administered until conception, even after MPA discontinuation. The primary end point was relapse-free survival (RFS) after remission. We analyzed all efficacy end points in the full analysis set. The body mass index was ≥25 kg/m(2) in 27 patients (mean, 31 kg/m(2); range, 19-51 kg/m(2)), and the homeostasis model assessment for insulin resistance index was ≥2.5 in 24 patients (mean, 4.7; range, 0.7-21). Two patients showed progression at 12 weeks [6%; 95% confidence interval (CI) 2-18]. At 36 weeks, 29 (81%; 95% CI 65-90) patients achieved CR, and 5 (14%; 95% CI 6-29) patients achieved partial response. During a median follow-up of 38 months (range, 9-66 months) after remission, relapse was confirmed in three of the patients who had achieved CR (relapse rate, 10%). The 3-year estimated RFS rate was 89%. No patients experienced severe toxicity. Metformin inhibited disease relapse after MPA therapy. The combination of metformin and MPA in EC treatment should be studied further. UMIN 000002210. © The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  10. Metformin protects rat hepatocytes against bile acid-induced apoptosis.

    Directory of Open Access Journals (Sweden)

    Titia E Woudenberg-Vrenken

    Full Text Available BACKGROUND: Metformin is used in the treatment of Diabetes Mellitus type II and improves liver function in patients with non-alcoholic fatty liver disease (NAFLD. Metformin activates AMP-activated protein kinase (AMPK, the cellular energy sensor that is sensitive to changes in the AMP/ATP-ratio. AMPK is an inhibitor of mammalian target of rapamycin (mTOR. Both AMPK and mTOR are able to modulate cell death. AIM: To evaluate the effects of metformin on hepatocyte cell death. METHODS: Apoptotic cell death was induced in primary rat hepatocytes using either the bile acid glycochenodeoxycholic acid (GCDCA or TNFα in combination with actinomycin D (actD. AMPK, mTOR and phosphoinositide-3 kinase (PI3K/Akt were inhibited using pharmacological inhibitors. Apoptosis and necrosis were quantified by caspase activation, acridine orange staining and Sytox green staining respectively. RESULTS: Metformin dose-dependently reduces GCDCA-induced apoptosis, even when added 2 hours after GCDCA, without increasing necrotic cell death. Metformin does not protect against TNFα/ActD-induced apoptosis. The protective effect of metformin is dependent on an intact PI3-kinase/Akt pathway, but does not require AMPK/mTOR-signaling. Metformin does not inhibit NF-κB activation. CONCLUSION: Metformin protects against bile acid-induced apoptosis and could be considered in the treatment of chronic liver diseases accompanied by inflammation.

  11. Effects of sitagliptin and metformin treatment on incretin hormone and insulin secretory responses to oral and "isoglycemic" intravenous glucose

    DEFF Research Database (Denmark)

    Vardarli, Irfan; Arndt, Elisabeth; Deacon, Carolyn F

    2014-01-01

    ,000 mg/day), sitagliptin (100 mg/day), or their combination, on GLP-1 responses and on the incretin effect in 20 patients with type 2 diabetes, comparing an oral glucose challenge (75 g, day 5) and an "isoglycemic" intravenous glucose infusion (day 6). Fasting total GLP-1 was significantly increased...... by metformin and not changed by sitagliptin. After oral glucose, metformin increased and sitagliptin significantly decreased (by 53%) total GLP-1. Fasting and postload intact GLP-1 increased with sitagliptin but not with metformin. After oral glucose, only sitagliptin, but not metformin, significantly...... the numerical contribution of the incretin effect. Insulin secretion with sitagliptin treatment was similarly stimulated with oral and "isoglycemic" intravenous glucose. This points to an important contribution of small changes in incretin concentrations within the basal range or to additional insulinotropic...

  12. Readiness for change and short-term outcomes of female adolescents in residential treatment for anorexia nervosa.

    Science.gov (United States)

    McHugh, Matthew D

    2007-11-01

    To determine if readiness for change (RFC) at admission predicted length of stay (LOS) and short-term outcomes among female adolescents in residential treatment for anorexia nervosa (AN). Using a prospective cohort design to collect data from participants (N = 65) at admission and discharge, Kaplan-Meier survival analysis and Cox regression tested whether RFC on admission predicted time in LOS to a favorable short-term outcome--a composite endpoint based on minimum criteria for weight gain, drive for thinness, depression, anxiety, and health-related quality of life (HRQOL). Participants with low RFC had a mean survival time to a favorable short-term outcome of 59.4 days compared to 34.1 days for those with high RFC (log rank = 8.44, df = 1, p = .003). The probability of a favorable short-term outcome was 5.30 times greater for participants with high RFC. Readiness for change is a useful predictor of a favorable short-term outcome and should be considered in the assessment profile of patients with AN. (c) 2007 by Wiley Periodicals, Inc.

  13. Metformin poisoning: which therapy?

    Directory of Open Access Journals (Sweden)

    Ivo Casagranda

    2006-12-01

    Full Text Available Lactic acidosis is a rare but serious adverse effect in metformintreated- patients. The authors report a case of metformin-associated lactic acidosis and discuss the appropriated therapy. The patient was treated with bicarbonate iv and with two short dialysis session, also because of acute renal failure. Many authors do not agree with using bicarbonate, and about hemodialysis some authors suggest that the session should go on at least 12 hours. In this case the use of bicarbonate and short hemodialysis determinated a favourable outcame.

  14. Hypothalamus-Related Resting Brain Network Underlying Short-Term Acupuncture Treatment in Primary Hypertension

    Directory of Open Access Journals (Sweden)

    Hongyan Chen

    2013-01-01

    Full Text Available The present study attempted to explore modulated hypothalamus-seeded resting brain network underlying the cardiovascular system in primary hypertensive patients after short-term acupuncture treatment. Thirty right-handed patients (14 male were divided randomly into acupuncture and control groups. The acupuncture group received a continuous five-day acupuncture treatment and undertook three resting-state fMRI scans and 24-hour ambulatory blood pressure monitoring (ABPM as well as SF-36 questionnaires before, after, and one month after acupuncture treatment. The control group undertook fMRI scans and 24-hour ABPM. For verum acupuncture, average blood pressure (BP and heart rate (HR decreased after treatment but showed no statistical differences. There were no significant differences in BP and HR between the acupuncture and control groups. Notably, SF-36 indicated that bodily pain (P = 0.005 decreased and vitality (P = 0.036 increased after acupuncture compared to the baseline. The hypothalamus-related brain network showed increased functional connectivity with the medulla, brainstem, cerebellum, limbic system, thalamus, and frontal lobes. In conclusion, short-term acupuncture did not decrease BP significantly but appeared to improve body pain and vitality. Acupuncture may regulate the cardiovascular system through a complicated brain network from the cortical level, the hypothalamus, and the brainstem.

  15. The effect of metformin on glucose homeostasis during moderate exercise

    DEFF Research Database (Denmark)

    Hansen, Merethe; Palsøe, Marie K.; Helge, Jørn Wulff

    2015-01-01

    OBJECTIVE: We investigated the role of metformin on glucose kinetics during moderate exercise. RESEARCH DESIGN AND METHODS: Before, during, and after a 45-min bout of exercise at 60% VO2max, glucose kinetics were determined by isotope tracer technique in patients with type 2 diabetes mellitus....... CONCLUSIONS: Metformin has a positive effect on glucose homeostasis during exercise....... with metformin treatment (DM2+Met) or without metformin treatment (DM2) and in healthy control subjects (CON) matched for BMI and age. Glucoregulatory hormones and metabolites were measured throughout the study. RESULTS: Plasma glucose concentration was unchanged during exercise in CON but decreased in DM2...

  16. Endogenous glucose production increases in response to metformin treatment in the glycogen-depleted state in humans

    DEFF Research Database (Denmark)

    Christensen, Mette Marie H; Højlund, Kurt; Hother-Nielsen, Ole

    2015-01-01

    with or without prior treatment with 1 g metformin twice daily. Participants were recruited from the Pharmacogenomics Biobank of the University of Southern Denmark. Treatment allocation was generated by the Good Clinical Practice Unit, Odense University Hospital, Denmark. Variables of whole-body glucose...

  17. Long-term effects of lifestyle intervention or metformin on diabetes development and microvascular complications over 15-year follow-up: the Diabetes Prevention Program Outcomes Study.

    Science.gov (United States)

    2015-11-01

    Effective prevention is needed to combat the worldwide epidemic of type 2 diabetes. We investigated the long-term extent of beneficial effects of lifestyle intervention and metformin on diabetes prevention, originally shown during the 3-year Diabetes Prevention Program (DPP), and assessed whether these interventions reduced diabetes-associated microvascular complications. The DPP (1996-2001) was a randomised trial comparing an intensive lifestyle intervention or masked metformin with placebo in a cohort selected to be at very high risk of developing diabetes. All participants were offered lifestyle training at the end of the DPP. 2776 (88%) of the surviving DPP cohort were followed up in the DPP Outcomes Study (DPPOS, Sept 1, 2002, to Jan 2, 2014) and analysed by intention to treat on the basis of their original DPP assignment. During DPPOS, the original lifestyle intervention group was offered lifestyle reinforcement semi-annually and the metformin group received unmasked metformin. The primary outcomes were the development of diabetes and the prevalence of microvascular disease. For the assessment of microvascular disease, we used an aggregate microvascular outcome, composed of nephropathy, retinopathy, and neuropathy. During a mean follow-up of 15 years, diabetes incidence was reduced by 27% in the lifestyle intervention group (hazard ratio 0·73, 95% CI 0·65-0·83; pdiabetes were 55% in the lifestyle group, 56% in the metformin group, and 62% in the placebo group. The prevalences at the end of the study of the aggregate microvascular outcome were not significantly different between the treatment groups in the total cohort (placebo 12·4%, 95% CI 11·1-13·8; metformin 13·0%, 11·7-14·5; lifestyle intervention 11·3%, 10·1-12·7). However, in women (n=1887) the lifestyle intervention was associated with a lower prevalence (8·7%, 95% CI 7·4-10·2) than in the placebo (11·0%, 9·6-12·6) and metformin (11·2%, 9·7-12·9) groups, with reductions in the

  18. Effect of Long-Term Metformin and Lifestyle in the Diabetes Prevention Program and Its Outcome Study on Coronary Artery Calcium.

    Science.gov (United States)

    Goldberg, Ronald B; Aroda, Vanita R; Bluemke, David A; Barrett-Connor, Elizabeth; Budoff, Matthew; Crandall, Jill P; Dabelea, Dana; Horton, Edward S; Mather, Kieren J; Orchard, Trevor J; Schade, David; Watson, Karol; Temprosa, Marinella

    2017-07-04

    Despite the reduced incidence of coronary heart disease with intensive risk factor management, people with diabetes mellitus and prediabetes remain at increased coronary heart disease risk. Diabetes prevention interventions may be needed to reduce coronary heart disease risk. This approach was examined in the DPP (Diabetes Prevention Program) and the DPPOS (Diabetes Prevention Program Outcome Study), a long-term intervention study in 3234 subjects with prediabetes (mean±SD age, 64±10 years) that showed reduced diabetes risk with lifestyle and metformin compared with placebo over 3.2 years. The DPPOS offered periodic group lifestyle sessions to all participants and continued metformin in the originally randomized metformin group. Subclinical atherosclerosis was assessed in 2029 participants with coronary artery calcium (CAC) measurements after an average of 14 years of follow-up. The CAC scores were analyzed continuously as CAC severity and categorically as CAC presence (CAC score >0) and reported separately in men and women. There were no CAC differences between lifestyle and placebo intervention groups in either sex. CAC severity and presence were significantly lower among men in the metformin versus the placebo group (age-adjusted mean CAC severity, 39.5 versus 66.9 Agatston units, P =0.04; CAC presence, 75% versus 84%, P =0.02), but no metformin effect was seen in women. In multivariate analysis, the metformin effect in men was not influenced by demographic, anthropometric, or metabolic factors; by the development of diabetes mellitus; or by use/nonuse of statin therapy. Metformin may protect against coronary atherosclerosis in prediabetes and early diabetes mellitus among men. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00038727. © 2017 American Heart Association, Inc.

  19. LSD treatment in Scandinavia: emphasizing indications and short-term treatment outcomes of 151 patients in Denmark.

    Science.gov (United States)

    Larsen, Jens Knud

    2017-10-01

    New research has suggested the clinical use of lysergic acid diethylamide (LSD) and psilocybin in selected patient populations. However, concerns about the clinical use of LSD were advanced in a large Danish follow-up study that assessed 151 LSD-treated psychiatric patients approximately 25 years after their treatment in the 1960s. The purpose of the present study was to give a retrospective account of the short-term outcome of LSD treatment in these 151 Danish psychiatric patients. The LSD case material in the Danish State Archives consists of medical case records of 151 LSD-treated patients, who complained and received economic compensation with the LSD Damages Law. The author carefully read and reviewed the LSD case material. LSD was used to treat a wide spectrum of mental disorders. Independent of diagnoses, 52 patients improved, and 48 patients worsened acutely with the LSD treatment. In a subgroup of 82 neurotic patients, the LSD dose-index (number of treatments multiplied by the maximal LSD dose) indicated the risk of acute worsening. In another subgroup of 19 patients with obsessive-compulsive neurosis, five patients later underwent psychosurgery. A small subgroup of 12 patients was treated with psilocybin. The long-term outcome was poor in most of the patients. Despite the significant limitations to a retrospective design, this database warrants caution in mental health patients. The use of LSD and psilocybin in mental health patients may be associated with serious short- and long-term side effects. Until further trials with rigorous designs have cleared these drugs of their potential harms, their clinical utility in these groups of patients has not been fully clarified.

  20. Repaglinide/metformin fixed-dose combination to improve glycemic control in patients with type 2 diabetes: an update

    Directory of Open Access Journals (Sweden)

    Robert G Moses

    2010-05-01

    Full Text Available Robert G MosesClinical Trials and Research Unit, South East Sydney and Illawarra Area Health Service, New South Wales, AustraliaAbstract: Type 2 diabetes is a progressive disease associated with high levels of morbidity and mortality and for which there is both a large and growing prevalence worldwide. Lifestyle advice plus metformin is commonly recommended initially to manage hyperglycemia and to minimize the risk of vascular complications. However, additional agents are required when glycemic targets cannot be achieved or maintained due to the progressive nature of the disease. Repaglinide/metformin fixed-dose combination (FDC therapy (PrandiMet®; Novo Nordisk, Bagsværd, Denmark has been approved for use in the USA. This FDC is a rational second-line therapy given the complementary mechanisms of action of the components. Repaglinide is a rapidly absorbed, short-acting insulin secretagogue targeting postprandial glucose excursions; metformin is an insulin sensitizer with a longer duration of action that principally regulates basal glucose levels. A pivotal, 26-week, randomized study with repaglinide/metformin FDC therapy has been conducted in patients experiencing suboptimal control with previous oral antidiabetes therapy. Repaglinide/metformin FDC improved glycemic control and weight neutrality without adverse effects on lipid profiles. There were no major hypoglycemic episodes and patients expressed greater satisfaction with repaglinide/metformin FDC than previous treatments. Repaglinide/metformin FDC is expected to be more convenient than individual tablets for patients taking repaglinide and metformin in loose combination, and it is expected to improve glycemic control in patients for whom meglitinide or metformin monotherapies provide inadequate control.Keywords: type 2 diabetes, metformin, repaglinide, PrandiMet®, fixed-dose combination

  1. IGF-1R and Leptin Expression Profile and the Effects of Metformin Treatment on Metabolic and Endocrine Parameters in PCOS Mice

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    Luis Eduardo Prado Correia

    2017-01-01

    Full Text Available We aim to assess the effects of metformin treatment on metabolic and endocrine parameters and genes expression related to the insulin-responsive pathway in polycystic ovary syndrome (PCOS. This study comprises twenty-eight obese mice divided into three metformin-treated groups for seven and twenty days and eight nonobese and nontreated ones. We found a significant decrease in glycemia after metformin treatment at days seven and twenty. However, we did not observe differences in body weight measurement. Histologically, after twenty days we observed follicular development with regression of androgenic effects. Levels of IGF-1R protein expression were low after twenty days of treatment, but LEP proteins showed an overexpression in the ovarian stroma. We assessed the IGF-1R and LEP mRNAs levels; data showed a significant overexpression of LEP after seven days of treatment, while the IGF-1R was downregulated. Metformin therapy seems to exert a beneficial effect on histological and anovulatory features, reducing follicular number and pyknosis formation, possibly involved in the reversion of androgenic stimulus. Expression of IGF-1 and LEPR indicates a relevant role in androgenic features reversion present in PCOS, hormonal equilibrium, body weight regulation, and glucose metabolism, therefore, under phenotype obesity and infertility regulation in this model.

  2. Treatment update: thiazolidinediones in combination with metformin for the treatment of type 2 diabetes

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    John M Stafford

    2007-10-01

    Full Text Available John M Stafford1, Tom Elasy21Division of Diabetes Endocrinology and Metabolism, Vanderbilt University; 2Vanderbilt Eskind Diabetes Clinic, Vanderbilt University Medical CenterAbstract: Type 2 diabetes mellitus (DM2 is characterized by excessive hepatic gluconeogenesis, increased insulin resistance and a progressive inability of pancreatic beta cells to produce sufficient insulin. DM2 evolves as a progression from normal glucose tolerance, to impaired glucose tolerance (IGT to frank diabetes mellitus, reflecting the establishment of insulin resistance and beta cell dysfunction. Insulin resistance not only contributes to impaired glycemic control in DM2, but to the development of hypertension, dyslipidemia and endothelial dysfunction. Cardiovascular disease is the primary morbidity for patients with DM2. The onset of insulin resistance and cardiovascular insult likely occurs well before the onset of IGT is detected clinically. Biguanides and thiazolidinediones (TZDs are two classes of oral agents for the management of DM2 that improve insulin resistance, and thus have potential cardiovascular benefits beyond glycemic control alone. Metformin additionally inhibits hepatic gluconeogenesis. The combined use of two of these agents targets key pathophysiologic defects in DM2. Single pill combinations of rosiglitazone/metformin and pioglitazone/metformin have recently been approved for use in the US and Europe. This article reviews the clinical data behind the use of metformin in combination with TZDs for the management of diabetes, its impact on vascular health, side effects and potential mechanisms of action for combined use.Keywords: thiazolidinediones; metformin; Type 2 diabetes

  3. Treatment update: thiazolidinediones in combination with metformin for the treatment of type 2 diabetes

    Directory of Open Access Journals (Sweden)

    John M Stafford

    2007-09-01

    Full Text Available John M Stafford1, Tom Elasy21Division of Diabetes Endocrinology and Metabolism, Vanderbilt University; 2Vanderbilt Eskind Diabetes Clinic, Vanderbilt University Medical CenterAbstract: Type 2 diabetes mellitus (DM2 is characterized by excessive hepatic gluconeogenesis, increased insulin resistance and a progressive inability of pancreatic beta cells to produce sufficient insulin. DM2 evolves as a progression from normal glucose tolerance, to impaired glucose tolerance (IGT to frank diabetes mellitus, reflecting the establishment of insulin resistance and beta cell dysfunction. Insulin resistance not only contributes to impaired glycemic control in DM2, but to the development of hypertension, dyslipidemia and endothelial dysfunction. Cardiovascular disease is the primary morbidity for patients with DM2. The onset of insulin resistance and cardiovascular insult likely occurs well before the onset of IGT is detected clinically. Biguanides and thiazolidinediones (TZDs are two classes of oral agents for the management of DM2 that improve insulin resistance, and thus have potential cardiovascular benefits beyond glycemic control alone. Metformin additionally inhibits hepatic gluconeogenesis. The combined use of two of these agents targets key pathophysiologic defects in DM2. Single pill combinations of rosiglitazone/metformin and pioglitazone/metformin have recently been approved for use in the US and Europe. This article reviews the clinical data behind the use of metformin in combination with TZDs for the management of diabetes, its impact on vascular health, side effects and potential mechanisms of action for combined use.Keywords: thiazolidinediones; metformin; Type 2 diabetes

  4. Changes of β-cell function after short-term transient intensive insulin treatment in newly diagnosed type 2 diabetes patients

    International Nuclear Information System (INIS)

    Tian Xiaoping; Zhuang Huiqin; Su Cainu; Xu Ning; Yin Dong; Hui Yuan; Wu Yan

    2007-01-01

    To evaluate the effect of short-term intensive insulin treatment on β-cell function in newly diagnosed type 2 diabetes patients with apparently hyperglycemia, twenty-four newly diagnosed type 2 diabetes patients with FPG more than 12.0 mmol/L were treated by short-term transient intensive insulin in average 9.04-4.8 days. Their β-cell function was assessed by oral glucose tolerance test. The FPG, HbAlc and HOMA IR of patients were significantly decreased (P<0.01), while the insulin, the Area Under Curve (AUC) of insulin and HOMA β were significantly increased (P<0.01) after the treatment with insulin. Improvement of β-cell function can be induced by short-term intensive insulin treatment for newly diagnosed type 2 diabetes patients with apparently hyperglycemia. (authors)

  5. Anti-tumor activity of metformin: from metabolic and epigenetic perspectives

    Science.gov (United States)

    Zhai, Yansheng; Tong, Chong; Liu, Min; Ma, Lixin; Yu, Xiaolan; Li, Shanshan

    2017-01-01

    Metformin has been used to treat type 2 diabetes for over 50 years. Epidemiological, preclinical and clinical studies suggest that metformin treatment reduces cancer incidence in diabetes patients. Due to its potential as an anti-cancer agent and its low cost, metformin has gained intense research interest. Its traditional anti-cancer mechanisms involve both indirect and direct insulin-dependent pathways. Here, we discussed the anti-tumor mechanism of metformin from the aspects of cell metabolism and epigenetic modifications. The effects of metformin on anti-cancer immunity and apoptosis were also described. Understanding these mechanisms will shed lights on application of metformin in clinical trials and development of anti-cancer therapy. PMID:27902459

  6. Cerebral hemodynamics and systemic endothelial function are already impaired in well-controlled type 2 diabetic patients, with short-term disease.

    Directory of Open Access Journals (Sweden)

    Paola Palazzo

    Full Text Available Impaired cerebral vasomotor reactivity (VMR and flow-mediated dilation (FMD were found in selected subgroups of type 2 diabetes mellitus (T2DM patients with long-term disease. Our study aimed to evaluate cerebral hemodynamics, systemic endothelial function and sympatho-vagal balance in a selected population of well-controlled T2DM patients with short-term disease and without cardiac autonomic neuropathy (CAN.Twenty-six T2DM patients with short-term (4.40±4.80 years and well-controlled (HbA1C = 6.71±1.29% disease, without any complications, treated with diet and/or metformin, were consecutively recruited. Eighteen controls, comparable by sex and age, were enrolled also.FMD and shear rate FMD were found to be reduced in T2DM subjects with short-term disease (8.5% SD 3.5 and 2.5 SD 1.3, respectively compared to controls (15.4% SD 4.1 and 3.5 SD 1.4; p.05.In well-controlled T2DM patients with short-term disease cerebral hemodynamics and systemic endothelial function are altered while autonomic balance appeared to be preserved.

  7. The role of metformin in ovulation induction: Current status

    Directory of Open Access Journals (Sweden)

    Aboubakr Mohamed Elnashar

    2011-09-01

    Full Text Available To define the exact role of metformin in ovulation induction, it is crucial to distinguish three different indications: naïve PCOS, CC-resistant PCOS and ART. In naïve PCOS: metformin as compared to placebo has been shown to improve ovulation rates, but metformin did not exert significant advantage over CC with respect to cumulative ovulation, pregnancy or live-birth rates. The combined approach of metformin plus CC is not better than CC or metformin monotherapy in naïve PCOS. In CC-resistant patients: metformin has no benefit over placebo in ovulation, pregnancy, and live-birth rates as a single agent, but the combination of metformin and CC significantly improved ovulation and pregnancy rates when compared with CC alone. However, combined therapy did not improve the odds of live birth. Metformin pretreatment improves the efficacy of CC in PCOS patients with CC resistance. In PCOS patients scheduled for ART: metformin addition to gonadotropins reduces the duration of gonadotropins administration and the doses of gonadotropins required, and increases the rate of monoovulations, reducing the risk of cancelled cycles. Metformin co-administration to IVF treatment does not improve pregnancy or live-birth rates but reduces the risk of OHSS.

  8. Metformin: from mechanisms of action to advanced clinical use

    Directory of Open Access Journals (Sweden)

    Miodrag Janić

    2017-04-01

    Full Text Available Metformin represents the first line of treatment and is the most widely prescribed antihypergycemic drug in type 2 diabetic patients. It can be used as monotherapy or in combination with other oral antihyperglycemic drugs or insulin. Additionally, it is also prescribed in type 1 diabetic patients, it proved to be effective in prediabetes and also provided beneficial effects in other insulin resistant states, for example in polycystic ovary syndrome. Nevertheless, the exact molecular mechanism of its action remains unknown. It was shown that it inhibits liver gluconeogenesis, facilitates glucose uptake into peripheral tissues, such as striated muscle; it also acts in the gut. Besides antihyperglycemic effects, metformin was also shown to possess several beneficial, protective effects, so-called pleiotropic effects: particularly on the cardiovascular system and in cancer patients. Metformin has only few side effects, the most serious being metformin-associated lactic acidosis. The latter appears in rare clinical cases with pre-existing chronic kidney disease or advanced heart failure with tissue hypoperfusion, which consequently represent relative contraindications for metformin use. In the past, metformin treatment was usually discontinued when performing iodine contrast imaging, however recently there is evidence of its safety even in patients with higher stages of chronic kidney disease. All in all, metformin is a drug with a long tradition and a promising future.

  9. Impact of long-term and short-term therapies on seminal parameters

    Directory of Open Access Journals (Sweden)

    Jlenia Elia

    2013-04-01

    Full Text Available Aim: The aim of this work was: i to evaluate the prevalence of male partners of subfertile couples being treated with long/short term therapies for non andrological diseases; ii to study their seminal profile for the possible effects of their treatments on spermatogenesis and/or epididymal maturation. Methods: The study group was made up of 723 subjects, aged between 25 and 47 years. Semen analysis was performed according to World Health Organization (WHO guidelines (1999. The Superimposed Image Analysis System (SIAS, which is based on the computerized superimposition of spermatozoa images, was used to assess sperm motility parameters. Results: The prevalence of subjects taking pharmacological treatments was 22.7% (164/723. The prevalence was 3.7% (27/723 for the Short-Term Group and 18.9% (137/723 for the Long-Term Group. The subjects of each group were also subdivided into subgroups according to the treatments being received. Regarding the seminal profile, we did not observe a significant difference between the Long-Term, Short-Term or the Control Group. However, regarding the subgroups, we found a significant decrease in sperm number and progressive motility percentage in the subjects receiving treatment with antihypertensive drugs compared with the other subgroups and the Control Group. Conclusions: In the management of infertile couples, the potential negative impact on seminal parameters of any drugs being taken as Long-Term Therapy should be considered. The pathogenic mechanism needs to be clarified.

  10. The anti-diabetic drug metformin protects against chemotherapy-induced peripheral neuropathy in a mouse model.

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    Qi-Liang Mao-Ying

    Full Text Available Chemotherapy-induced peripheral neuropathy (CIPN characterized by loss of sensory sensitivity and pain in hands and feet is the major dose-limiting toxicity of many chemotherapeutics. At present, there are no FDA-approved treatments for CIPN. The anti-diabetic drug metformin is the most widely used prescription drug in the world and improves glycemic control in diabetes patients. There is some evidence that metformin enhances the efficacy of cancer treatment. The aim of this study was to test the hypothesis that metformin protects against chemotherapy-induced neuropathic pain and sensory deficits. Mice were treated with cisplatin together with metformin or saline. Cisplatin induced increased sensitivity to mechanical stimulation (mechanical allodynia as measured using the von Frey test. Co-administration of metformin almost completely prevented the cisplatin-induced mechanical allodynia. Co-administration of metformin also prevented paclitaxel-induced mechanical allodynia. The capacity of the mice to detect an adhesive patch on their hind paw was used as a novel indicator of chemotherapy-induced sensory deficits. Co-administration of metformin prevented the cisplatin-induced increase in latency to detect the adhesive patch indicating that metformin prevents sensory deficits as well. Moreover, metformin prevented the reduction in density of intra-epidermal nerve fibers (IENFs in the paw that develops as a result of cisplatin treatment. We conclude that metformin protects against pain and loss of tactile function in a mouse model of CIPN. The finding that metformin reduces loss of peripheral nerve endings indicates that mechanism underlying the beneficial effects of metformin includes a neuroprotective activity. Because metformin is widely used for treatment of type II diabetes, has a broad safety profile, and is currently being tested as an adjuvant drug in cancer treatment, clinical translation of these findings could be rapidly achieved.

  11. Metformin in gestational diabetes: An emerging contender

    Directory of Open Access Journals (Sweden)

    Awadhesh Kumar Singh

    2015-01-01

    Full Text Available Gestational diabetes mellitus (GDM is defined as any degree of glucose intolerance occurring first time during pregnancy. Its prevalence is simultaneously increasing with the global rise of diabesity. GDM commonly develops, when maternal glucose metabolism is unable to compensate for the progressive development of insulin resistance, arising primarily from the consistently rising diabetogenic placental hormones. It classically develops during the second or third trimester. Theoretically, insulin sensitizers should have been the ideal agent in its treatment, given the insulin resistance, the major culprit in its pathogenesis. Fortunately, majority of women can be treated satisfactorily with lifestyle modification, and approximately 20% requires more intensive treatment. For several decades, insulin has been the most reliable treatment strategy and the gold standard in GDM. Metformin is effective insulin sensitizing agent and an established first line drug in type 2 diabetes currently. As it crosses the placenta, a safety issue remains an obstacle and, therefore, metformin is currently not recommended in the treatment of GDM. Nevertheless, given the emerging clinically equivalent safety and efficacy data of metformin compared to insulin, it appears that it may perhaps open a rather new door in managing GDM. The aim of this review is to critically analyze, the safety and efficacy data of metformin regarding its use in GDM and pregnant mothers with polycystic ovarian disease, which has emerged in past decades.

  12. The effect of metformin treatment on the serum levels of homocysteine, folic acid, and vitamin B12 in patients with polycystic ovary syndrome

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    Sedigheh Esmaeilzadeh

    2017-01-01

    Full Text Available Background and Objective: Hyperhomocysteinemia is a well-known risk factor for cardiovascular disease. Although metformin therapy can increase homocysteine (Hcy levels, it frequently is used as an oral medicine in women with polycystic ovary syndrome (PCOS, who might be at risk of catching diabetes mellitus. The aim of this study was to investigate the effect of metformin on the levels of serum Hcy, vitamin B12 (vit B12, and folic acid in patients with PCOS. Materials and Methods: An interventional study was designed with 18 patients with PCOS at the Fatemehzahra infertility Hospital in Babol, Iran. Metformin treatment (500 mg twice daily was initiated in all patients for a period of consecutive 6 months. The levels of serum Hcy, vit B12, and folic acid were measured in the participants before and after metformin treatment. Results: The mean vit B12 level showed a significant decrease in patients after 6 months of metformin treatment (P = 0.002. However, there was no significant difference in serum folic acid levels. The mean Hcy levels increased after treatment, but this difference not was statistically significant. When patients were stratified into four subgroups by their insulin sensitivity and body mass index (BMI, relatively similar results were obtained in the subgroups, except that Hcy levels in the overweight/obesity group (BMI > 25 kg/m2 after treatment showed a significant increase (P = 0.01. Conclusion: These findings indicate that metformin increases the serum Hcy concentration in patients with PCOS especially in the women with BMI > 25 kg/m2. The possible mechanism for this effect would be the obvious reduction in the levels of vit B12.

  13. Clinical profile of congenital adrenal hyperplasia and short-term response to treatment

    International Nuclear Information System (INIS)

    Lal, S.; Lal, S.; Jamro, B.U.; Jamro, S.

    2015-01-01

    To determine the clinical presentation of congenital adrenal hyperplasia and short- term response to treatment. Background: Congenital adrenal hyperplasia (CAH) is a genetic disorder which usually presents with life threatening emergencies. Awareness of physicians regarding these presentations is an essential for early diagnosis and lifesaving treatment. In view of the prevalence of the condition as reported from tertiary care centers within the country and other parts of the globe, we had carried out a study in the paediatric department of Shaheed Mohtrama Benazir Bhutto Medical University Larkana. Material and Methods: The study was conducted over a period of one year from July 2012 to June 2013. All infants presenting with vomiting, dehydration, shock, failure to thrive and ambiguous genitalia were examined and investigated thoroughly. The diagnosis was based upon a raised level of serum 17 OHP in a child with suggestive clinical features. Results: A total of 40 children were diagnosed to have CAH during the study period. The major presenting features were vomiting in 13 (32.5%), ambiguous genitalia 17 (42.5%), vomiting and ambiguous genitalia 10 (25%), shock 5(12.5%) and failure to thrive in 13 (32.5%) of cases. All the patients were followed up after initiation of treatment and good response was observed to short-term treatment. Conclusion: This study highlights the importance of common clinical features like vomiting, unreasonable dehydration, shock and ambiguous genitalia being the presenting features of CAH and the effectiveness of replacement therapy in amending life threatening emergencies due to this condition. (author)

  14. Intracerebroventricular metformin attenuates salt-induced hypertension in spontaneously hypertensive rats

    DEFF Research Database (Denmark)

    Petersen, J S; Andersen, D; Muntzel, M S

    2001-01-01

    The aim of this study was to examine the effects of long-term continuous intracerebroventricular (icv) infusion of metformin on blood pressure (BP) in spontaneously hypertensive rats (SHR). To accelerate the development of hypertension, SHR were fed a 8% NaCl diet during the 3-week study period...... to hexamethonium was attenuated by all doses of metformin suggesting that chronic icv metformin decreased central sympathetic outflow. The highest doses of metformin (100 and 200 microg/day) also prevented development of hypertension, but these doses were highly neurotoxic as demonstrated by histologic evaluation...... doses of metformin attenuates hypertension and decreases the hypotensive responses to ganglionic blockade in SHR, suggesting a centrally elicited sympathoinhibitory action....

  15. Metformin in reproductive health, pregnancy and gynaecological cancer: established and emerging indications.

    Science.gov (United States)

    Sivalingam, Vanitha N; Myers, Jenny; Nicholas, Susie; Balen, Adam H; Crosbie, Emma J

    2014-01-01

    Metformin is an effective oral anti-hyperglycaemic drug used as first-line medical treatment for type 2 diabetes. It improves systemic hyperglycaemia by reducing hepatic glucose production and enhancing peripheral insulin sensitivity. It also stimulates fat oxidation and reduces fat synthesis and storage. The molecular mechanism of this drug is thought to be secondary to its actions on the mitochondrial respiratory chain. This paper reviews the relevant literature (research articles up to October 2013) on the use of metformin in infertility, polycystic ovary syndrome (PCOS), pregnancy and gynaecological cancers. We present a comprehensive discussion of the evidence supporting the efficacy of metformin in these clinical conditions. Metformin is used clinically off-label in the management of hirsutism, acne and insulin resistance in PCOS, although the evidence for anti-androgenic effects is inconsistent. Metformin is also used to improve ovulation in women with PCOS both alone and in combination with clomiphene citrate. Trial findings are conflicting but metformin treatment in IVF/ICSI cycles may reduce the risk of ovarian hyperstimulation syndrome and increase live birth rates. Metformin also appears to be effective and safe for the treatment of gestational diabetes mellitus (GDM), particularly for overweight and obese women. Studies have shown that metformin is safe in pregnancy and women with GDM treated with metformin have less weight gain during pregnancy than those treated with insulin. One study with a 2-year follow-up demonstrated that babies born to women treated with metformin also developed less visceral fat, making them less prone to insulin resistance in later life. These findings have sparked interest in the use of metformin for pregnant, obese, non-diabetic women. On-going clinical trials are underway to determine if women treated prophylactically with metformin have a reduced incidence of GDM and demonstrate less weight gain during pregnancy. The

  16. Toxicity and toxicokinetics of metformin in rats

    International Nuclear Information System (INIS)

    Quaile, Michael P.; Melich, David H.; Jordan, Holly L.; Nold, James B.; Chism, Jack P.; Polli, Joseph W.; Smith, Glenn A.; Rhodes, Melissa C.

    2010-01-01

    Metformin is a first-line drug for the treatment of type 2 diabetes (T2D) and is often prescribed in combination with other drugs to control a patient's blood glucose level and achieve their HbA1c goal. New treatment options for T2D will likely include fixed dose combinations with metformin, which may require preclinical combination toxicology studies. To date, there are few published reports evaluating the toxicity of metformin alone to aid in the design of these studies. Therefore, to understand the toxicity of metformin alone, Crl:CD(SD) rats were administered metformin at 0, 200, 600, 900 or 1200 mg/kg/day by oral gavage for 13 weeks. Administration of ≥ 900 mg/kg/day resulted in moribundity/mortality and clinical signs of toxicity. Other adverse findings included increased incidence of minimal necrosis with minimal to slight inflammation of the parotid salivary gland for males given 1200 mg/kg/day, body weight loss and clinical signs in rats given ≥ 600 mg/kg/day. Metformin was also associated with evidence of minimal metabolic acidosis (increased serum lactate and beta-hydroxybutyric acid and decreased serum bicarbonate and urine pH) at doses ≥ 600 mg/kg/day. There were no significant sex differences in mean AUC 0-24 or C max nor were there significant differences in mean AUC 0-24 or C max following repeated dosing compared to a single dose. The no observable adverse effect level (NOAEL) was 200 mg/kg/day (mean AUC 0-24 = 41.1 μg h/mL; mean C max = 10.3 μg/mL based on gender average week 13 values). These effects should be taken into consideration when assessing potential toxicities of metformin in fixed dose combinations.

  17. Efficiency and safety of transfer of type 2 diabetes patients inadequately controlled on metformin alone to combined therapy with metformin and diabeton MB

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    Alexander Sergeevich Ametov

    2009-12-01

    Full Text Available Aim. To evaluate efficiency and tolerability of diabeton MB/metformin combination in patients failing to achieve optimal glycemic control when onmetformin monotherapy and prove advantages of this combination over combined low-dose therapy with glibenclamide and metformin. Materials and methods. The study included 464 patients with type 2 diabetes mellitus who poorly responded to metformin monotherapy. It was supplementedby diabeton MB. Efficiency and tolerability of combined treatment was evaluated from dynamics of glycemia and frequency of side-effects.40 patients were included in detailed comparative assessment (laboratory and instrumental, CGMS of this monotherapy and fixed low-dose combinationof glibenclamide with metformin. Results. Results of comparison show that diabeton MB/metformin combination ensured most optimal glycemic control with a minimal risk of side effects. Conclusion. Diabeton MB/metformin combination is convenient, efficient and safe.

  18. Treatment progression in sulfonylurea and dipeptidyl peptidase-4-inhibitor cohorts of type 2 diabetes patients on metformin

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    Peng X

    2016-08-01

    Full Text Available Xiaomei Peng, Dingfeng Jiang, Dongju Liu, Oralee J Varnado, Jay P Bae Eli Lilly and Company, Global Patient Outcomes and Real World Evidence, Indianapolis, IN, USA Background: Metformin is an oral antidiabetic drug (OAD widely used as first-line therapy in type 2 diabetes (T2D treatments. Numerous treatment pathways after metformin failure exist. It is important to understand how treatment choices influence subsequent therapy progressions. This retrospective study compares adherence to, persistence with, and treatment progression in sulfonylurea (SU and dipeptidyl peptidase-4 (DPP-4 inhibitor patient cohorts with T2D on metformin. Methods: Using health insurance claims data, matched patient cohorts were created and OAD use was compared in patients with T2D initiating SU or DPP-4 inhibitors (index drugs since January 1, 2010, to December 31, 2010, with background metformin therapy. Propensity score matching adjusted for possible selection bias. Persistence was measured via Cox regression as days to a ≥60-day gap in index drug possession; adherence was defined as proportion of days covered (PDC ≥80%. Evolving treatment patterns were traced at 6-month intervals for 24 months following index drug discontinuation. Results: From among 19,621 and 7,484 patients in the SU and DPP-4 inhibitor cohorts, respectively, 6,758 patient pairs were matched. Persistence at 12 months in the SU cohort was 48.0% compared to 52.5% for the DPP-4 inhibitor cohort. PDC adherence (mean [SD] during the 12-month follow-up period was 63.3 (29.7 for the SU cohort and 65.5 (28.7 for the DPP-4 inhibitor cohort. PDC ≥80% was 40.5% and 43.4% in the SU and DPP-4 inhibitor cohorts, respectively. A higher percentage of patients in the SU cohort remained untreated. Following index drug discontinuation, monotherapy was more common in the SU cohort, while use of two or three OADs was more common in the DPP-4 inhibitor cohort. Insulin therapy initiation was higher in the SU

  19. Protocol for a randomised controlled trial of the effect of dapagliflozin, metformin and exercise on glycaemic variability, body composition and cardiovascular risk in prediabetes (the PRE-D Trial)

    DEFF Research Database (Denmark)

    Færch, Kristine; Amadid, Hanan; Nielsen, Lea Bruhn

    2017-01-01

    INTRODUCTION: The primary aim of this study is to compare the efficacy of three short-term glucose-lowering interventions (exercise, metformin and dapagliflozin) on glycaemic variability in overweight or obese men and women with elevated diabetes risk (ie, prediabetes, defined as haemoglobin A1c...... questions concerning the effect of exercise versus dapagliflozin or metformin in HbA1c-defined prediabetes to be addressed. TRIAL REGISTRATION: NCT02695810....

  20. Cardiovascular safety of combination therapies with incretin-based drugs and metformin compared with a combination of metformin and sulphonylurea in type 2 diabetes mellitus – a retrospective nationwide study

    DEFF Research Database (Denmark)

    Mogensen, U M; Andersson, Charlotte; Fosbøl, E L

    2014-01-01

    AIM: Dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 (GLP-1) agonists are widely used in combinations with metformin in the treatment of type 2 diabetes; however, data on long-term safety compared with conventional combination therapies are limited. METHODS: Danish individuals...... of myocardial infarction, stroke and CV mortality. Rate ratios (RR) were calculated using time-dependent multivariable Poisson regression analysis. RESULTS: A total of 40 028 patients (59% men, mean age 60 ± 13 years) used metformin with SU (n = 25 092), DPP-4 inhibitor (n = 11 138), GLP-1 agonist (n = 4345...... with metformin were safe compared with conventional combinations of glucose-lowering therapy. Use of incretin-based therapy may be target for strategies to lower CV risk in type 2 diabetes, although it should be recognized that the multivariable analysis may not have fully accounted for important baseline...

  1. [Metformin in pregnancy].

    Science.gov (United States)

    Bijok, Julia; Bińkowska, Małgorzata; Jakiel, Grzegorz

    2014-07-01

    Metformin is an oral insulin-sensitizing anti-diabetic drug. Polycystic ovary syndrome (PCOS) and gestational diabetes (GDM) are both associated with insulin resistance and hyperinsulinemia. Metformin can bring potential benefits in pregnant women due to its favorable metabolic effect. Nevertheless, there is a possibility of adverse effects on the fetus as metformin crosses the placenta. In this review we discuss safety and indications for metformin administration in pregnancy.

  2. Prenatal androgenization of female mice programs an increase in firing activity of gonadotropin-releasing hormone (GnRH) neurons that is reversed by metformin treatment in adulthood.

    Science.gov (United States)

    Roland, Alison V; Moenter, Suzanne M

    2011-02-01

    Prenatal androgenization (PNA) of female mice with dihydrotestosterone programs reproductive dysfunction in adulthood, characterized by elevated luteinizing hormone levels, irregular estrous cycles, and central abnormalities. Here, we evaluated activity of GnRH neurons from PNA mice and the effects of in vivo treatment with metformin, an activator of AMP-activated protein kinase (AMPK) that is commonly used to treat the fertility disorder polycystic ovary syndrome. Estrous cycles were monitored in PNA and control mice before and after metformin administration. Before metformin, cycles were longer in PNA mice and percent time in estrus lower; metformin normalized cycles in PNA mice. Extracellular recordings were used to monitor GnRH neuron firing activity in brain slices from diestrous mice. Firing rate was higher and quiescence lower in GnRH neurons from PNA mice, demonstrating increased GnRH neuron activity. Metformin treatment of PNA mice restored firing activity and LH to control levels. To assess whether AMPK activation contributed to the metformin-induced reduction in GnRH neuron activity, the AMPK antagonist compound C was acutely applied to cells. Compound C stimulated cells from metformin-treated, but not untreated, mice, suggesting that AMPK was activated in GnRH neurons, or afferent neurons, in the former group. GnRH neurons from metformin-treated mice also showed a reduced inhibitory response to low glucose. These studies indicate that PNA causes enhanced firing activity of GnRH neurons and elevated LH that are reversible by metformin, raising the possibility that central AMPK activation by metformin may play a role in its restoration of reproductive cycles in polycystic ovary syndrome.

  3. Short-term oleoyl-estrone treatment affects capacity to manage lipids in rat adipose tissue.

    Science.gov (United States)

    Salas, Anna; Noé, Véronique; Ciudad, Carlos J; Romero, M Mar; Remesar, Xavier; Esteve, Montserrat

    2007-08-28

    Short-term OE (oleoyl-estrone) treatment causes significant decreases in rat weight mainly due to adipose tissue loss. The aim of this work was to determine if OE treatment affects the expression of genes that regulate lipid metabolism in white adipose tissue. Gene expression in adipose tissue from female treated rats (48 hours) was analysed by hybridization to cDNA arrays and levels of specific mRNAs were determined by real-time PCR. Treatment with OE decreased the expression of 232 genes and up-regulated 75 other genes in mesenteric white adipose tissue. The use of real-time PCR validate that, in mesenteric white adipose tissue, mRNA levels for Lipoprotein Lipase (LPL) were decreased by 52%, those of Fatty Acid Synthase (FAS) by 95%, those of Hormone Sensible Lipase (HSL) by 32%, those of Acetyl CoA Carboxylase (ACC) by 92%, those of Carnitine Palmitoyltransferase 1b (CPT1b) by 45%, and those of Fatty Acid Transport Protein 1 (FATP1) and Adipocyte Fatty Acid Binding Protein (FABP4) by 52% and 49%, respectively. Conversely, Tumour Necrosis Factor (TNFalpha) values showed overexpression (198%). Short-term treatment with OE affects adipose tissue capacity to extract fatty acids from lipoproteins and to deal with fatty acid transport and metabolism.

  4. Major malformation risk, pregnancy outcomes, and neurodevelopmental outcomes associated with metformin use during pregnancy.

    Science.gov (United States)

    Andrade, Chittaranjan

    2016-04-01

    There are several reasons why metformin treatment may be considered for women in neuropsychiatric practice. These include prevention or attenuation of antipsychotic-associated weight gain, prevention or treatment of gestational diabetes mellitus (GDM), treatment of type 2 diabetes mellitus, and improvement of conception chances and pregnancy outcomes in the presence of polycystic ovarian disease (PCOD). This article examines the benefits and risks associated with metformin use during pregnancy. The available data suggest that metformin exposure during the first trimester is not associated with major congenital malformations; that metformin reduces the risk of early pregnancy loss, preeclampsia, preterm delivery, and GDM in women with PCOD; that metformin is associated with at least comparable benefits relative to insulin treatment in women with mild GDM; and that neurodevelopmental outcomes at age 1.5-2.5 years are comparable after gestational exposure to metformin and insulin. Whereas study designs were not always ideal and sample sizes were mostly small to modest, the study findings are more encouraging than discouraging and can guide shared decision-making in women who are receiving or may need metformin during pregnancy. © Copyright 2016 Physicians Postgraduate Press, Inc.

  5. Metformin-letrozole in comparison with Metformin-clomiphene citrate in clomiphene-resistance PCOS patients undergoing IUI

    Directory of Open Access Journals (Sweden)

    Mohammad Hossein Fallahzadeh

    2011-01-01

    Full Text Available Background: Polycystic ovary syndrome (PCOS is associated with approximately 75% of women who suffer from infertility due to anovulation. Additionally, around 20– 25% of anovulatory women with PCOS do not respond at all to clomiphene citrate and are considered to be “clomiphene– resistant”. Aromatase inhibitors have been suggested as an alternative treatment to clomiphene as the discrepancy between ovulation and pregnancy rates with clomiphene citrate has been attributed to its anti-estrogenic action and estrogen receptor depletion. Objective: The aim of this study is to compare results of Metformin-letrozole with Metformin-clomiphene citrate in clomiphene resistance PCOS patients undergoing IUI.Materials and Methods: In this single blind randomized trial, ovarian cycles were studied in 100 clomiphene- resistant patients with PCOS. The inclusion criteria were patients who received 150mg clomiphene citrate daily for 3 cycles and failed to become pregnant. The patients were matched for their age, body mass index (BMI, and infertility period. They were randomly allocated to a metformin-letrozole group (n=50 and a metformin-clomiphene citrate group (n=50. Chemical and clinical pregnancies were assessed after IUI. Abortion rates were determined in both groups. Results: Regarding pregnancy rate, there was no significant difference between the two groups. One miscarriage (2% occurred in the metformin-clomiphene citrate group, whereas none was seen in the metformin-letrozole group. Conclusion: There is no significant difference in pregnancy rate between clomiphene citrate and letrozole groups although it has been 2% in the former and 5% in the latter.

  6. Short-term effects of manipulative treatment versus a therapeutic home exercise protocol for chronic cervical pain

    DEFF Research Database (Denmark)

    Galindez-Ibarbengoetxea, Xabier; Setuain, Igor; Ramírez-Velez, Robinson

    2018-01-01

    BACKGROUND: While both manipulative treatment and physical exercises are used to treat cervical pain, it remains unclear which is most effective. OBJECTIVE: To compare the short-term effects of high-velocity, low-amplitude manipulation techniques (MT) with those of home-exercise (HE) with stretch......BACKGROUND: While both manipulative treatment and physical exercises are used to treat cervical pain, it remains unclear which is most effective. OBJECTIVE: To compare the short-term effects of high-velocity, low-amplitude manipulation techniques (MT) with those of home-exercise (HE...... scale (VAS); neck disability index (NDI); pressure pain thresholds; cervical spine range of motion and electromyography during the cranio-cervical flexion test was measured before and one week after the intervention. RESULTS: After the intervention, both groups showed improved (P

  7. Adsorption of emerging contaminant metformin using graphene oxide.

    Science.gov (United States)

    Zhu, Shuai; Liu, Yun-Guo; Liu, Shao-Bo; Zeng, Guang-Ming; Jiang, Lu-Hua; Tan, Xiao-Fei; Zhou, Lu; Zeng, Wei; Li, Ting-Ting; Yang, Chun-Ping

    2017-07-01

    The occurrence of emerging contaminants in our water resources poses potential threats to the livings. Due to the poor treatment in wastewater management, treatment technologies are needed to effectively remove these products for living organism safety. In this study, Graphene oxide (GO) was tested for the first time for its capacity to remove a kind of emerging wastewater contaminants, metformin. The research was conducted by using a series of systematic adsorption and kinetic experiments. The results indicated that GO could rapidly and efficiently reduce the concentration of metformin, which could provide a solution in handling this problem. The uptake of metformin on the graphene oxide was strongly dependent on temperature, pH, ionic strength, and background electrolyte. The adsorption kinetic experiments revealed that almost 80% removal of metformin was achieved within 20 min for all the doses studied, corresponding to the relatively high k 1 (0.232 min -1 ) and k 2 (0.007 g mg -1  min -1 ) values in the kinetic models. It indicated that the highest adsorption capacity in the investigated range (q m ) of GO for metformin was at pH 6.0 and 288 K. Thermodynamic study indicated that the adsorption was a spontaneous (ΔG 0  adsorption of metformin increased when the pH values changed from 4.0 to 6.0, and decreased adsorption were observed at pH 6.0-11.0. GO still exhibited excellent adsorption capacity after several desorption/adsorption cycles. Besides, both so-called π-π interactions and hydrogen bonds might be mainly responsible for the adsorption of metformin onto GO. Copyright © 2017 Elsevier Ltd. All rights reserved.

  8. Effects of metformin on learning and memory behaviors and brain mitochondrial functions in high fat diet induced insulin resistant rats.

    Science.gov (United States)

    Pintana, Hiranya; Apaijai, Nattayaporn; Pratchayasakul, Wasana; Chattipakorn, Nipon; Chattipakorn, Siriporn C

    2012-10-05

    Metformin is a first line drug for the treatment of type 2 diabetes mellitus (T2DM). Our previous study reported that high-fat diet (HFD) consumption caused not only peripheral and neuronal insulin resistance, but also induced brain mitochondrial dysfunction as well as learning impairment. However, the effects of metformin on learning behavior and brain mitochondrial functions in HFD-induced insulin resistant rats have never been investigated. Thirty-two male Wistar rats were divided into two groups to receive either a normal diet (ND) or a high-fat diet (HFD) for 12weeks. Then, rats in each group were divided into two treatment groups to receive either vehicle or metformin (15mg/kg BW twice daily) for 21days. All rats were tested for cognitive behaviors using the Morris water maze (MWM) test, and blood samples were collected for the determination of glucose, insulin, and malondialdehyde. At the end of the study, animals were euthanized and the brain was removed for studying brain mitochondrial function and brain oxidative stress. We found that in the HFD group, metformin significantly attenuated the insulin resistant condition by improving metabolic parameters, decreasing peripheral and brain oxidative stress levels, and improving learning behavior, compared to the vehicle-treated group. Furthermore, metformin completely prevented brain mitochondrial dysfunction caused by long-term HFD consumption. Our findings suggest that metformin effectively improves peripheral insulin sensitivity, prevents brain mitochondrial dysfunction, and completely restores learning behavior, which were all impaired by long-term HFD consumption. Copyright © 2012 Elsevier Inc. All rights reserved.

  9. Long and short term effects of plasma treatment on meristematic plant cells

    Science.gov (United States)

    Puač, N.; Živković, S.; Selaković, N.; Milutinović, M.; Boljević, J.; Malović, G.; Petrović, Z. Lj.

    2014-05-01

    In this paper, we will present results of plasma treatments of meristematic cells of Daucus carota. Plasma needle was used as an atmospheric pressure/gas composition source of non-equilibrium plasma in all treatments. Activity of antioxidant enzymes superoxide dismutase and catalase was measured immediately after plasma treatment and after two weeks following the treatment. Superoxide dismutase activity was increased in samples immediately after the plasma treatment. On the other hand, catalase activity was much higher in treated samples when measured two weeks after plasma treatment. These results show that there is a direct proof of the triggering of signal transduction in the cells by two reactive oxygen species H2O2 and O2-, causing enzyme activity and short and long term effects even during the growth of calli, where the information is passed to newborn cells over the period of two weeks.

  10. Metformin for treatment of antipsychotic-induced amenorrhea and weight gain in women with first-episode schizophrenia: a double-blind, randomized, placebo-controlled study.

    Science.gov (United States)

    Wu, Ren-Rong; Jin, Hua; Gao, Keming; Twamley, Elizabeth W; Ou, Jian-Jun; Shao, Ping; Wang, Juan; Guo, Xiao-Feng; Davis, John M; Chan, Philip K; Zhao, Jing-Ping

    2012-08-01

    Data on the treatment of antipsychotic-induced amenorrhea, particularly when occurring with weight gain, are limited. The authors investigated the efficacy and safety of metformin in the treatment of antipsychotic-induced amenorrhea and weight gain in women with first-episode schizophrenia. Eighty-four women (ages 18-40 years) with first-episode schizophrenia who suffered from amenorrhea during antipsychotic treatment were randomly assigned, in a double-blind study design, to receive 1000 mg/day of metformin or placebo in addition to their antipsychotic treatment for 6 months. The primary outcome measures were restoration of menstruation and change in body weight and body mass index (BMI). Secondary outcome measures were changes in levels of prolactin, luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol, and testosterone; in fasting levels of insulin and glucose; in LH/FSH ratio; and in insulin resistance index. Repeated mixed models with repeated-measures regression analyses and binary logistic regression were used in the analysis. A total of 76 patients completed the 6-month trial. Significantly more patients in the metformin group (N=28, 66.7%) than in placebo group (N=2, 4.8%) resumed their menstruation. Among patients treated with metformin, BMI decreased by a mean of 0.93 and the insulin resistance index by 2.04. In contrast, patients who received placebo had a mean increase in BMI of 0.85. The prolactin, LH, and testosterone levels and LH/FSH ratio decreased significantly in the metformin group at months 2, 4, and 6, but these levels did not change in the placebo group. Metformin was effective in reversing antipsychotic-induced adverse events, including restoration of menstruation, promotion of weight loss, and improvement in insulin resistance in female patients with schizophrenia.

  11. Metformin increases liver accumulation of vitamin B12 - An experimental study in rats

    DEFF Research Database (Denmark)

    Greibe, E; Miller, J W; Foutouhi, S H

    2013-01-01

    AIMS/HYPOTHESIS: Patients treated with metformin exhibit low levels of plasma vitamin B(12) (B(12)), and are considered at risk for developing B(12) deficiency. In this study, we investigated the effect of metformin treatment on B(12) uptake and distribution in rats. METHODS: Sprague Dawley rats (n...... that metformin has no decreasing effect on the B(12) absorption. CONCLUSIONS/INTERPRETATION: These results show that metformin treatment increases liver accumulation of B(12), thereby resulting in decreases in circulating B(12) and kidney accumulation of the vitamin. Our data questions whether the low plasma B......(12) observed in patients treated with metformin reflects impaired B(12) status, and rather suggests altered tissue distribution and metabolism of the vitamin....

  12. Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase

    DEFF Research Database (Denmark)

    Madiraju, Anila K; Erion, Derek M; Rahimi, Yasmeen

    2014-01-01

    Metformin is considered to be one of the most effective therapeutics for treating type 2 diabetes because it specifically reduces hepatic gluconeogenesis without increasing insulin secretion, inducing weight gain or posing a risk of hypoglycaemia. For over half a century, this agent has been...... prescribed to patients with type 2 diabetes worldwide, yet the underlying mechanism by which metformin inhibits hepatic gluconeogenesis remains unknown. Here we show that metformin non-competitively inhibits the redox shuttle enzyme mitochondrial glycerophosphate dehydrogenase, resulting in an altered...... hepatocellular redox state, reduced conversion of lactate and glycerol to glucose, and decreased hepatic gluconeogenesis. Acute and chronic low-dose metformin treatment effectively reduced endogenous glucose production, while increasing cytosolic redox and decreasing mitochondrial redox states. Antisense...

  13. Metformin-associated risk of acute dialysis in patients with type 2 diabetes

    DEFF Research Database (Denmark)

    Carlson, Nicholas; Hommel, Kristine; Olesen, Jonas Bjerring

    2016-01-01

    . The metformin-associated 1-year risk of acute dialysis was increased by 50.3 per 100 000 (95% CI, 7.9-88.6), corresponding to a risk ratio of 1.53 (95% CI, 1.06-2.23), and a number needed to harm of 1988, thus providing evidence of potential concerns pertaining to the increasing use of metformin.......Recent guidelines governing anti-diabetic medications increasingly advocate metformin as first-line therapy in all patients with type 2 diabetes. However, metformin could be associated with increased risk of acute kidney injury (AKI), acute dialysis and lactate acidosis in marginal patients....... In a retrospective nationwide cohort study, a total of 168 443 drug-naïve patients with type 2 diabetes ≥50 years, initiating treatment with either metformin or sulphonyl in Denmark between 2000 and 2012 were included in this study (70.7% initiated treatment with metformin); calculation of 1-year risk of acute...

  14. Impact of Short-Term Treatment with Telmisartan on Cerebral Arterial Remodeling in SHR

    OpenAIRE

    Foulquier , Sébastien; Lartaud , Isabelle; Dupuis , François

    2014-01-01

    International audience; Background and Purpose: Chronic hypertension decreases internal diameter of cerebral arteries and arterioles. We recently showed that short-term treatment with the angiotensin II receptor blocker telmisartan restored baseline internal diameter of small cerebral arterioles in spontaneously hypertensive rats (SHR), via reversal of structural remodeling and inhibition of the angiotensin II vasoconstrictor response. As larger arteries also participate in the regulation of ...

  15. Glimepiride versus pioglitazone combination therapy in subjects with type 2 diabetes inadequately controlled on metformin monotherapy: results of a randomized clinical trial.

    Science.gov (United States)

    Umpierrez, Guillermo; Issa, Maher; Vlajnic, Aleksandra

    2006-04-01

    To compare the effect of add-on glimepiride or pioglitazone in subjects with type 2 diabetes inadequately controlled on metformin monotherapy. Multicenter, randomized, parallel-group, open-label, forcedtitration study involving 203 adults with poorly controlled type 2 diabetes (A1C 7.5-10%) on metformin monotherapy. Subjects were randomized to receive glimepiride or pioglitazone, titrated to the maximum dose for 26 weeks. Subjects were evaluated for A1C changes, fasting plasma glucose (FPG), insulin, C-peptide, and lipid levels. Safety outcomes and diabetes-related healthcare resource utilization were also evaluated. Both treatment groups achieved similar and significant mean decreases from baseline to endpoint (week 26) in A1C (p = 0.0001) and FPG (p use of fasting C-peptide concentration > or = 0.27 nmol/L in the inclusion criteria was a potential limitation as it may have included those patients with an improved probability for glimepiride or pioglitazone response. In addition, a larger patient population would have provided a greater degree of data applicability. In patients with type 2 diabetes inadequately controlled on metformin monotherapy, add-on glimepiride or pioglitazone results in similar overall improvements in glycemic control. Compared with pioglitazone, glimepiride is associated with faster glycemic control, lower total and LDL cholesterol levels and reduced short-term healthcare costs.

  16. Efficacy of metformin in maintaining euglycemia in patients with gestational diabetes mellitus

    International Nuclear Information System (INIS)

    Amir, Z.E.; Saifuddin, Z.; Tanveer, S.; Khan, S.A.

    2017-01-01

    To determine efficacy of metformin in maintaining euglycemia in patients with GDM among women presenting in our institution. Methodology: It was a prospective study conducted at the department of Obstetrics and Gynecology Railway teaching Hospital IIMCT, Rawalpindi from October 2014 to April 2015 and included 60 patients of 18-45 years of age at 10-32 weeks gestation in singleton pregnancy with fasting blood glucose levels > 6.1 mmol /L and 2 hours Post Prandial levels > 7.8 mml/L Metformin is started at a dose of 500 mg daily and increased up to 2500 mg daily. Aim was to keep fasting sugar level between 3.5 - 5.9 mmol/L and 2 hours post prandial < 7.8 mmol/L. Results: The median daily dose of metformin was 1500 mg. The mean gestational age at delivery was 38.1 weeks. Neonatal hypoglycemia (glucose level < 1.6mmol/L ) was less common. The only adverse effects of metformin was GI upset (13.1 %) The results of postpartum questionnaire assessing acceptability of treatment among women treated with metformin alone, 65.6 % said they would chose metformin in subsequent pregnancy. The efficacy of metformin alone was 85.7%. Conclusion: In women with gestational diabetes mellitus, metformin (alone or with supplemental insulin) is not associated with increased prenatal complications. The women preferred metformin to insulin treatment. (author)

  17. Clinical diagnosis of polycystic ovarian syndrome and response to metformin therapy

    International Nuclear Information System (INIS)

    Tariq, N.; Ayub, R.; Alam, A.Y.; Raees, S.R.

    2007-01-01

    To determine the accuracy of diagnosing polycystic ovarian syndrome (PCOS) predominantly on clinical features and the response to metformin therapy. Women fulfilling the inclusion criteria (oligo/hypomenorrhea, infertility, weight gain, hyperandrogenism) were enrolled. Ultrasound pelvis was obtained in all women. Presence of eight or more multiple follicles in both or one ovary without presence of mature follicle was the cutoff number for positive ultrasound. Thyroid stimulating hormone levels were performed in all patients, and patients with abnormal levels were excluded from the study. Metformin was adjusted to 500 mg thrice daily. Six months later patients were again evaluated for response to metformin therapy and those who failed to conceive were given clomiphene citrate along with metformin. Fertility was re-evaluated at the end of one year. At the start of the study, 81% women had menstrual irregularity and 84% had infertility. Hirsutism was seen in 72% while history of weight gain was present in 62% of patients. Ultrasound evidence of polycystic ovaries was seen in 93% of women. After 6 months of metformin therapy, 80% patients had achieved correction in their menstrual irregularity. After 6 months on metformin alone, 51% patients conceived while an additional 20% conceived on both metformin and clomiphene citrate during next 6 months. Overall fertility rate was 71% at the end of one year. There was statistically significant change in pre-treatment and post-treatment BMI. Combination of three or more of the clinical features (irregular cycles, history of weight gain, infertility and hirsutism) provide an appropriate basis for the diagnosis of PCOS. Metformin alone was an effective treatment for PCOS in this series. (author)

  18. Early Discontinuation of Metformin in Individuals Treated with Inhibitors of Transporters of Metformin

    DEFF Research Database (Denmark)

    Stage, Tore Bjerregaard; Lee, Moa P; Hallas, Jesper

    2016-01-01

    The aim of this study was to examine the risk of early discontinuation of metformin as a proxy for intolerance, associated with use of drugs known to inhibit transporters involved in metformin distribution. We analysed all incident users of metformin in Denmark between 2000 and 2012 (n = 132......,221) and in a cohort of US patients (n = 296,903). Risk of early discontinuation of metformin was assessed using adjusted logistic regression for 28 drugs putatively inhibiting metformin transporters and four negative controls. Increased odds ratio of early discontinuation of metformin was only associated with codeine...... drugs were associated with a decreased risk. These findings indicate that codeine use may be associated with risk of early discontinuation of metformin and could be used as a basis for further investigation....

  19. Metformin-associated lactic acidosis (MALA)

    DEFF Research Database (Denmark)

    Lalau, Jean-Daniel; Kajbaf, Farshad; Protti, Alessandro

    2017-01-01

    Although metformin has been used for over 60 years, the balance between the drug's beneficial and adverse effects is still subject to debate. Following an analysis of how cases of so-called "metformin-associated lactic acidosis" (MALA) are reported in the literature, the present article reviews...... the pitfalls to be avoided when assessing the purported association between metformin and lactic acidosis. By starting from pathophysiological considerations, we propose a new paradigm for lactic acidosis in metformin-treated patients. Metformin therapy does not necessarily induce metformin accumulation, just...... as metformin accumulation does not necessarily induce hyperlactatemia, and hyperlactatemia does not necessarily induce lactic acidosis. In contrast to the conventional view, MALA probably accounts for a smaller proportion of cases than either metformin-unrelated lactic acidosis or metformin-induced lactic...

  20. Involvement of glucagon-like peptide-1 in the glucose-lowering effect of metformin

    DEFF Research Database (Denmark)

    Bahne, Emilie; Hansen, Morten; Brønden, Andreas

    2016-01-01

    Metformin is an oral antihyperglycaemic drug used in the first-line treatment of type 2 diabetes. Metformin's classic and most well-known blood glucose-lowering mechanisms include reduction of hepatic gluconeogenesis and increased peripheral insulin sensitivity. Interestingly, intravenously...... administered metformin is ineffective and recently, metformin was shown to increase plasma concentrations of the glucose-lowering gut incretin hormone glucagon-like peptide-1 (GLP-1), which may contribute to metformin's glucose-lowering effect in patients with type 2 diabetes. The mechanisms behind metformin......-induced increments in GLP-1 levels remain unknown, but it has been hypothesized that metformin stimulates GLP-1 secretion directly and/or indirectly and that metformin prolongs the half-life of GLP-1. Also, it has been suggested that metformin may potentiate the glucose-lowering effects of GLP-1 by increasing target...

  1. Role of AMP-activated protein kinase in mechanism of metformin action.

    Science.gov (United States)

    Zhou, G; Myers, R; Li, Y; Chen, Y; Shen, X; Fenyk-Melody, J; Wu, M; Ventre, J; Doebber, T; Fujii, N; Musi, N; Hirshman, M F; Goodyear, L J; Moller, D E

    2001-10-01

    Metformin is a widely used drug for treatment of type 2 diabetes with no defined cellular mechanism of action. Its glucose-lowering effect results from decreased hepatic glucose production and increased glucose utilization. Metformin's beneficial effects on circulating lipids have been linked to reduced fatty liver. AMP-activated protein kinase (AMPK) is a major cellular regulator of lipid and glucose metabolism. Here we report that metformin activates AMPK in hepatocytes; as a result, acetyl-CoA carboxylase (ACC) activity is reduced, fatty acid oxidation is induced, and expression of lipogenic enzymes is suppressed. Activation of AMPK by metformin or an adenosine analogue suppresses expression of SREBP-1, a key lipogenic transcription factor. In metformin-treated rats, hepatic expression of SREBP-1 (and other lipogenic) mRNAs and protein is reduced; activity of the AMPK target, ACC, is also reduced. Using a novel AMPK inhibitor, we find that AMPK activation is required for metformin's inhibitory effect on glucose production by hepatocytes. In isolated rat skeletal muscles, metformin stimulates glucose uptake coincident with AMPK activation. Activation of AMPK provides a unified explanation for the pleiotropic beneficial effects of this drug; these results also suggest that alternative means of modulating AMPK should be useful for the treatment of metabolic disorders.

  2. In Vivo Imaging of Human 11C-Metformin in Peripheral Organs: Dosimetry, Biodistribution and Kinetic Analyses

    DEFF Research Database (Denmark)

    Gormsen, Lars Christian; Sundelin, Elias Immanuel; Jensen, Jonas Brorson

    2016-01-01

    -metformin through the bile both during the intravenous and during the oral part of the study. CONCLUSION: (11)C-metformin is suitable for imaging metformin uptake in target tissues and may prove a valuable tool to assess the impact of metformin treatment in patients with varying metformin transport capacity....

  3. Effects of Long-term Use of Polyphenols on the Absorption and Tissue Distribution of Orally Administered Metformin and Atenolol in Rats

    Directory of Open Access Journals (Sweden)

    Saad Abdulrahman Hussain

    2013-06-01

    Full Text Available Aim: To evaluate the effect of long-term use of silibinin, epigallocatechin (ECGC, quercetin and rutin on the absorption and tissue distribution of metformin and atenolol. Materials and Methods: Thirty male rats were used, allocated into 5 groups and treated as follow: 1st group treated with olive oil and served as control; the other 4 groups were treated with either silibinin, EPGC, quercetin or rutin, administered orally as oily solutions for 30 days. At day 30, a 300mg/kg metformin and 50mg/kg atenolol were administered orally; 3.0 hrs later, the animals were sacrificed and blood samples, tissues of brain, kidney and liver were obtained for evaluation of the drugs level. Results: The polyphenols increased both serum and tissue levels of metformin compared with controls. This effect was relatively varied according to the structural differences among flavonoids. Conclusion: Long-term use of supraphysiological doses of flavonoids increase absorption of Zn, Cu and Fe and their tissue availability in brain, kidney and liver; this effect seems to be different with variations in structural features. [J Intercult Ethnopharmacol 2013; 2(3.000: 147-154

  4. Effects of Metformin on Endocrine and Metabolic Parameters in Patients with Polycystic Ovary Syndrome.

    Science.gov (United States)

    Zahra, M; Shah, M; Ali, A; Rahim, R

    2017-02-01

    The present study was designed to evaluate the effects of metformin on metabolic and endocrine parameters in patients with polycystic ovary syndrome (PCOS). The study included 40 patients with PCOS. Patients were divided into 2 groups based on whether they will receive metformin (500 mg 3 times a day, n=20) or placebo (n=20) for 3 consecutive months. Serum concentrations of fasting blood glucose, insulin, HOMA-IR, INSL-3, visfatin, FSH, and LH were measured at baseline and after 3 months of therapy. The key endocrine and metabolic parameters significantly changed after metformin treatment. The systolic and diastolic blood pressures were significantly reduced in the metformin group after treatment compared to placebo (povary was observed after metformin treatment (p=0.05), while no change was found in the size of left ovary (p>0.12). Moreover, a significant reduction was observed in the serum levels of FSH (p>0.01), LH (p>0.001), and visfatin (p>0.001) after metformin treatment. However, HOMA-IR (which is used to assess insulin resistance) failed to reach the statistical significance (p=0.20). We conclude that metformin treatment in females with PCOS showed significant improvement in systolic and diastolic blood pressures. In addition, an improvement in the hormonal profile in the form of reduction in LH, FSH, and visfatin levels was observed. Thus, therapeutic intervention with metformin could be of clinical importance in high-risk group of young females with PCOS. © Georg Thieme Verlag KG Stuttgart · New York.

  5. Short-term antibiotic treatment has differing long-term impacts on the human throat and gut microbiome

    Energy Technology Data Exchange (ETDEWEB)

    Jakobsson, H.; Jernberg, C.; Andersson, A.F.; Sjolund-Karlsson, M.; Jansson, J.K.; Engstrand, L.

    2010-01-15

    Antibiotic administration is the standard treatment for the bacterium Helicobacter pylori, the main causative agent of peptic ulcer disease and gastric cancer. However, the long-term consequences of this treatment on the human indigenous microbiota are relatively unexplored. Here we studied short- and long-term effects of clarithromycin and metronidazole treatment, a commonly used therapy regimen against H. pylori, on the indigenous microbiota in the throat and in the lower intestine. The bacterial compositions in samples collected over a four year period were monitored by analyzing the 16S rRNA gene using 454-based pyrosequencing and terminal-restriction fragment length polymorphism (T-RFLP). While the microbial communities of untreated control subjects were relatively stable over time, dramatic shifts were observed one week after antibiotic treatment with reduced bacterial diversity in all treated subjects in both locations. While the microbiota of the different subjects responded uniquely to the antibiotic treatment some general trends could be observed; such as a dramatic decline in Actinobacteria in both throat and feces immediately after treatment. Although the diversity of the microbiota subsequently recovered to resemble the pre treatment states, the microbiota remained perturbed in some cases for up to four years post treatment. In addition, four years after treatment high levels of the macrolide resistance gene erm(B) were found, indicating that antibiotic resistance, once selected for, can persist for longer periods of time than previously recognized. This highlights the importance of a restrictive antibiotic usage in order to prevent subsequent treatment failure and potential spread of antibiotic resistance.

  6. Short-term oleoyl-estrone treatment affects capacity to manage lipids in rat adipose tissue

    Directory of Open Access Journals (Sweden)

    Remesar Xavier

    2007-08-01

    Full Text Available Abstract Background Short-term OE (oleoyl-estrone treatment causes significant decreases in rat weight mainly due to adipose tissue loss. The aim of this work was to determine if OE treatment affects the expression of genes that regulate lipid metabolism in white adipose tissue. Results Gene expression in adipose tissue from female treated rats (48 hours was analysed by hybridization to cDNA arrays and levels of specific mRNAs were determined by real-time PCR. Treatment with OE decreased the expression of 232 genes and up-regulated 75 other genes in mesenteric white adipose tissue. The use of real-time PCR validate that, in mesenteric white adipose tissue, mRNA levels for Lipoprotein Lipase (LPL were decreased by 52%, those of Fatty Acid Synthase (FAS by 95%, those of Hormone Sensible Lipase (HSL by 32%, those of Acetyl CoA Carboxylase (ACC by 92%, those of Carnitine Palmitoyltransferase 1b (CPT1b by 45%, and those of Fatty Acid Transport Protein 1 (FATP1 and Adipocyte Fatty Acid Binding Protein (FABP4 by 52% and 49%, respectively. Conversely, Tumour Necrosis Factor (TNFα values showed overexpression (198%. Conclusion Short-term treatment with OE affects adipose tissue capacity to extract fatty acids from lipoproteins and to deal with fatty acid transport and metabolism.

  7. Metformin radiosensitization effect of low and high linear energy transfer radiation in HCC

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Eun Ho; Jung, Won Gyun [Division of Heavy Ion Clinical Research, Korea University, Seoul (Korea, Republic of); Kim, Mi Sook; Cho, Chul Koo; Jeong, Youn Kyoung [Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of)

    2014-04-15

    Metformin (1,1-dimethylbiguanide hydrochloride), the most widely used treatment for type 2 diabetes, provides a good tolerability profile and low cost and has recently sparked keen interest as a potential anticancer agent. Recent evidence has suggested Metformin provides a synergistic benefit with chemotherapy or radiotherapy against certain cancers in several clinical cohort studies.Treatment response rates are higher in patients treated with metformin in cohort studies of breast cancer treated with neoadjuvant chemotherapy in head and neck cancer treated with radiation and in esophageal cancer treated with chemoradiotherapy. As the sensitizing effect of Metformin in HCC has been characterized in vitro and in vivo, we investigated the radio-sensitizing effect of Metformin in HCC cells in combination with γ-ray (low LET) and neutron (high LET) radiation. The radiosensitizing effect of Metformin was much higher in neutron-irradiated than in γ -irradiated cell lines. Fortunately, Metformin had little effect on normal tissues. Our studies revealed no interaction between Metformin and radiation in normal hepatocytes. High LET radiation,including neutron and carbon ion, would produce more complicated and different cellular effects; indeed, the molecular biological mechanism of high LET radiation remains a topic of investigation.

  8. Metformin radiosensitization effect of low and high linear energy transfer radiation in HCC

    International Nuclear Information System (INIS)

    Kim, Eun Ho; Jung, Won Gyun; Kim, Mi Sook; Cho, Chul Koo; Jeong, Youn Kyoung

    2014-01-01

    Metformin (1,1-dimethylbiguanide hydrochloride), the most widely used treatment for type 2 diabetes, provides a good tolerability profile and low cost and has recently sparked keen interest as a potential anticancer agent. Recent evidence has suggested Metformin provides a synergistic benefit with chemotherapy or radiotherapy against certain cancers in several clinical cohort studies.Treatment response rates are higher in patients treated with metformin in cohort studies of breast cancer treated with neoadjuvant chemotherapy in head and neck cancer treated with radiation and in esophageal cancer treated with chemoradiotherapy. As the sensitizing effect of Metformin in HCC has been characterized in vitro and in vivo, we investigated the radio-sensitizing effect of Metformin in HCC cells in combination with γ-ray (low LET) and neutron (high LET) radiation. The radiosensitizing effect of Metformin was much higher in neutron-irradiated than in γ -irradiated cell lines. Fortunately, Metformin had little effect on normal tissues. Our studies revealed no interaction between Metformin and radiation in normal hepatocytes. High LET radiation,including neutron and carbon ion, would produce more complicated and different cellular effects; indeed, the molecular biological mechanism of high LET radiation remains a topic of investigation

  9. Does metformin treatment during pregnancy modify future metabolic profile in women with PCOS?

    DEFF Research Database (Denmark)

    Underdal, Maria Othelie; Stridsklev, Solhild; Oppen, Ingrid Hennum

    2018-01-01

    with PCOS. Design: Follow-up study of a randomized controlled trial, which compared metformin to placebo in women with PCOS. Mean follow-up period was 8 years (5-11). Setting: Three university hospitals, seven local hospitals, and one gynecological specialist practice. Participants: Women with PCOS......Context: Worldwide, metformin is prescribed in an attempt to improve pregnancy outcome in PCOS. Metformin may also benefit future health by modulating the increased metabolic stress during pregnancy. Objective: To investigate if metformin during pregnancy modified future metabolic health in women......-up period. Weight, body mass index, waist and hip circumferences and blood pressure were registered. Body composition was assessed by bioelectrical impedance analysis, and fasting lipids, glucose and insulin were analysed. Results: 131 out of 239 (55%) invited women participated in the follow-up. Weight...

  10. Differences in health status between long-term and short-term benzodiazepine users.

    NARCIS (Netherlands)

    Zandstra, S.M.; Furer, J.W.; Lisdonk, E.H. van de; Bor, J.H.J.; Zitman, F.G.; Weel, C. van

    2002-01-01

    BACKGROUND: Despite generally accepted advice to keep treatment short, benzodiazepines are often prescibed for more than six months. Prevention of long-term benzodiazepine use could be facilitated by the utilisation of risk indicators for long-term use. However, the characteristics of long-term

  11. Adequacy of clinical trial evidence of metformin fixed-dose combinations for the treatment of type 2 diabetes mellitus in India.

    Science.gov (United States)

    Evans, Valerie; Roderick, Peter; Pollock, Allyson M

    2018-01-01

    There is growing national and international concern about the drug regulatory system in India. Parliamentary reports have highlighted the presence of high numbers of unapproved medicines and irrational combinations of both approved and unapproved drugs in the Indian market-place. Fixed-dose combinations (FDCs) are a peculiar feature of the Indian pharmaceutical landscape. Although metformin is a first-line treatment, FDCs for diabetes in India account for two-thirds of all diabetes medicine sales, and some have not been approved by the Central Drugs Standard Control Organization (CDSCO). This study examines the basis of efficacy and safety of top-selling metformin FDCs in India against four WHO criteria from clinical trials guidelines for the approval of FDCs. Data from a commercial drug sales database (PharmaTrac) were combined with searches through published literature, clinical trial registries, and published and unpublished trial websites of metformin FDCs in adults with type 2 diabetes mellitus. Five metformin FDCs in India from November 2011 to October 2012 accounted for 80% of all metformin FDC sales by value and volume. Although all five had obtained CDSCO approval, three had been sold and marketed prior to receiving this approval. Evaluation of published and unpublished clinical trials of these five FDCs found none provided robust evidence of safety and efficacy for the treatment of type 2 diabetes. Recommendations are made for publishing evidence that underpins drug approvals, marketing bans, greater transparency through updated clinical trials databases and legislative reform in order to prevent irrational FDCs from entering the market.

  12. Short-term efficacy of surgical treatment of secondary hyperparathyroidism.

    Science.gov (United States)

    Liang, Y; Sun, Y; Ren, L; Qi, X-W; Li, Y; Zhang, F

    2015-10-01

    We wished to explore short-term efficacy of surgical treatment of secondary hyperparathyroidism in patients with the end-stage renal disease. The treatment methods were subtotal or total parathyroidectomy, or total parathyroidectomy and autotransplantation. 63 patients with secondary hyperparathyroidism were randomly divided into three groups which were respectively treated with subtotal parathyroidectomy (SPTX group), total parathyroidectomy (TPTX group), or total parathyroidectomy and autotransplantation (TPTX+AT group). The surgical outcomes included operating time, transoperative bleeding volume, length of stay, and cost of hospitalization. In addition, complication (e.g., postoperative wound infection, hematoma, hypocalcemia in perioperative period) rates were compared among groups. Blood levels of calcium and parathyroid hormone were assessed before the surgery, and 1 day, 1 months, 3 months and 6 months after the surgery. The follow-up period comprised 6 months. Surgical outcomes were the lowest in SPTX group and the highest in in TPTX+AT group. There were no significant differences among groups in treatment efficacy. Complication rates were also comparable among the three groups. The occurrence of hypocalcemia was the lowest in SPTX group (p < 0.05 vs. other groups). However, postoperative relapse rate was the highest in this group (p < 0.05 vs. other groups). There were no correlations between the levels of blood calcium and PTH preoperatively and postoperatively. Appropriate surgical treatment is selected in accordance with the patient's condition and willingness, with the attention paid to the prevention of hypocalcemia.

  13. Use of Metformin in Pregnancy: A Survey of Turkish Physicians’ Attitudes

    OpenAIRE

    Barış Akıncı; Pınar Tosun; Emine Bekçi; Serkan Yener; Tevfik Demir; Sena Yeşil

    2009-01-01

    Objective: Although metformin crosses the placenta, there is no current evidence whether the use of metformin in pregnancy is associated with increased risk of fetal and maternal complications. The aim of this present study is to investigate the attitudes of Turkish physicians in different specialties in terms of metformin use in pregnancy. Materials and Methods: Current opinions were assessed by a questionnaire. Nine hundred forty physicians were invited to join the study; however, completel...

  14. Metformin induces differentiation in acute promyelocytic leukemia by activating the MEK/ERK signaling pathway

    International Nuclear Information System (INIS)

    Huai, Lei; Wang, Cuicui; Zhang, Cuiping; Li, Qihui; Chen, Yirui; Jia, Yujiao; Li, Yan; Xing, Haiyan; Tian, Zheng; Rao, Qing; Wang, Min; Wang, Jianxiang

    2012-01-01

    Highlights: ► Metformin induces differentiation in NB4 and primary APL cells. ► Metformin induces activation of the MEK/ERK signaling pathway in APL cells. ► Metformin synergizes with ATRA to trigger maturation of NB4 and primary APL cells. ► Metformin induces the relocalization and degradation of the PML-RARα fusion protein. ► The study may be applicable for new differentiation therapy in cancer treatment. -- Abstract: Recent studies have shown that metformin, a widely used antidiabetic agent, may reduce the risk of cancer development. In this study, we investigated the antitumoral effect of metformin on both acute myeloid leukemia (AML) and acute promyelocytic leukemia (APL) cells. Metformin induced apoptosis with partial differentiation in an APL cell line, NB4, but only displayed a proapoptotic effect on several non-M3 AML cell lines. Further analysis revealed that a strong synergistic effect existed between metformin and all-trans retinoic acid (ATRA) during APL cell maturation and that metformin induced the hyperphosphorylation of extracellular signal-regulated kinase (ERK) in APL cells. U0126, a specific MEK/ERK activation inhibitor, abrogated metformin-induced differentiation. Finally, we found that metformin induced the degradation of the oncoproteins PML-RARα and c-Myc and activated caspase-3. In conclusion, these results suggest that metformin treatment may contribute to the enhancement of ATRA-induced differentiation in APL, which may deepen the understanding of APL maturation and thus provide insight for new therapy strategies.

  15. Metformin and lifestyle modification in polycystic ovary syndrome: systematic review and meta-analysis.

    Science.gov (United States)

    Naderpoor, Negar; Shorakae, Soulmaz; de Courten, Barbora; Misso, Marie L; Moran, Lisa J; Teede, Helena J

    2015-01-01

    Polycystic ovary syndrome (PCOS) is a common endocrine disorder with diverse reproductive and metabolic features. It is underpinned by insulin resistance that is exacerbated by obesity. Lifestyle modification is the first line treatment in PCOS, but it is associated with low adherence and sustainability. In small studies, metformin improves outcomes such as hyperinsulinaemia, ovulation and menstrual cyclicity. We conducted a systematic review and meta-analysis to compare the effect of lifestyle modification + metformin with lifestyle modification ± placebo, and of metformin alone with lifestyle modification ± placebo in PCOS on anthropometric, metabolic, reproductive and psychological outcomes. Databases including MEDLINE, EMBASE, Pubmed, Scopus, Cochrane, PsycINFO, CINAHL, Clinical Trials registry and ANZCTR were searched for RCTs conducted on humans and published in English up to August 2014. Inclusion criteria were diagnosis of PCOS based on Rotterdam criteria (inclusive of National Institutes of Health criteria) at any age and with any BMI. Interventions of interest included lifestyle + metformin (with any dose and any duration) or metformin alone compared with lifestyle ± placebo. Of 2372 identified studies, 12 RCTs were included for analysis comprising 608 women with PCOS. Lifestyle + metformin were associated with lower BMI (mean difference (MD) -0.73 kg/m(2), 95% confidence intervals (CI) -1.14, -0.32, P = 0.0005) and subcutaneous adipose tissue (MD -92.49 cm(2), 95% CI -164.14, -20.84, P = 0.01) and increased number of menstrual cycles (MD 1.06, 95% CI 0.30, 1.82, P = 0.006) after 6 months compared with lifestyle ± placebo. There were no differences in other anthropometric, metabolic (surrogate markers of insulin resistance, fasting and area under the curve glucose, lipids and blood pressure), reproductive (clinical and biochemical hyperandrogenism), and psychological (quality of life) outcomes after 6 months between lifestyle + metformin compared with

  16. Dose comparison and side effect profile of metformin extended release versus metformin immediate release

    International Nuclear Information System (INIS)

    Hameed, M.; Khan, K.; Salman, S.; Mehmood, N.

    2017-01-01

    Diabetes Mellitus type 2 is very common worldwide, with majority of cases in Asia Pacific region. Metformin is the first line therapy, along with lifestyle modification for all type 2 diabetics as recommended by ADA. Metformin is available as conventional Metformin Immediate Release (MIR) and Metformin Extended Release (MXR). Metformin XR has better gastrointestinal tolerability and fewer side effects as compared to Metformin IR, with similar efficacy regarding anti-hyperglycaemic effects. The objective of this study was to determine whether metformin XR is as effective as Metformin IR in maintaining glycaemic control at equivalent doses or even at reduced doses; and to compare the side effect profile of the two preparations. Methods: This randomized control trial was conducted at Medical and Endocrinology OPD of Jinnah Hospital Lahore A total of 90 type 2 diabetics of both genders were recruited using nonprobability purposive sampling. Patients were randomized into 3 groups; 30 in each group. Group 1 received Metformin IR 1000 mg twice daily; group 2 received metformin XR 1000mg twice daily; and group 3 received metformin XR 500 mg twice daily, for a period of three months. HbA1c was done at baseline and after three months of therapy along with fasting blood sugars and random blood sugars weekly. Results: The mean age of patients was 46+-9 years, with 54% being males and 46% being females. There was a 1% reduction in HbA1c in group 1, 0.7% reduction in group 2 and only 0.4% reduction in group 3. Similarly, all three therapies were equally effective in reducing blood sugar fasting and blood sugar random at three months. Side effects namely diarrhoea, dyspepsia and flatulence were greatest with Metformin IR (40%) but less than half with Metformin XR at equivalent dose and negligible at half the dose. Conclusions: All three Metformin groups were effective in reduction of HbA1C and glycaemic control clinically and there is no statistical difference in HbA1c reduction

  17. Metformin and phenethyl isothiocyanate combined treatment in vitro is cytotoxic to ovarian cancer cultures

    Directory of Open Access Journals (Sweden)

    Chan Daniel K

    2012-07-01

    Full Text Available Abstract Background High mortality rates in ovarian cancer are largely a result of resistance to currently used chemotherapies. Expanding therapies with a variety of drugs has the potential to reduce this high mortality rate. Metformin and phenethyl isothiocyanate (PEITC are both potentially useful in ovarian cancer, and they are particularly attractive because of their safety. Methods Cell proliferation of each drug and drug combination was evaluated by hemacytometry with Trypan blue exclusion or Sytox green staining for cell death. Levels of total and cleaved PARP were measured by Western blot. General cellular and mitochondrial reactive oxygen species were measured by flow cytometry and live cell confocal microscopy with the fluorescent dyes dihydroethidine and MitoSOX. Results Individually, metformin and PEITC each show inhibition of cell growth in multiple ovarian cancer cell lines. Alone, PEITC was also able to induce apoptosis, whereas metformin was primarily growth inhibitory. Both total cellular and mitochondrial reactive oxygen species were increased when treated with either metformin or PEITC. The growth inhibitory effects of metformin were reversed by methyl succinate supplementation, suggesting complex I plays a role in metformin's anti-cancer mechanism. PEITC's anti-cancer effect was reversed by N-acetyl-cysteine supplementation, suggesting PEITC relies on reactive oxygen species generation to induce apoptosis. Metformin and PEITC together showed a synergistic effect on ovarian cancer cell lines, including the cisplatin resistant A2780cis. Conclusions Here we show that when used in combination, these drugs are effective in both slowing cancer cell growth and killing ovarian cancer cells in vitro. Furthermore, the combination of these drugs remains effective in cisplatin resistant cell lines. Novel combinations such as metformin and PEITC show promise in expanding ovarian cancer therapies and overcoming the high incidence of

  18. Metformin (dimethyl-biguanide induced DNA damage in mammalian cells

    Directory of Open Access Journals (Sweden)

    Rubem R. Amador

    2012-01-01

    Full Text Available Metformin (dimethyl-biguanide is an insulin-sensitizing agent that lowers fasting plasma-insulin concentration, wherefore it's wide use for patients with a variety of insulin-resistant and prediabetic states, including impaired glucose tolerance. During pregnancy it is a further resource for reducing first-trimester pregnancy loss in women with the polycystic ovary syndrome. We tested metformin genotoxicity in cells of Chinese hamster ovary, CHO-K1 (chromosome aberrations; comet assays and in mice (micronucleus assays. Concentrations of 114.4 µg/mL and 572 µg/mL were used in in vitro tests, and 95.4 mg/kg, 190.8 mg/kg and 333.9 mg/kg in assaying. Although the in vitro tests revealed no chromosome aberrations in metaphase cells, DNA damage was detected by comet assaying after 24 h of incubation at both concentrations. The frequency of DNA damage was higher at concentrations of 114.4 µg/mL. Furthermore, although mortality was not observed in in vitro tests, the highest dose of metformin suppressed bone marrow cells. However, no statistically significant differences were noted in micronuclei frequencies between treatments. In vitro results indicate that chronic metformin exposure may be potentially genotoxic. Thus, pregnant woman undergoing treatment with metformin should be properly evaluated beforehand, as regards vulnerability to DNA damage.

  19. Pharmacokinetics of metformin during pregnancy.

    Science.gov (United States)

    Eyal, Sara; Easterling, Thomas R; Carr, Darcy; Umans, Jason G; Miodovnik, Menachem; Hankins, Gary D V; Clark, Shannon M; Risler, Linda; Wang, Joanne; Kelly, Edward J; Shen, Danny D; Hebert, Mary F

    2010-05-01

    Our objective was to evaluate the pharmacokinetics of metformin during pregnancy. Serial blood and urine samples were collected over one steady-state dosing interval in women treated with metformin during early to late pregnancy (n = 35) and postpartum (n = 16). Maternal and umbilical cord blood samples were obtained at delivery from 12 women. Metformin concentrations were also determined in breast milk samples obtained over one dosing interval in 6 women. Metformin renal clearance increased significantly in mid (723 +/- 243 ml/min, P pregnancy (625 +/- 130 ml/min, P metformin net secretion clearance (480 +/- 190 ml/min, P pregnancy versus postpartum, respectively. Metformin concentrations at the time of delivery in umbilical cord plasma ranged between nondetectable (metformin through breast milk was 0.13 to 0.28 mg, and the relative infant dose was metformin pharmacokinetics are affected by pregnancy-related changes in renal filtration and net tubular transport and can be roughly estimated by the use of creatinine clearance. At the time of delivery, the fetus is exposed to metformin concentrations from negligible to as high as maternal concentrations. In contrast, infant exposure to metformin through the breast milk is low.

  20. Short-term overlap lamivudine treatment with adefovir dipivoxil in patients with lamivudine-resistant chronic hepatitis B

    Science.gov (United States)

    Nam, Soon Woo; Bae, Si Hyun; Lee, Seung Woo; Kim, Yeon Soo; Kang, Sang Bum; Choi, Jong Young; Cho, Se Hyun; Yoon, Seung Kew; Han, Joon-Yeol; Yang, Jin Mo; Lee, Young Suk

    2008-01-01

    AIM: To evaluate the efficacy of short-term overlap lamivudine therapy with adefovir in patients with lamivudine-resistant and naïve chronic hepatitis B, we compared patients receiving overlap therapy with those receiving adefovir alone. METHODS: Eighty patients who had received lamivudine treatment for various periods and had a lamivudine-resistant liver function abnormality were enrolled. Forty of these patients received adefovir treatment combined with lamivudine treatment for ≥ 2 mo, while the other 40 received adefovir alone. We assessed the levels of hepatitis B virus (HBV) DNA at 0, 12 and 48 wk and serum alanine aminotransferase (ALT) levels after 0, 12, 24 and 48 wk of adefovir treatment in each group. RESULTS: We found serum ALT became normalized in 72 (87.5%) of the 80 patients, and HBV DNA decreased by ≥ 2 log10 copies/mL in 60 (75%) of the 80 patients at the end of a 48-wk treatment. HBV DNA levels were not significantly different between the groups. The improvements in serum ALT were also not significantly different between the two groups. CONCLUSION: These findings suggest short-term overlap lamivudine treatment results in no better virological and biological outcomes than non-overlap adefovir monotherapy. PMID:18350610

  1. Metformin Effects on Biochemical Recurrence and Metabolic Signaling in the Prostate

    Science.gov (United States)

    Winters, Brian; Plymate, Stephen; Zeliadt, Steven B; Holt, Sarah; Zhang, Xiaotun; Hu, Elaine; Lin, Daniel W.; Morrissey, Colm; Wooldridge, Bryan; Gore, John L; Porter, Michael P; Wright, Jonathan L

    2015-01-01

    Background Metformin has received considerable attention as a potential anti-cancer agent. Animal and in-vitro prostate cancer (PCa) models have demonstrated decreased tumor growth with metformin, however the precise mechanisms are unknown. We examine the effects of metformin on PCa biochemical recurrence (BCR) in a large clinical database followed by evaluating metabolic signaling changes in a cohort of men undergoing prostate needle biopsy (PNB). Methods Men treated for localized PCa were identified in a comprehensive clinical database between 2001 and 2010. Cox regression was performed to determine association with BCR relative to metformin use. We next identified a separate case-control cohort of men undergoing prostate needle biopsy (PNB) stratified by metformin use. Differences in mean IHC scores were compared with linear regression for phosphorylated IR, IGF-IR, AKT, and AMPK. Results 1,734 men were evaluated for BCR with mean follow up of 41 months (range 1-121 months). ‘Ever’ metformin use was not associated with BCR (HR 1.12, 0.77-1.65), however men reporting both pre/post-treatment metformin use had a 45% reduction in BCR (HR=0.55 (0.31-0.96)). For the tissue-based study, 48 metformin users and 42 controls underwent PNB. Significantly greater staining in phosphorylated nuclear (p-IR, p-AKT) and cytoplasmic (p-IR, p-IGF-1R) insulin signaling proteins were seen in patients with PCa detected compared to those with negative PNB (p-values all < 0.006). When stratified by metformin use, IGF-1R remained significantly elevated (p=0.01) in men with PCa detected whereas p-AMPK (p=0.05) was elevated only in those without PCa. Conclusion Metformin use is associated with reduced BCR after treatment of localized PCa when considering pre-diagnostic and cumulative dosing. In men with cancer detected on PNB, insulin signaling markers were significantly elevated compared to negative PNB patients. The finding of IGF-1R elevation in positive PNBs versus p-AMPK elevation

  2. Metformin induces differentiation in acute promyelocytic leukemia by activating the MEK/ERK signaling pathway

    Energy Technology Data Exchange (ETDEWEB)

    Huai, Lei; Wang, Cuicui; Zhang, Cuiping; Li, Qihui; Chen, Yirui; Jia, Yujiao; Li, Yan; Xing, Haiyan; Tian, Zheng; Rao, Qing; Wang, Min [State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020 (China); Wang, Jianxiang, E-mail: wangjx@ihcams.ac.cn [State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020 (China)

    2012-06-08

    Highlights: Black-Right-Pointing-Pointer Metformin induces differentiation in NB4 and primary APL cells. Black-Right-Pointing-Pointer Metformin induces activation of the MEK/ERK signaling pathway in APL cells. Black-Right-Pointing-Pointer Metformin synergizes with ATRA to trigger maturation of NB4 and primary APL cells. Black-Right-Pointing-Pointer Metformin induces the relocalization and degradation of the PML-RAR{alpha} fusion protein. Black-Right-Pointing-Pointer The study may be applicable for new differentiation therapy in cancer treatment. -- Abstract: Recent studies have shown that metformin, a widely used antidiabetic agent, may reduce the risk of cancer development. In this study, we investigated the antitumoral effect of metformin on both acute myeloid leukemia (AML) and acute promyelocytic leukemia (APL) cells. Metformin induced apoptosis with partial differentiation in an APL cell line, NB4, but only displayed a proapoptotic effect on several non-M3 AML cell lines. Further analysis revealed that a strong synergistic effect existed between metformin and all-trans retinoic acid (ATRA) during APL cell maturation and that metformin induced the hyperphosphorylation of extracellular signal-regulated kinase (ERK) in APL cells. U0126, a specific MEK/ERK activation inhibitor, abrogated metformin-induced differentiation. Finally, we found that metformin induced the degradation of the oncoproteins PML-RAR{alpha} and c-Myc and activated caspase-3. In conclusion, these results suggest that metformin treatment may contribute to the enhancement of ATRA-induced differentiation in APL, which may deepen the understanding of APL maturation and thus provide insight for new therapy strategies.

  3. Effect of short-term intensive atorvastatin treatment on interventional treatment effect and cardiac function of patients with acute coronary syndrome

    Directory of Open Access Journals (Sweden)

    Yu Lei

    2016-06-01

    Full Text Available Objective: To study the effect of short-term intensive atorvastatin treatment on interventional treatment effect and cardiac function of patients with acute coronary syndrome. Methods: A total of 104 cases of patients with acute coronary syndrome who received PCI treatment in Emergency Department of our hospital from May 2014 to November 2015 were retrospectively analyzed and divided into intensive group and routine group according to different atorvastatin treatment methods, and then biochemical indexes, cardiac ultrasound indicators and inflammatory indexes of two groups were compared. Results: Serum TG, TC, LDL-C, hs- CRP, LDH, α-HBDH, CK and CK-MB content of intensive group were significantly lower than those of routine group while HDL-C content was higher than that of routine group; E/ A ratio and LVEF of intensive group were higher than those of routine group while Tei index, systolic index and diastolic index were lower than those of routine group; TLR4 and NF-kB expression levels in peripheral blood as well as TNF-α and IL-6 content in serum of intensive group were significantly lower than those of routine group. Conclusion: Short-term intensive atorvastatin treatment improves the interventional treatment effect of patients with acute coronary syndrome, and can reduce myocardial injury, improve cardiac diastolic and systolic function and inhibit the inflammation mediated by TLR4/NF-kB.

  4. Metformin prevents methylglyoxal-induced apoptosis of mouse Schwann cells

    International Nuclear Information System (INIS)

    Ota, Kimiko; Nakamura, Jiro; Li, Weiguo; Kozakae, Mika; Watarai, Atsuko; Nakamura, Nobuhisa; Yasuda, Yutaka; Nakashima, Eirtaro; Naruse, Keiko; Watabe, Kazuhiko; Kato, Koichi; Oiso, Yutaka; Hamada, Yoji

    2007-01-01

    Methylglyoxal (MG) is involved in the pathogenesis of diabetic complications via the formation of advanced glycation end products (AGEs) and reactive oxygen species (ROS). To clarify whether the antidiabetic drug metformin prevents Schwann cell damage induced by MG, we cultured mouse Schwann cells in the presence of MG and metformin. Cell apoptosis was evaluated using Hoechst 33342 nuclear staining, caspase-3 activity, and c-Jun-N-terminal kinase (JNK) phosphorylation. Intracellular ROS formation was determined by flow cytometry, and AMP-activated kinase (AMPK) phosphorylation was also examined. MG treatment resulted in blunted cell proliferation, an increase in the number of apoptotic cells, and the activation of caspase-3 and JNK along with enhanced intracellular ROS formation. All of these changes were significantly inhibited by metformin. No significant activation of AMPK by MG or metformin was observed. Taken together, metformin likely prevents MG-induced apoptotic signals in mouse Schwann cells by inhibiting the formation of AGEs and ROS

  5. Metformin, besides exhibiting strong in vivo anti-inflammatory properties, increases mptp-induced damage to the nigrostriatal dopaminergic system

    International Nuclear Information System (INIS)

    Ismaiel, Afrah A.K.; Espinosa-Oliva, Ana M.; Santiago, Martiniano; García-Quintanilla, Albert; Oliva-Martín, María J.; Herrera, Antonio J.; Venero, José L.; Pablos, Rocío M. de

    2016-01-01

    Metformin is a widely used oral antidiabetic drug with known anti-inflammatory properties due to its action on AMPK protein. This drug has shown a protective effect on various tissues, including cortical neurons. The aim of this study was to determine the effect of metformin on the dopaminergic neurons of the substantia nigra of mice using the animal model of Parkinson's disease based on the injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, an inhibitor of the mitochondrial complex I. In vivo and in vitro experiments were used to study the activation of microglia and the damage of the dopaminergic neurons. Our results show that metformin reduced microglial activation measured both at cellular and molecular levels. Rather than protecting, metformin exacerbated dopaminergic damage in response to MPTP. Our data suggest that, contrary to other brain structures, metformin treatment could be deleterious for the dopaminergic system. Hence, metformin treatment may be considered as a risk factor for the development of Parkinson's disease. - Highlights: • Metformin treatment decreases microglial activation in the MPTP model of Parkinson's disease. • Metformin treatment increases the neurodegeneration in the MPTP model of Parkinson's disease, both in vivo and vitro. • Metformin treatment could be a risk factor for the development of Parkinson's disease.

  6. Metformin, besides exhibiting strong in vivo anti-inflammatory properties, increases mptp-induced damage to the nigrostriatal dopaminergic system

    Energy Technology Data Exchange (ETDEWEB)

    Ismaiel, Afrah A.K.; Espinosa-Oliva, Ana M.; Santiago, Martiniano; García-Quintanilla, Albert; Oliva-Martín, María J.; Herrera, Antonio J.; Venero, José L.; Pablos, Rocío M. de, E-mail: depablos@us.es

    2016-05-01

    Metformin is a widely used oral antidiabetic drug with known anti-inflammatory properties due to its action on AMPK protein. This drug has shown a protective effect on various tissues, including cortical neurons. The aim of this study was to determine the effect of metformin on the dopaminergic neurons of the substantia nigra of mice using the animal model of Parkinson's disease based on the injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, an inhibitor of the mitochondrial complex I. In vivo and in vitro experiments were used to study the activation of microglia and the damage of the dopaminergic neurons. Our results show that metformin reduced microglial activation measured both at cellular and molecular levels. Rather than protecting, metformin exacerbated dopaminergic damage in response to MPTP. Our data suggest that, contrary to other brain structures, metformin treatment could be deleterious for the dopaminergic system. Hence, metformin treatment may be considered as a risk factor for the development of Parkinson's disease. - Highlights: • Metformin treatment decreases microglial activation in the MPTP model of Parkinson's disease. • Metformin treatment increases the neurodegeneration in the MPTP model of Parkinson's disease, both in vivo and vitro. • Metformin treatment could be a risk factor for the development of Parkinson's disease.

  7. Metformin for weight loss and metabolic control in overweight outpatients with schizophrenia and schizoaffective disorder.

    Science.gov (United States)

    Jarskog, L Fredrik; Hamer, Robert M; Catellier, Diane J; Stewart, Dawn D; Lavange, Lisa; Ray, Neepa; Golden, Lauren H; Lieberman, Jeffrey A; Stroup, T Scott

    2013-09-01

    The purpose of this study was to determine whether metformin promotes weight loss in overweight outpatients with chronic schizophrenia or schizoaffective disorder. In a double-blind study, 148 clinically stable, overweight (body mass index [BMI] ≥27) outpatients with chronic schizophrenia or schizoaffective disorder were randomly assigned to receive 16 weeks of metformin or placebo. Metformin was titrated up to 1,000 mg twice daily, as tolerated. All patients continued to receive their prestudy medications, and all received weekly diet and exercise counseling. The primary outcome measure was change in body weight from baseline to week 16. Fifty-eight (77.3%) patients who received metformin and 58 (81.7%) who received placebo completed 16 weeks of treatment. Mean change in body weight was -3.0 kg (95% CI=-4.0 to -2.0) for the metformin group and -1.0 kg (95% CI=-2.0 to 0.0) for the placebo group, with a between-group difference of -2.0 kg (95% CI=-3.4 to -0.6). Metformin also demonstrated a significant between-group advantage for BMI (-0.7; 95% CI=-1.1 to -0.2), triglyceride level (-20.2 mg/dL; 95% CI=-39.2 to -1.3), and hemoglobin A1c level (-0.07%; 95% CI=-0.14 to -0.004). Metformin-associated side effects were mostly gastrointestinal and generally transient, and they rarely led to treatment discontinuation. Metformin was modestly effective in reducing weight and other risk factors for cardiovascular disease in clinically stable, overweight outpatients with chronic schizophrenia or schizoaffective disorder over 16 weeks. A significant time-by-treatment interaction suggests that benefits of metformin may continue to accrue with longer treatment. Metformin may have an important role in diminishing the adverse consequences of obesity and metabolic impairments in patients with schizophrenia.

  8. Cellular and molecular mechanisms of metformin: an overview

    Science.gov (United States)

    Viollet, Benoit; Guigas, Bruno; Sanz Garcia, Nieves; Leclerc, Jocelyne; Foretz, Marc; Andreelli, Fabrizio

    2012-01-01

    Considerable efforts have been made since the 1950s to better understand the cellular and molecular mechanisms of action of metformin, a potent antihyperglycemic agent now recommended as the first line oral therapy for type 2 diabetes (T2D). The main effect of this drug from the biguanide family is to acutely decrease hepatic glucose production, mostly through a mild and transient inhibition of the mitochondrial respiratory-chain complex 1. In addition, the resulting decrease in hepatic energy status activates the AMP-activated protein kinase (AMPK), a cellular metabolic sensor, providing a generally accepted mechanism for metformin action on hepatic gluconeogenic program. The demonstration that the respiratory-chain complex 1, but not AMPK, is the primary target of metformin was recently strengthened by showing that the metabolic effect of the drug is preserved in liver-specific AMPK-deficient mice. Beyond its effect on glucose metabolism, metformin was reported to restore ovarian function in polycystic ovary syndrome, reduce fatty liver and to lower microvascular and macrovascular complications associated with T2D. Its use was also recently suggested as an adjuvant treatment for cancer or gestational diabetes, and for the prevention in pre-diabetic populations. These emerging new therapeutic areas for metformin will be reviewed together with recent data from pharmacogenetic studies linking genetic variations to drug response, a promising new step towards personalized medicine in the treatment of T2D. PMID:22117616

  9. Audit of long-term and short-term liabilities

    Directory of Open Access Journals (Sweden)

    Korinko M.D.

    2017-03-01

    Full Text Available The article determines the importance of long-term and short-term liabilities for the management of financial and material resources of an enterprise. It reviews the aim, objects and information generators for realization of audit of short-term and long-term obligations. The organizing and methodical providing of audit of long-term and short-term liabilities of an enterprise are generalized. The authors distinguish the stages of realization of audit of long-term and short-term liabilities, the aim of audit on each of the presented stages, and recommend methodical techniques. It is fixed that it is necessary to conduct the estimation of the systems of internal control and record-keeping of an enterprise by implementation of public accountant procedures for determination of volume and maintenance of selection realization. After estimating the indicated systems, a public accountant determines the methodology for realization of public accountant verification of long-term and short-term liabilities. The analytical procedures that public accountants are expedient to use for realization of audit of short-term and long-term obligations are determined. The authors suggest the classification of the educed defects on the results of the conducted public accountant verification of short-term and long-term obligations.

  10. Metformin promotes focal angiogenesis and neurogenesis in mice following middle cerebral artery occlusion.

    Science.gov (United States)

    Liu, Yanqun; Tang, Guanghui; Zhang, Zhijun; Wang, Yongting; Yang, Guo-Yuan

    2014-09-05

    Current studies demonstrated that metformin is not only a hypoglycemic drug, but also a neuro-protective agent. However, the effect of metformin during ischemic brain injury is unclear. The aim of the present study is to explore the effect of metformin during ischemic brain injury. Adult male CD1 mice underwent 90min transient middle cerebral artery occlusion. Metformin (200mg/kg) was given at the time of reperfusion daily until sacrifice. Results showed that metformin treatment significantly reduced ischemia-induced brain atrophy volume compared to the control (pcerebral artery occlusion, suggesting that metformin is a potential new drug for ischemic stroke therapy. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  11. Effect of vildagliptin add-on treatment to metformin on plasma asymmetric dimethylarginine in type 2 diabetes mellitus patients

    Directory of Open Access Journals (Sweden)

    Cakirca M

    2014-02-01

    Full Text Available Mustafa Cakirca,1 Cumali Karatoprak,1 Mehmet Zorlu,1 Muharrem Kiskac,1 Mustafa Kanat,2 Mehmet Ali Cikrikcioglu,1 Pinar Soysal,3 Mehmet Hursitoglu,4 Ahmet Adil Camli,1 Reha Erkoc,1 Muhammad Abdul-Ghani5 1Internal Medicine Clinic, Faculty of Medicine, Bezmialem Vakif University, 2Department of Internal Medicine, Medical Faculty, Istanbul Medipol University, 3Department of Geriatric Medicine, Medical Faculty, Dokuz Eylül University, 4Department of Internal Medicine, Kanuni Sultan Suleyman Training and Research Hospital, Istanbul, Turkey; 5Division of Medicine – Diabetes, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA Aims: A close association has been demonstrated between increased cardiovascular risk and high asymmetric dimethylarginine (ADMA levels in type 2 diabetes mellitus (DM patients. We planned to measure serum ADMA levels in type 2 DM patients using vildagliptin, a dipeptidyl peptidase-4 (DPP-4 inhibitor. Materials and methods: A total of 68 type 2 DM patients who were on metformin were enrolled in the study. Based on the glycemic levels of patients, vildagliptin was added on to treatment in 33 patients. Patients were followed for 6 months. Serum ADMA, C-reactive protein, and fibrinogen levels were compared in groups of patients using metformin or metformin + vildagliptin, after 6 months. Results: Serum ADMA levels were found to be significantly lower in the group using vildagliptin compared to the group using metformin + vildagliptin (P<0.001. However, serum C-reactive protein and fibrinogen levels were statistically similar in the two study groups (P=0.34 and P=0.23, respectively. Conclusion: Metformin + vildagliptin treatment was observed to lower serum ADMA levels in type 2 DM patients. Our findings notwithstanding, large-scale prospective randomized controlled studies are warranted to conclude that vildagliptin provides cardiovascular protection along with diabetes regulation. Keywords: asymmetric

  12. Valproic acid sensitizes metformin-resistant human renal cell carcinoma cells by upregulating H3 acetylation and EMT reversal.

    Science.gov (United States)

    Wei, Muyun; Mao, Shaowei; Lu, Guoliang; Li, Liang; Lan, Xiaopeng; Huang, Zhongxian; Chen, Yougen; Zhao, Miaoqing; Zhao, Yueran; Xia, Qinghua

    2018-04-17

    Metformin (Met) is a widely available diabetic drug and shows suppressed effects on renal cell carcinoma (RCC) metabolism and proliferation. Laboratory studies in RCC suggested that metformin has remarkable antitumor activities and seems to be a potential antitumor drug. But the facts that metformin may be not effective in reducing the risk of RCC in cancer clinical trials made it difficult to determine the benefits of metformin in RCC prevention and treatment. The mechanisms underlying the different conclusions between laboratory experiments and clinical analysis remains unclear. The goal of the present study was to determine whether long-term metformin use can induce resistance in RCC, whether metformin resistance could be used to explain the disaccord in laboratory and clinical studies, and whether the drug valproic acid (VPA), which inhibits histone deacetylase, exhibits synergistic cytotoxicity with metformin and can counteract the resistance of metformin in RCC. We performed CCK8, transwell, wound healing assay, flow cytometry and western blotting to detect the regulations of proliferation, migration, cell cycle and apoptosis in 786-O, ACHN and metformin resistance 786-O (786-M-R) cells treated with VPA, metformin or a combination of two drugs. We used TGF-β, SC79, LY294002, Rapamycin, protein kinase B (AKT) inhibitor to treat the 786-O or 786-M-R cells and detected the regulations in TGF-β /pSMAD3 and AMPK/AKT pathways. 786-M-R was refractory to metformin-induced antitumor effects on proliferation, migration, cell cycle and cell apoptosis. AMPK/AKT pathways and TGF-β/SMAD3 pathways showed low sensibilities in 786-M-R. The histone H3 acetylation diminished in the 786-M-R cells. However, the addition of VPA dramatically upregulated histone H3 acetylation, increased the sensibility of AKT and inhibited pSMAD3/SMAD4, letting the combination of VPA and metformin remarkably reappear the anti-tumour effects of metformin in 786-M-R cells. VPA not only exhibits

  13. Effect of Short-Term Hypergravity Treatment on Mouse 2-Cell Embryo Development

    Science.gov (United States)

    Ning, Li-Na; Lei, Xiao-Hua; Cao, Yu-Jing; Zhang, Yun-Fang; Cao, Zhong-Hong; Chen, Qi; Duan, En-Kui

    2015-11-01

    Though there are numerous biological experiments, which have been performed in a space environment, to study the physiological effect of space travel on living organisms, while the potential effect of weightlessness or short-term hypergravity on the reproductive system in most species, particularly in mammalian is still controversial and unclear. In our previous study, we investigated the effect of space microgravity on the development of mouse 4-cell embryos by using Chinese SJ-8. .Unexpectedly, we did not get any developed embryo during the space-flight. Considering that the process of space experiment is quite different from most experiments done on earth in several aspects such as, the vibration and short-term hypergravity during the rock launching and landing. Thus we want to know whether the short-term hypergravity produced by the launch process affect the early embryo development in mice, and howthe early embryos respond to the hypergravity. In present study, we are mimicking the short-term hypergravity during launch by using a centrifuge to investigate its influence on the development of early embryo (2-cell) in mice. We also examined the actin filament distribution in 2-cell embryos by immunostaining to test their potential capacity of development under short-term hypergravity exposure. Our results showed that most 2-cell embryos in the hypergravity exposure groups developed into blastocysts with normal morphology after 72h cultured in vitro, and there is no obvious difference in the development rate of blastocyst formation compared to the control. Moreover, there were no statistically significant differences in birth rates after oviduct transfer of 2-cell mouse embryos exposed on short-term hypergravity compared with 1 g condition. In addition, the well-organized actin distribution appeared in 2-cell embryos after exposed on hypergravity and also in the subsequent developmental blastocysts. Taken together, our data shows that short-term exposure in

  14. Metformin Use During Treatment of Potentially Curable Esophageal Cancer Patients is not Associated with Better Outcomes

    NARCIS (Netherlands)

    Spierings, L. E. A. M. M.; Lagarde, S. M.; van Oijen, M. G. H.; Gisbertz, S. S.; Wilmink, J. W.; Hulshof, M. C. C. M.; Meijer, S. L.; Anderegg, M. C.; van Berge Henegouwen, M. I.; van Laarhoven, H. W. M.

    2015-01-01

    Metformin use has been associated with a dose-dependent increased response to neoadjuvant chemo(radio)therapy in esophageal cancer patients. However, no association between metformin use and overall survival has been reported yet. The purpose of our study was to investigate the effect of metformin

  15. Enhancement of radiation response in human hepatocarcinoma cells by Metformin

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Eun Ho; Kim, Won Woo; Kim, Joon; Jung, Won Gyun [Division of heavy ion clinical research, Korea University, Seoul (Korea, Republic of); Jeong, Jae Hoon; Jeong, Youn Kyoung; Kim, Mi Sook [Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of)

    2012-11-15

    Metformin (1, 1-dimethylbiguanide hydrochloride), the most widely used drug to treat type 2 diabetic patients under benefit good tolerability profile and low cost, has sparked keen interest as potential anticancer agent. Preclinical studies showed that the primary mechanism of action of metformin is through its ability to activate AMP-activated protein kinase (AMPK). Metformin inhibits complex 1 in the mitochondrial electron transport chain, leading to an increase in the AMP-to-ATP ratio, then, phospholylated AMPK increase energy generation or suppress energy consumption and then, inhibits cell growth. However, important caveat in direct action theory of metformin is that millimorlar range, effective dose for inhibition tumor cell growth in vitro, cannot be achieved in patients. This is probably because metformin enter cells through the organic cation transporters OCT1 and OCT2, which is lowly expressed in human cells except liver and adipose cells. dependent pathway rather than through direct effects of the tumor cells. We analyzed combination effect of metformin and radiation focusing to HCC cell lines, which theoretically express high organic cation transporters, producing high centration of metformin in tumor cells. The purpose of this study is to investigate whether metformin had anti-tumor effects when combined with radiation as radiosensitizer in HCC. The results showed that metformin increased radiosensitizing efficacy in HCC cells , as well as in Huh7 xenograft mouse models. Interestingly, metformin effectively sensitizes IR-induced apoptosis in HCC through upregulation of cleaved PARP and caspase3 and increase synergically on DNA damage response with combined treatment.HCC, suggesting potential usefulness of combined therapy of metformin together with radiation for HCC cancer therapy.

  16. Enhancement of radiation response in human hepatocarcinoma cells by Metformin

    International Nuclear Information System (INIS)

    Kim, Eun Ho; Kim, Won Woo; Kim, Joon; Jung, Won Gyun; Jeong, Jae Hoon; Jeong, Youn Kyoung; Kim, Mi Sook

    2012-01-01

    Metformin (1, 1-dimethylbiguanide hydrochloride), the most widely used drug to treat type 2 diabetic patients under benefit good tolerability profile and low cost, has sparked keen interest as potential anticancer agent. Preclinical studies showed that the primary mechanism of action of metformin is through its ability to activate AMP-activated protein kinase (AMPK). Metformin inhibits complex 1 in the mitochondrial electron transport chain, leading to an increase in the AMP-to-ATP ratio, then, phospholylated AMPK increase energy generation or suppress energy consumption and then, inhibits cell growth. However, important caveat in direct action theory of metformin is that millimorlar range, effective dose for inhibition tumor cell growth in vitro, cannot be achieved in patients. This is probably because metformin enter cells through the organic cation transporters OCT1 and OCT2, which is lowly expressed in human cells except liver and adipose cells. dependent pathway rather than through direct effects of the tumor cells. We analyzed combination effect of metformin and radiation focusing to HCC cell lines, which theoretically express high organic cation transporters, producing high centration of metformin in tumor cells. The purpose of this study is to investigate whether metformin had anti-tumor effects when combined with radiation as radiosensitizer in HCC. The results showed that metformin increased radiosensitizing efficacy in HCC cells , as well as in Huh7 xenograft mouse models. Interestingly, metformin effectively sensitizes IR-induced apoptosis in HCC through upregulation of cleaved PARP and caspase3 and increase synergically on DNA damage response with combined treatment.HCC, suggesting potential usefulness of combined therapy of metformin together with radiation for HCC cancer therapy

  17. Antiproliferative and metabolic effects of metformin in a preoperative window clinical trial for endometrial cancer

    International Nuclear Information System (INIS)

    Schuler, Kevin M; Rambally, Brooke S; DiFurio, Megan J; Sampey, Brante P; Gehrig, Paola A; Makowski, Liza; Bae-Jump, Victoria L

    2015-01-01

    We conducted a preoperative window study of metformin in endometrial cancer (EC) patients and evaluated its antiproliferative, molecular and metabolic effects. Twenty obese women with endometrioid EC were treated with metformin (850 mg) daily for up to 4 weeks prior to surgical staging. Expression of the proliferation marker Ki-67, estrogen receptor (ER), progesterone receptor (PR), adenosine monophosphate-activated protein kinase (AMPK), and downstream targets of the mammalian target of rapamycin (mTOR) pathway were measured by immunohistochemistry. Global, untargeted metabolomics analysis of serum pre- and postmetformin treatment, and matched tumor, was performed. Metformin reduced proliferation by 11.75% (P = 0.008) based on the comparison of pre- and posttreatment endometrial tumors. A total of 65% of patients responded to metformin as defined by a decrease in Ki-67 staining in their endometrial tumors post-treatment. Metformin decreased expression of phosphorylated (p)-AMPK (P = 0.00001), p-Akt (P = 0.0002), p-S6 (51.2%, P = 0.0002), p-4E-BP-1 (P = 0.001), and ER (P = 0.0002) but not PR expression. Metabolomic profiling of serum indicated that responders versus nonresponders to treatment were more sensitive to metformin's effects on induction of lipolysis, which correlated with increased fatty acid oxidation and glycogen metabolism in matched tumors. In conclusion, metformin reduced tumor proliferation in a pre-operative window study in obese EC patients, with dramatic effects on inhibition of the mTOR pathway. Metformin induced a shift in lipid and glycogen metabolism that was more pronounced in the serum and tumors of responders versus nonresponders to treatment.This study provides support for therapeutic clinical trials of metformin in obese patients with EC

  18. Effects of vildagliptin relative to sulfonylureas in Muslim patients with type 2 diabetes fasting during Ramadan: influence of age and treatment with/without metformin in the VIRTUE study.

    Science.gov (United States)

    Hassoun, Ahmed Ak; Pathan, Md Faruque; Medlej, Rita C; Alarouj, Monira; Shaltout, Inass; Chawla, Manoj S; Knap, Ditte; Vaz, Julius A

    2016-01-01

    VIRTUE was a prospective, observational study assessing the effectiveness and safety of vildagliptin vs sulfonylureas (SUs) (both as monotherapy and in combination with metformin) in patients with type 2 diabetes mellitus who fasted during Ramadan. A post hoc analysis was carried out to assess the effect of treatment with/without metformin and age (vildagliptin and 631 received SUs. Most patients received dual therapy with metformin (n=1,148) and were aged vildagliptin vs SU monotherapy (6.5% vs 14.5%) and with vildagliptin + metformin vs SUs + metformin (5.3% vs 20.6%); the latter achieved statistical significance (PVildagliptin was associated with numerically greater HbA1c and body weight reductions vs SUs, regardless of the therapy type or age. A higher proportion of SU- vs vildagliptin-treated patients experienced adverse events across all subgroups. A few patients experienced HEs with vildagliptin vs SUs regardless of age, and in patients on dual therapy. Vildagliptin ± metformin was also associated with good glycemic and weight control and was well tolerated. Vildagliptin might be a useful treatment option for patients with type 2 diabetes mellitus, particularly high-risk populations such as the elderly fasting during Ramadan.

  19. Effects of metformin on body weight in patients with type 2 diabetes mellitus,receiving insulin analogue treatment

    Directory of Open Access Journals (Sweden)

    T I Romantsova

    2013-03-01

    Full Text Available Aims. To study the dynamics of body weight, waist circumference, blood lipid and insulin demand in patients with type 2 diabetes mellitus (T2DM during first year of combined treatment with metformin and insulin analogues, compared with insulin analogue monotherapy.Materials and Methods. We examined 78 patients with T2DM on newly initiated insulin therapy, including 54 females and 24 males. Median age was 56 [51.0; 64.0] years, median disease duration – 9 [6.8;14.0] years. Participants were subdivided in two groups. First group was comprised of 48 subjects (33 females and 15 males, who received monotherapy with insulin analogues (glargine, de- temir, biphasic Aspart 30 and Humalog Mix 25 or rapid-acting lispro and aspart. Second group included 30 patients (18 females and12 males, who were treated with combined therapy (insulin analogues plus metformin. We measured HbA1c, plasma lipid composition, BMI, waist circumference and insulin demand initially and after one year of follow-up.Results. We showed that combined therapy vs. insulin monotherapy allows better glycemic compensation while reducing insulin demand and lowering risks for weight gain.Conclusions. Combined insulin analogue plus metformin treatment delivers better metabolic control in patients with T2DM and is as- sociated with lower risks for body weight gain and increase in insulin demand against monotherapy with insulin analogues.

  20. Effects of metformin on body weight in patients with type 2 diabetes mellitus,receiving insulin analogue treatment

    Directory of Open Access Journals (Sweden)

    Tatiana Ivanovna Romantsova

    2013-03-01

    Full Text Available Aims. To study the dynamics of body weight, waist circumference, blood lipid and insulin demand in patients with type 2 diabetes mellitus (T2DM during first year of combined treatment with metformin and insulin analogues, compared with insulin analogue monotherapy. Materials and Methods. We examined 78 patients with T2DM on newly initiated insulin therapy, including 54 females and 24 males. Median age was 56 [51.0; 64.0] years, median disease duration ? 9 [6.8;14.0] years. Participants were subdivided in two groups. First group was comprised of 48 subjects (33 females and 15 males, who received monotherapy with insulin analogues (glargine, de- temir, biphasic Aspart 30 and Humalog Mix 25 or rapid-acting lispro and aspart. Second group included 30 patients (18 females and12 males, who were treated with combined therapy (insulin analogues plus metformin. We measured HbA1c, plasma lipid composition, BMI, waist circumference and insulin demand initially and after one year of follow-up. Results. We showed that combined therapy vs. insulin monotherapy allows better glycemic compensation while reducing insulin demand and lowering risks for weight gain. Conclusions. Combined insulin analogue plus metformin treatment delivers better metabolic control in patients with T2DM and is as- sociated with lower risks for body weight gain and increase in insulin demand against monotherapy with insulin analogues.

  1. Massage therapy has short-term benefits for people with common musculoskeletal disorders compared to no treatment: a systematic review

    Directory of Open Access Journals (Sweden)

    Diederik C Bervoets

    2015-07-01

    Full Text Available Question: Is massage therapy effective for people with musculoskeletal disorders compared to any other treatment or no treatment? Design: Systematic review of randomised clinical trials. Participants: People with musculoskeletal disorders. Interventions: Massage therapy (manual manipulation of the soft tissues as a stand-alone intervention. Outcome: The primary outcomes were pain and function. Results: The 26 eligible randomised trials involved 2565 participants. The mean sample size was 95 participants (range 16 to 579 per study; 10 studies were considered to be at low risk of bias. Overall, low-to-moderate-level evidence indicated that massage reduces pain in the short term compared to no treatment in people with shoulder pain and osteoarthritis of the knee, but not in those with low back pain or neck pain. Furthermore, low-to-moderate-level evidence indicated that massage improves function in the short term compared to no treatment in people with low back pain, knee arthritis or shoulder pain. Low-to-very-low-level evidence from single studies indicated no clear benefits of massage over acupuncture, joint mobilisation, manipulation or relaxation therapy in people with fibromyalgia, low back pain and general musculoskeletal pain. Conclusions: Massage therapy, as a stand-alone treatment, reduces pain and improves function compared to no treatment in some musculoskeletal conditions. When massage is compared to another active treatment, no clear benefit was evident. [Bervoets DC, Luijsterburg PAJ, Alessie JJN, Buijs MJ, Verhagen AP (2015 Massage therapy has short-term benefits for people with common musculoskeletal disorders compared to no treatment: a systematic review. Journal of Physiotherapy 61: 106–116

  2. Metformin Targets Brown Adipose Tissue in vivo and Reduces Oxygen Consumption in vitro

    DEFF Research Database (Denmark)

    Breining, Peter; Jensen, Jonas B; Sundelin, Elias I

    2018-01-01

    basic metabolic rate, making BAT an attractive target for treatment of type 2 diabetes. Under the hypothesis that BAT is a metformin target tissue, we investigated in vivo uptake of [11 C]-metformin tracer in mice and studied in vitro effects of metformin on cultured human brown adipocytes. Injected [11......Metformin is the most widely prescribed oral antidiabetic drug worldwide. Despite well-documented beneficial effects on health outcomes in diabetic patients, the target organs that mediate the effects of metformin remain to be established. In adult humans, brown adipose tissue (BAT) can influence...... uptake. Gene expression profiles of OCTs in BAT revealed ample OCT3 expression in both human and mouse BAT. Incubation of a human brown adipocyte cell models with metformin reduced cellular oxygen consumption in a dose dependent manner. Collectively, these results support BAT as a putative metformin...

  3. Metformin induces a Senescence-associated gene Signature in Breast Cancer Cells

    Science.gov (United States)

    Williams, Christopher C.; Singleton, Brittany A.; Llopis, Shawn D.; Skripnikova, Elena V.

    2013-01-01

    Diabetic patients taking metformin have lower incidence of breast cancer than those taking other anti-diabetic medications. Additionally, triple negative breast cancer (TNBC), a form of breast cancer disproportionately afflicting premenopausal African American women, shows atypical susceptibility to metformin’s antiproliferative effect. The mechanisms involved in metformin’s function in TNBC has not yet been fully elucidated. Therefore, we sought to identify pathways regulated by metformin in using the MDA-MB-468 TNBC cell model. Metformin dose-dependently caused apoptosis, decreased cell viability, and induced cell morphology/chromatin condensation consistent with the permanent proliferative arrest. Furthermore, gene expression arrays revealed that metformin caused expression of stress markers DDIT3, CYP1A1, and GDF-15 and a concomitant reduction in PTGS1 expression. Our findings show that metformin may affect the viability and proliferative capacity of TNBC by inducing an antiproliferative gene signature, and that metformin may be effective in the treatment/prevention of TNBC. PMID:23395946

  4. Low and high linear energy transfer radiation sensitization of HCC cells by metformin

    International Nuclear Information System (INIS)

    Kim, Eun Ho; Jung, Won-Gyun; Kim, Mi-Sook; Cho, Chul-Koo; Jeong, Youn Kyoung; Jeong, Jae-Hoon

    2014-01-01

    The purpose of this study was to investigate the efficacy of metformin as a radiosensitizer for use in combination therapy for human hepatocellular carcinoma (HCC). Three human HCC cell lines (Huh7, HepG2, Hep3B) and a normal human hepatocyte cell line were treated with metformin alone or with radiation followed by metformin. In vitro tests were evaluated by clonogenic survival assay, FACS analysis, western blotting, immunofluorescence and comet assay. Metformin significantly enhanced radiation efficacy under high and low Linear Energy Transfer (LET) radiation conditions in vitro. In combination with radiation, metformin abrogated G2/M arrest and increased the cell population in the sub-G1 phase and the ROS level, ultimately increasing HCC cellular apoptosis. Metformin inhibits the repair of DNA damage caused by radiation. The radiosensitizing effects of metformin are much higher in neutron (high LET)-irradiated cell lines than in γ (low LET)-irradiated cell lines. Metformin only had a moderate effect in normal hepatocytes. Metformin enhances the radiosensitivity of HCC, suggesting it may have clinical utility in combination cancer treatment with high-LET radiation. (author)

  5. Buccal delivery of metformin

    DEFF Research Database (Denmark)

    Sander, Camilla; Nielsen, Hanne Mørck; Jacobsen, Jette

    2013-01-01

    system. The in vitro TR146 cell culture model was used to study the effect of drug concentration (5-100mM) and the impact of a bioadhesive chitosan formulation (discs) and chitosan in solution (0-20mg/mL) acting as a permeation enhancer. The permeation of metformin occurred by passive diffusion via...... metformin discs and, metformin permeation may be increased due to a combination of bioadhesion and permeation enhancement induced by chitosan, although the permeation enhancing effect of chitosan was not statistically significant. The limited apparent buccal permeability of metformin observed in vitro...

  6. Association of Metformin Use with Outcomes in Advanced Endometrial Cancer Treated with Chemotherapy.

    Directory of Open Access Journals (Sweden)

    Obiageli Ezewuiro

    Full Text Available There is increasing evidence that metformin, a commonly used treatment for diabetes, might have the potential to be repurposed as an economical and safe cancer therapeutic. The aim of this study was to determine whether stage III-IV or recurrent endometrial cancer patients who are using metformin during treatment with chemotherapy have improved survival. To test this we analyzed a retrospective cohort of subjects at two independent institutions who received chemotherapy for stage III-IV or recurrent endometrial cancer from 1992 to 2011. Diagnosis of diabetes, metformin use, demographics, endometrial cancer clinico-pathologic parameters, and survival duration were abstracted. The primary outcome was overall survival. The final cohort included 349 patients, 31 (8.9% had diabetes and used metformin, 28 (8.0% had diabetes but did not use metformin, and 291 (83.4% did not have diabetes. The results demonstrate that the median overall survival was 45.6 months for patients with diabetes who used metformin compared to 12.5 months for patients with diabetes who did not use metformin and 28.5 months for patients without diabetes (log-rank test comparing the three groups P = 0.006. In a model adjusted for confounders, the difference in survival between the three groups remained statistically significant (P = 0.023. The improvement in survival among metformin users was not explained by better baseline health status or more aggressive use of chemotherapy. Overall, the findings in this retrospective cohort of endometrial cancer patients with stage III-IV or recurrent disease treated with chemotherapy indicate that patients with diabetes who were concurrently treated with metformin survived longer than patients with diabetes who did not use metformin.

  7. Twenty years of ovulation induction with metformin for PCOS; what is the best available evidence?

    Science.gov (United States)

    Abu Hashim, Hatem

    2016-01-01

    The potential reproductive benefits of metformin, a drug endowed with the capacity to ameliorate insulin resistance in polycystic ovary syndrome (PCOS), has garnered much interest over the past 2 decades. In this review, randomized-controlled trials (RCT) and meta-analyses of RCT comparing metformin are critically appraised and summarized. PubMed and CENTRAL databases were consulted. Evidence is insufficient to favour the use of metformin or metformin plus clomiphene citrate instead of clomiphene citrate for ovulation induction in women with newly diagnosed PCOS. Evidence is also insufficient to recommend metformin as a primary treatment for non-obese women with PCOS. Metformin plus clomiphene citrate should be considered as an effective option in clomiphene citrate-resistant PCOS. In women with PCOS undergoing gonadotrophin ovulation induction, metformin significantly increased pregnancy and live birth rates (P treatment in increasing clinical pregnancy rates and reducing the risk of OHSS in PCOS patients undergoing assisted reproduction techniques has been shown. No evidence was found of reduced risk of spontaneous abortion or increased risk of major anomalies in women with PCOS taking metformin during the first trimester. Copyright © 2015 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.

  8. Involvement of catalase in the protective benefits of metformin in mice with oxidative liver injury.

    Science.gov (United States)

    Dai, Jie; Liu, Mingwei; Ai, Qing; Lin, Ling; Wu, Kunwei; Deng, Xinyu; Jing, Yuping; Jia, Mengying; Wan, Jingyuan; Zhang, Li

    2014-06-05

    Metformin is a commonly used anti-diabetic drug with AMP-activated protein kinase (AMPK)-dependent hypoglycemic activities. Recent studies have revealed its anti-inflammatory and anti-oxidative properties. In the present study, the anti-oxidative potential of metformin and its potential mechanisms were investigated in a mouse model with carbon tetrachloride (CCl₂)-induced severe oxidative liver injury. Our results showed that treatment with metformin significantly attenuated CCl₂-induced elevation of serum aminotransferases and hepatic histological abnormalities. The alleviated liver injury was associated with decreased hepatic contents of oxidized glutathione (GSSG) and malondialdehyde (MDA). In addition, metformin treatment dose-dependently enhanced the activities of catalase (CAT) and decreased CCl₄-induced elevation of hepatic H₂O₂ levels, but it had no obvious effects on the protein level of CAT. We also found that metformin increased the level of phosphorylated AMP-activated protein kinase (AMPK), but treatment with AMPK activator AICAR had no obvious effects on CAT activity. A molecular docking analysis indicated that metformin might interact with CAT via hydrogen bonds. These data suggested that metformin effectively alleviated CCl₄-induced oxidative liver injury in mice and these hepatoprotective effects might be associated with CAT. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  9. Synergistic effects of metformin, resveratrol, and hydroxymethylbutyrate on insulin sensitivity

    Directory of Open Access Journals (Sweden)

    Bruckbauer A

    2013-02-01

    Full Text Available Antje Bruckbauer,1 Michael B Zemel1,21NuSirt Sciences Inc, 2Department of Nutrition, University of Tennessee, Knoxville, TN, USABackground: The purpose of this study was to determine whether a mixture of the polyphenol, resveratrol, and the leucine metabolite, hydroxymethylbutyrate (HMB, acts synergistically with low doses of metformin to impact insulin sensitivity and AMP-activated protein kinase-dependent outcomes in cell culture and in diabetic mice.Methods: C2C12 skeletal myotubes and 3T3-L1 adipocytes were treated with resveratrol 0.2 µM, HMB 5 µM, and metformin 0.1 mM alone or in combination. db/db mice were treated for 2 weeks with high (1.5 g/kg diet, low (0.75 g/kg diet, or very low (0.25 g/kg diet doses of metformin alone or in combination with a diet containing resveratrol 12.5 mg and CaHMB 2 g/kg.Results: The combination of metformin-resveratrol-HMB significantly increased fat oxidation, AMP-activated protein kinase, and Sirt1 activity in muscle cells compared with metformin or resveratrol-HMB alone. A similar trend was found in 3T3L1 adipocytes. In mice, the two lower doses of metformin exerted no independent effect but, when combined with resveratrol-HMB, both low-dose and very low-dose metformin improved insulin sensitivity (HOMAIR, plasma insulin levels, and insulin tolerance test response to a level comparable with that found for high-dose metformin. In addition, the metformin-resveratrol-HMB combination decreased visceral fat and liver weight in mice.Conclusion: Resveratrol-HMB combined with metformin may act synergistically on AMP-activated protein kinase-dependent pathways, leading to increased insulin sensitivity, which may reduce the therapeutic doses of metformin necessary in the treatment of diabetes.Keywords: diabetes, AMP-activated protein kinase, Sirt1, fat oxidation

  10. The effect of metformin on blood pressure and metabolism in nondiabetic hypertensive patients

    DEFF Research Database (Denmark)

    Snorgaard, O; Køber, L; Carlsen, J

    1997-01-01

    ), metformin 500 mg b.i.d. (n = 10), or placebo b.i.d. (n = 5) for 12 weeks. Office blood pressure (oBP), ambulatory blood pressure (aBP), lipoproteins, and oral glucose tolerance (OGTT) were measured/performed before and during treatment. SUBJECTS: Sixteen male and nine female nondiabetic (OGTT) patients......, not significantly different comparing metformin and placebo. Systolic oBP, diastolic aBP, and systolic aBP showed no significant change by treatment. The decline in diastolic oBP was 5 mmHg in the pooled group of metformin-treated patients, P

  11. Metformin Elicits Antitumor Effects and Downregulates the Histone Methyltransferase Multiple Myeloma SET Domain (MMSET) in Prostate Cancer Cells.

    Science.gov (United States)

    White-Al Habeeb, Nicole M A; Garcia, Julia; Fleshner, Neil; Bapat, Bharati

    2016-12-01

    This study explored the biological effects of metformin on prostate cancer (PCa) cells and determined molecular pathways and epigenetic regulators implicated in its mechanism of action. We performed mRNA expression profiling in 22Rv1 cells following 2.5 mM and 5 mM metformin treatment. Genes significantly modified by metformin treatment were ranked based on altered expression, involvement with cancer-related processes, and reported dysregulation in PCa. The effects of the top ranked gene, MMSET, on the proliferative and invasive capabilities of PCa cells were investigated via siRNA knockdown alone and also combined with metformin treatment. Metformin treatment decreased cell growth of PCa cell line 22Rv1 and stalled cells at the G1/S checkpoint in a time- and dose-dependent manner, resulting in increased cells in G1 (P prostate epithelium-derived cell-line RWPE-1, and its expression was decreased upon metformin treatment. siRNA-mediated knockdown of MMSET showed decreased cellular migration and invasion in DU-145 cells. MMSET knockdown in combination with metformin treatment resulted in further reduction in the capacity of PCa cells to migrate and invade. These data suggest MMSET may play a role in the inhibitory effect of metformin on PCa and could serve as a potential novel therapeutic target for PCa. Prostate 76:1507-1518, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  12. Metformin sensitizes chemotherapy by targeting cancer stem cells and the mTOR pathway in esophageal cancer

    OpenAIRE

    HONJO, SOICHIRO; AJANI, JAFFER A.; SCOTT, AILING W.; CHEN, QIONGRONG; SKINNER, HEATH D.; STROEHLEIN, JOHN; JOHNSON, RANDY L.; SONG, SHUMEI

    2014-01-01

    Our clinical study indicates esophageal adenocarcinoma patients on metformin had a better treatment response than those without metformin. However, the effects of metformin and the mechanisms of its action in esophageal cancer (EC) are unclear. EC cell lines were used to assess the effects of metformin alone or in combination with 5-fluorouracil on survival and apoptosis. RPPA proteomic array and immunoblots were used to identify signaling affected by metformin. Standard descriptive statistic...

  13. Caffeine induces metformin anticancer effect on fibrosarcoma in hamsters.

    Science.gov (United States)

    Popović, D J; Lalošević, D; Miljković, D; Popović, K J; Čapo, I; Popović, J K

    2018-04-01

    We investigated the effect of metformin and caffeine on fibrosarcoma in hamsters. 32 Syrian golden hamsters of both sexes, weighing approximately 100 g, were randomly allocated to 3 experimental and 2 control groups, with a minimum of 6 animals per group. 2 x 106 BHK-21/C13 cells in 1 ml were injected subcutaneously into the animals' back in 4 groups. The first experimental group started peroral treatment with metformin 500 mg/kg daily, the second with caffeine 100 mg/kg daily and the third with a combination of metformin 500 mg/kg and caffeine 100 mg/kg daily, via a gastric probe 3 days before tumor inoculation. After 2 weeks, when the tumors were approximately 2 cm in the control group, all animals were sacrificed. The blood was collected for glucose and other analyses. The tumors were excised and weighed and their diameters were measured. The tumor samples were pathohistologically (HE) and immunohistochemically (Ki-67, CD 31, COX IV, GLUT-1, iNOS) assessed and the main organs toxicologically analyzed, including the control animals that had received metformin and caffeine. Tumor volume was determined using the formula LxS2/2, where L was the longest and S the shortest diameter. Ki-67-positive cells in the tumor samples were quantified. Images were taken and processed by software UTHSCSA Image Tools for Windows Version 3.00. Statistical significances were determined by the Student's t-test. The combination of metformin and caffeine inhibited fibrosarcoma growth in hamsters without toxicity. Administration of metformin with caffeine might be an effective and safe approach in novel nontoxic adjuvant anticancer treatment.

  14. Metformin inhibits the proliferation of human prostate cancer PC-3 cells via the downregulation of insulin-like growth factor 1 receptor

    International Nuclear Information System (INIS)

    Kato, Haruo; Sekine, Yoshitaka; Furuya, Yosuke; Miyazawa, Yoshiyuki; Koike, Hidekazu; Suzuki, Kazuhiro

    2015-01-01

    Metformin is a biguanide drug that is widely used for the treatment of type 2 diabetes. Recent studies have shown that metformin inhibits cancer cell proliferation and tumor growth both in vitro and in vivo. The anti-tumor mechanisms of metformin include activation of the AMP-activated protein kinase/mTOR pathway and direct inhibition of insulin/insulin-like growth factor (IGF)-mediated cellular proliferation. However, the anti-tumor mechanism in prostate cancer remains unclear. Because activation of the IGF-1 receptor (IGF-1R) is required for prostate cell proliferation, IGF-1R inhibitors may be of therapeutic value. Accordingly, we examined the effects of metformin on IGF-1R signaling in prostate cancer cells. Metformin significantly inhibited PC-3 cell proliferation, migration, and invasion. IGF-1R mRNA expression decreased significantly after 48 h of treatment, and IGF-1R protein expression decreased in a similar manner. IGF-1R knockdown by siRNA transfection led to inhibited proliferation, migration and invasion of PC-3 cells. IGF-1 activated both ERK1/2 and Akt, but these effects were attenuated by metformin treatment. In addition, intraperitoneal treatment with metformin significantly reduced tumor growth and IGF-1R mRNA expression in PC-3 xenografts. Our results suggest that metformin is a potent inhibitor of the IGF-1/IGF-1R system and may be beneficial in prostate cancer treatment. - Highlights: • Metformin inhibited PC-3 cell proliferation, migration, and invasion. • Metformin decreased IGF-1R mRNA and protein expressions in PC-3 cells. • Metformin inhibited IGF-1 induced ERK and Akt phosphorylations in PC-3 cells. • Metformin treatment inhibited PC-3 cell growth and IGF-1R expression in vivo. • Metformin may be a potent inhibitor of the IGF-1/IGF-1R signaling

  15. Metformin inhibits the proliferation of human prostate cancer PC-3 cells via the downregulation of insulin-like growth factor 1 receptor

    Energy Technology Data Exchange (ETDEWEB)

    Kato, Haruo, E-mail: hal.kato@gunma-u.ac.jp; Sekine, Yoshitaka; Furuya, Yosuke; Miyazawa, Yoshiyuki; Koike, Hidekazu; Suzuki, Kazuhiro

    2015-05-22

    Metformin is a biguanide drug that is widely used for the treatment of type 2 diabetes. Recent studies have shown that metformin inhibits cancer cell proliferation and tumor growth both in vitro and in vivo. The anti-tumor mechanisms of metformin include activation of the AMP-activated protein kinase/mTOR pathway and direct inhibition of insulin/insulin-like growth factor (IGF)-mediated cellular proliferation. However, the anti-tumor mechanism in prostate cancer remains unclear. Because activation of the IGF-1 receptor (IGF-1R) is required for prostate cell proliferation, IGF-1R inhibitors may be of therapeutic value. Accordingly, we examined the effects of metformin on IGF-1R signaling in prostate cancer cells. Metformin significantly inhibited PC-3 cell proliferation, migration, and invasion. IGF-1R mRNA expression decreased significantly after 48 h of treatment, and IGF-1R protein expression decreased in a similar manner. IGF-1R knockdown by siRNA transfection led to inhibited proliferation, migration and invasion of PC-3 cells. IGF-1 activated both ERK1/2 and Akt, but these effects were attenuated by metformin treatment. In addition, intraperitoneal treatment with metformin significantly reduced tumor growth and IGF-1R mRNA expression in PC-3 xenografts. Our results suggest that metformin is a potent inhibitor of the IGF-1/IGF-1R system and may be beneficial in prostate cancer treatment. - Highlights: • Metformin inhibited PC-3 cell proliferation, migration, and invasion. • Metformin decreased IGF-1R mRNA and protein expressions in PC-3 cells. • Metformin inhibited IGF-1 induced ERK and Akt phosphorylations in PC-3 cells. • Metformin treatment inhibited PC-3 cell growth and IGF-1R expression in vivo. • Metformin may be a potent inhibitor of the IGF-1/IGF-1R signaling.

  16. Metformin: A Novel Biological Modifier of Tumor Response to Radiation Therapy

    International Nuclear Information System (INIS)

    Koritzinsky, Marianne

    2015-01-01

    Over the last decade, evidence has emerged to support a role for the antidiabetic drug metformin in the prevention and treatment of cancer. In particular, recent studies demonstrate that metformin enhances tumor response to radiation in experimental models, and retrospective analyses have shown that diabetic cancer patients treated with radiation therapy have improved outcomes if they take metformin to control their diabetes. Metformin may therefore be of utility for nondiabetic cancer patients treated with radiation therapy. The purpose of this review is to examine the data pertaining to an interaction between metformin and radiation, highlighting the essential steps needed to advance our current knowledge. There is also a focus on key biomarkers that should accompany prospective clinical trials in which metformin is being examined as a modifying agent with radiation therapy. Existing evidence supports that the mechanism underlying the ability of metformin to enhance radiation response is multifaceted, and includes direct radiosensitization as well as a reduction in tumor stem cell fraction, proliferation, and tumor hypoxia. Interestingly, metformin may enhance radiation response specifically in certain genetic backgrounds, such as in cells with loss of the tumor suppressors p53 and LKB1, giving rise to a therapeutic ratio and potential predictive biomarkers

  17. Metformin: A Novel Biological Modifier of Tumor Response to Radiation Therapy

    Energy Technology Data Exchange (ETDEWEB)

    Koritzinsky, Marianne, E-mail: mkoritzi@uhnresearch.ca

    2015-10-01

    Over the last decade, evidence has emerged to support a role for the antidiabetic drug metformin in the prevention and treatment of cancer. In particular, recent studies demonstrate that metformin enhances tumor response to radiation in experimental models, and retrospective analyses have shown that diabetic cancer patients treated with radiation therapy have improved outcomes if they take metformin to control their diabetes. Metformin may therefore be of utility for nondiabetic cancer patients treated with radiation therapy. The purpose of this review is to examine the data pertaining to an interaction between metformin and radiation, highlighting the essential steps needed to advance our current knowledge. There is also a focus on key biomarkers that should accompany prospective clinical trials in which metformin is being examined as a modifying agent with radiation therapy. Existing evidence supports that the mechanism underlying the ability of metformin to enhance radiation response is multifaceted, and includes direct radiosensitization as well as a reduction in tumor stem cell fraction, proliferation, and tumor hypoxia. Interestingly, metformin may enhance radiation response specifically in certain genetic backgrounds, such as in cells with loss of the tumor suppressors p53 and LKB1, giving rise to a therapeutic ratio and potential predictive biomarkers.

  18. Cost-effectiveness of add-on treatments to metformin in a Swedish setting: liraglutide vs sulphonylurea or sitagplitin.

    Science.gov (United States)

    Steen Carlsson, Katarina; Persson, Ulf

    2014-09-01

    To evaluate long-run cost-effectiveness in a Swedish setting for liraglutide compared with sulphonylureas (glimepiride) or sitagliptin, all as add-on to metformin for patients with type 2 diabetes insufficiently controlled with metformin in monotherapy. The IHE Cohort Model of Type 2 Diabetes was used to evaluate clinical and economic outcomes from a societal perspective. Model input data were obtained from two clinical trials, the Swedish National Diabetes Register and the literature. Cost data reflected year 2013 price level. The robustness of results was checked with one-way-sensitivity analysis and probability sensitivity analysis. The cost per QALY gained for liraglutide (1.2 mg) compared to SU (glimepiride 4 mg), both as add-on to metformin, ranged from SEK 226,000 to SEK 255,000 in analyzed patient cohorts. The cost per QALY for liraglutide (1.2 mg) vs sitagliptin (100 mg) as second-line treatment was lower, ranging from SEK 149,000 to SEK 161,000. Costs of preventive treatment were driving costs, but there was also a cost offset from reduced costs of complications of ∼ 20%. Notable cost differences were found for nephropathy, stroke, and heart failure. The predicted life expectancy with liraglutide increased the cost of net consumption for liraglutide. The analysis was an ex-ante analysis using model input data from clinical trials which may not reflect effectiveness in real-world clinical practice in broader patient populations. This limitation was explored in the sensitivity analysis. The lack of specific data on loss of production due to diabetes complications implied that these costs may be under-estimated. Treatment strategies with liraglutide 1.2 mg improved the expected quality-of-life and increased costs when compared to SU and to sitagliptin for second-line add-on treatments. The cost per QALY for liraglutide was in the range considered medium by Swedish authorities.

  19. The efficacy of metformin in pregnant women with polycystic ovary syndrome: a meta-analysis of clinical trials.

    Science.gov (United States)

    Zheng, J; Shan, P F; Gu, W

    2013-11-01

    The role of metformin in the treatment of pregnant women with polycystic ovary syndrome (PCOS) is controversial. Therefore, we evaluated whether the use of metformin during pregnancy in women with PCOS could reduce pregnancy-related complications. MEDLINE was searched to retrieve relevant trials. In addition, reviews and reference lists of the retrieved articles were scanned for further appropriate studies. The primary outcome measure was the incidence of complications of pregnancy, which included early pregnancy loss (EPL), gestational diabetes (GDM), pre-eclampsia (PE), and pre-term delivery (PD). In total, eight studies with 1106 patients were included. The pooled odds ratio (OR) (95% confidence interval) of outcome for pregnant women with PCOS prescribed metformin were 0.32 (0.19-0.55) for EPL, 0.37 (0.25-0.56) for GDM, 0.53 (0.30-0.95) for PE and 0.30 (0.13-0.68) for PD. Metformin therapy throughout pregnancy decreased the OR of EPL, GDM, PE, and PD in pregnant PCOS women with no serious detrimental side effects.

  20. Metformin for Weight Loss and Metabolic Control in Overweight Outpatients With Schizophrenia and Schizoaffective Disorder

    Science.gov (United States)

    Jarskog, L. Fredrik; Hamer, Robert M.; Catellier, Diane J.; Stewart, Dawn D.; LaVange, Lisa; Ray, Neepa; Golden, Lauren H.; Lieberman, Jeffrey A.; Stroup, T. Scott

    2013-01-01

    Objective The purpose of this study was to determine whether metformin promotes weight loss in overweight out-patients with chronic schizophrenia or schizoaffective disorder. Method In a double-blind study, 148 clinically stable, overweight (body mass index [BMI] ≥27) outpatients with chronic schizophrenia or schizoaffective disorder were randomly assigned to receive 16 weeks of metformin or placebo. Metformin was titrated up to 1,000 mg twice daily, as tolerated. All patients continued to receive their prestudy medications, and all received weekly diet and exercise counseling. The primary outcome measure was change in body weight from baseline to week 16. Results Fifty-eight (77.3%) patients who received metformin and 58 (81.7%) who received placebo completed 16 weeks of treatment. Mean change in body weight was −3.0 kg (95% CI=−4.0 to −2.0) for the metformin group and −1.0 kg (95% CI= −2.0 to 0.0) for the placebo group, with a between-group difference of −2.0 kg (95% CI=−3.4 to −0.6). Metformin also demonstrated a significant between-group advantage for BMI (−0.7; 95% CI=−1.1 to −0.2), triglyceride level (−20.2 mg/dL; 95% CI=−39.2 to −1.3), and hemoglobin A1c level (−0.07%; 95% CI=−0.14 to −0.004). Metformin-associated side effects were mostly gastrointestinal and generally transient, and they rarely led to treatment discontinuation. Conclusions Metformin was modestly effective in reducing weight and other risk factors for cardiovascular disease in clinically stable, overweight outpatients with chronic schizophrenia or schizoaffective disorder over 16 weeks. A significant time-by-treatment interaction suggests that benefits of metformin may continue to accrue with longer treatment. Metformin may have an important role in diminishing the adverse consequences of obesity and metabolic impairments in patients with schizophrenia. PMID:23846733

  1. Metformin Ameliorates Uterine Defects in a Rat Model of Polycystic Ovary Syndrome

    Directory of Open Access Journals (Sweden)

    Yuehui Zhang

    2017-04-01

    Full Text Available Adult rats treated concomitantly with insulin and human chorionic gonadotropin exhibit endocrine, metabolic, and reproductive abnormalities that are very similar to those observed in polycystic ovary syndrome (PCOS patients. In this study, we used this rat model to assess the effects of metformin on PCOS-related uterine dysfunction. In addition to reducing androgen levels, improving insulin sensitivity, and correcting the reproductive cycle, metformin treatment induced morphological changes in the PCOS-like uterus. At the molecular and cellular levels, metformin normalized the androgen receptor-mediated transcriptional program and restored epithelial–stromal interactions. In contrast to glucose transport, uterine inflammatory gene expression was suppressed through the PI3K–Akt–NFκB network, but without affecting apoptosis. These effects appeared to be independent of AMPK subunit and autophagy-related protein regulation. We found that when metformin treatment partially restored implantation, several implantation-related genes were normalized in the PCOS-like rat uterus. These results improve our understanding of how metformin rescues the disruption of the implantation process due to the uterine defects that result from hyperandrogenism and insulin resistance. Our data provide insights into the molecular and functional clues that might help explain, at least in part, the potential therapeutic options of metformin in PCOS patients with uterine dysfunction.

  2. Formulation and Evaluation of a Sustained-Release Tablets of Metformin Hydrochloride Using Hydrophilic Synthetic and Hydrophobic Natural Polymers

    OpenAIRE

    Wadher, K. J.; Kakde, R. B.; Umekar, M. J.

    2011-01-01

    Metformin hydrochloride has relatively short plasma half-life, low absolute bioavailability. The need for the administration two to three times a day when larger doses are required can decrease patient compliance. Sustained release formulation that would maintain plasma level for 8-12 h might be sufficient for daily dosing of metformin. Sustained release products are needed for metformin to prolong its duration of action and to improve patient compliances. The overall objective of this study ...

  3. Hepatic Glucose Production Increases in Response to Metformin Treatment in the Glycogen-depleted State

    DEFF Research Database (Denmark)

    Christensen, Mette Marie Hougaard; Højlund, Kurt; Hother-Nielsen, Ole

    with two reduced-function alleles) were fasted for 42 h twice. In one of the periods, before the fasting, the volunteers were titrated to steady-state with 1 g metformin twice daily for seven days. Parameters of whole-body glucose metabolism were assessed using [3-3^H] glucose, indirect calorimetry......Metformin is believed to reduce glucose levels primarily by inhibiting hepatic glucose production, but at the same time do not cause hypoglycemia. Recent data indicate that metformin antagonizes the major glucose counterregulatory hormone, glucagon suggesting that other mechanisms protect against...... hypoglycemia. Here, we examined the effect of metformin on whole-body glucose metabolism after a glycogen-depleting 40 h fast and the role of reduced-function alleles in OCT1. In a randomized cross-over trial, 34 healthy volunteers with known OCT1 genotypes (12 with two wild-type alleles, 13 with one and 9...

  4. Effects of metformin hydrochloride on blood glucose and insulin responses to oral dextrose in horses.

    Science.gov (United States)

    Rendle, D I; Rutledge, F; Hughes, K J; Heller, J; Durham, A E

    2013-11-01

    Metformin is a potential therapeutic agent for the treatment of insulin resistance (IR). In laboratory animals, orally administered metformin reduces intestinal glucose absorption and may therefore affect insulinaemic responses to oral carbohydrate ingestion. To determine whether pretreatment with metformin reduces plasma glucose concentration and insulin responses following consumption of dextrose in horses. Therapeutic cross-over study. Seven healthy Standardbred and Thoroughbred geldings were subjected to an oral dextrose challenge test on 4 occasions: with and without metformin, before and after induction of IR with dexamethasone. Metformin was administered by nasogastric tube at 30 mg/kg bwt 1 h before administration of dextrose. Glucose and insulin concentrations in plasma/serum were measured at regular intervals during each test. Linear mixed models were specified for each predetermined outcome variable, and for each model the 'treatment' was included as a fixed effect with 4 categorical levels (none, metformin, dexamethasone and dexamethasone with metformin) and horse accounted for as a random effect. In healthy horses, the administration of metformin resulted in a statistically significant reduction in peak glucose concentration (P = 0.002), area under the glucose curve (Pdextrose administration (P = 0.011). Following the induction of IR, administration of metformin was associated with significant differences in peak glucose concentration (Pdextrose administration (P = 0.014). Metformin resulted in reduced glycaemic and insulinaemic responses both in healthy horses and in horses with experimentally induced IR. Metformin may benefit horses with naturally acquired IR by reducing glycaemic and insulinaemic responses to dietary nonstructural carbohydrates. Further investigations into the mechanisms of action of metformin in horses and controlled clinical trials are warranted. © 2013 EVJ Ltd.

  5. Short-term therapy with combination dipeptidyl peptidase-4 inhibitor saxagliptin/metformin extended release (XR) is superior to saxagliptin or metformin XR monotherapy in prediabetic women with polycystic ovary syndrome: a single-blind, randomized, pilot study.

    Science.gov (United States)

    Elkind-Hirsch, Karen E; Paterson, Martha S; Seidemann, Ericka L; Gutowski, Hanh C

    2017-01-01

    To evaluate efficacy with the dipeptidyl peptidase-4 inhibitor saxagliptin (SAXA), metformin extended release (MET), and combination (SAXA-MET) in patients with polycystic ovary syndrome (PCOS) and impaired glucose regulation. Prospective, randomized, single-blind drug study. Outpatient clinic. Patients (n = 38) with PCOS (aged 18-42 years) and prediabetic hyperglycemia determined by a 75-gram oral glucose tolerance test. Patients were randomized to SAXA-MET (5 mg/2,000 mg), SAXA (5 mg), or MET (2,000 mg) for 16 weeks. Fasting and mean blood glucose, insulin sensitivity, insulin secretion, and insulin secretion-sensitivity index (IS-SI) by oral glucose tolerance tests. Free androgen index and lipid levels, average menstrual interval, and anthropometric measurements (body mass index, waist circumference, and waist/height ratio). The study was completed by 34 patients. Nineteen patients had normal glucose tolerance: 3 of 12 (25%) on MET; 6 of 11 (55%) on SAXA; and 10 of 11 (91%) on SAXA-MET (SAXA-MET statistically superior to MET) at study completion. Body mass index, waist circumference, waist/height ratio, free androgen index, insulin sensitivity, IS-SI, and menses improved in all groups; however, IS-SI and menstrual regularity were significantly better with SAXA-MET vs. MET treatment. Triglyceride, triglyceride/high-density lipoprotein cholesterol ratio and mean blood glucose significantly declined in the SAXA-MET and SAXA groups only. This pilot work provides the first evidence regarding the effects of a dipeptidyl peptidase-4 inhibitor alone and in combination with MET in this patient population. Treatment with SAXA-MET was superior to either drug alone in terms of clinical and metabolic benefits in prediabetic patients with PCOS. NCT02022007. Copyright © 2016 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

  6. Postmeal exercise blunts postprandial glucose excursions in people on metformin monotherapy.

    Science.gov (United States)

    Erickson, Melissa L; Little, Jonathan P; Gay, Jennifer L; McCully, Kevin K; Jenkins, Nathan T

    2017-08-01

    Metformin is used clinically to reduce fasting glucose with minimal effects on postprandial glucose. Postmeal exercise reduces postprandial glucose and may offer additional glucose-lowering benefit beyond that of metformin alone, yet controversy exists surrounding exercise and metformin interactions. It is currently unknown how postmeal exercise and metformin monotherapy in combination will affect postprandial glucose. Thus, we examined the independent and combined effects of postmeal exercise and metformin monotherapy on postprandial glucose. A randomized crossover design was used to assess the influence of postmeal exercise on postprandial glucose excursions in 10 people treated with metformin monotherapy (57 ± 10 yr, HbA 1C  = 6.3 ± 0.6%). Each participant completed the following four conditions: sedentary and postmeal exercise (5 × 10-min bouts of treadmill walking at 60% V̇o 2max ) with metformin and sedentary and postmeal exercise without metformin. Peak postprandial glucose within a 2-h time window and 2-h total area under the curve was assessed after a standardized breakfast meal, using continuous glucose monitoring. Postmeal exercise significantly blunted 2-h peak ( P = 0.001) and 2-h area under the curve ( P = 0.006), with the lowest peak postprandial glucose excursion observed with postmeal exercise and metformin combined ( P exercise: 9.7 ± 2.3, washout/sedentary: 13.3 ± 3.2, washout/exercise: 11.1 ± 3.4 mmol/l). Postmeal exercise and metformin in combination resulted in the lowest peak postprandial glucose excursion compared with either treatment modality alone. Exercise timed to the postprandial phase may be important for optimizing glucose control during metformin monotherapy. NEW & NOTEWORTHY The interactive effects of metformin and exercise on key physiological outcomes remain an area of controversy. Findings from this study show that the combination of metformin monotherapy and moderate-intensity postmeal exercise led to

  7. The Role of Metformin in the Management of NAFLD

    Directory of Open Access Journals (Sweden)

    Angela Mazza

    2012-01-01

    Full Text Available Nonalcoholic fatty liver disease (NAFLD is the most common liver disorder worldwide. Its prevalence ranges 10–24% in the general population, reaching 60–95% and 28–55% in obese and diabetic patients, respectively. Although the etiology of NAFLD is still unclear, several lines of evidences have indicated a pathogenetic role of insulin resistance in this disorder. This concept has stimulated several clinical studies where antidiabetic drugs, such as insulin sensitizers including metformin, have been evaluated in insulin-resistant, NAFLD patients. These studies indicate that metformin might be of benefit in the treatment of NAFLD, also in nondiabetic patients, when associated to hypocaloric diet and weight control. However, the heterogeneity of these studies still prevents us from reaching firm conclusions about treatment guidelines. Moreover, metformin could have beneficial tissue-specific effects in NAFLD patients irrespective of its effects as insulin sensitizer.

  8. Fatal Metformin Overdose Presenting with Progressive Hyperglycemia

    Directory of Open Access Journals (Sweden)

    Suchard, Jeffrey R

    2008-08-01

    Full Text Available A 29-year-old man with no history of diabetes ingested over 60 grams of metformin in a suicide attempt. He presented to the emergency department with acute renal insufficiency, severe lactic acidosis, and rapidly-progressive hyperglycemia. The patient’s peak serum glucose level of 707 mg/dL is the highest yet reported in a case of metformin toxicity. Treatment included sodium bicarbonate infusion and hemodialysis, but the patient suffered several cardiac arrests with pulseless electrical activity and ultimately expired 25 hours after the ingestion.

  9. Past, Present, and Future Research Avenues for Metformin

    Science.gov (United States)

    Sparkes, Steven T.; Patel, Dhiren K.

    2014-01-01

    Objective: To review why metformin is considered first-line therapy for type 2 diabetes mellitus (T2DM) and review newer avenues of research currently being evaluated. Data Sources: The Cochrane Library and Medline (to January 2014) were searched for case–control and cohort studies, clinical trials, and systematic reviews and meta-analyses involving metformin for any indication. Study Selection and Data Extraction: The literature search found 5 major avenues of research for metformin: reduction in mortality, delayed-onset or prevention of T2DM in the presence of prediabetes, nonalcoholic fatty liver disease (NAFLD), polycystic ovarian syndrome (PCOS), and decreased cancer risk. When available, multi-center, double-blind, controlled clinical trials or meta-analyses thereof were selected for review. If these types of studies did not exist, other types of studies were chosen for review. Data Synthesis: Metformin significantly decreases all-cause and diabetes-related mortality in overweight and obese patients with T2DM. It may also decrease risk of progression to T2DM in patients with prediabetes. Metformin has been studied for the treatment of NAFLD though data are limited. Metformin alone or combined with clomiphene may increase pregnancy and ovulation rates but has not yet been shown to increase live-birth rates in patients with PCOS. Metformin may decrease risk of colorectal cancer but not all-cancer risk. Conclusions: Metformin’s clinical role in T2DM and prediabetes is well established. Other avenues of research being evaluated at this time are NAFLD, PCOS, and reduced risk of cancer; more data are needed before it has a clinical role in these indications.

  10. The Antidiabetic Drug Metformin Inhibits the Proliferation of Bladder Cancer Cells in Vitro and in Vivo

    Directory of Open Access Journals (Sweden)

    Tao Zhang

    2013-12-01

    Full Text Available Recent studies suggest that metformin, a widely used antidiabetic agent, may reduce cancer risk and improve prognosis of certain malignancies. However, the mechanisms for the anti-cancer effects of metformin remain uncertain. In this study, we investigated the effects of metformin on human bladder cancer cells and the underlying mechanisms. Metformin significantly inhibited the proliferation and colony formation of 5637 and T24 cells in vitro; specifically, metformin induced an apparent cell cycle arrest in G0/G1 phases, accompanied by a strong decrease of cyclin D1, cyclin-dependent kinase 4 (CDK4, E2F1 and an increase of p21waf-1. Further experiments revealed that metformin activated AMP-activated protein kinase (AMPK and suppressed mammalian target of rapamycin (mTOR, the central regulator of protein synthesis and cell growth. Moreover, daily treatment of metformin led to a substantial inhibition of tumor growth in a xenograft model with concomitant decrease in the expression of proliferating cell nuclear antigen (PCNA, cyclin D1 and p-mTOR. The in vitro and in vivo results demonstrate that metformin efficiently suppresses the proliferation of bladder cancer cells and suggest that metformin may be a potential therapeutic agent for the treatment of bladder cancer.

  11. Polycystic ovary syndrome (PCOS): metformin.

    Science.gov (United States)

    Cahill, David J; O'Brien, Katherine

    2015-03-27

    Polycystic ovary syndrome (PCOS) is classically characterised by an accumulation of incompletely developed follicles in the ovaries due to anovulation. However, since the publication of the Rotterdam criteria, there is acceptance that menstrual cycle and endocrine dysfunction with hyperandrogenism is more important in reaching the diagnosis than ultrasound findings. It is diagnosed in up to 10% of women attending gynaecology clinics, but the prevalence in the population as a whole varies from 10% to 20%, depending on which diagnostic criteria are used. PCOS has been associated with hirsutism, infertility, acne, weight gain, type 2 diabetes, cardiovascular disease (CVD), and endometrial hyperplasia. We conducted a systematic review and aimed to answer the following clinical question: What are the effects of metformin on hirsutism and menstrual frequency in women with PCOS? We searched: Medline, Embase, The Cochrane Library, and other important databases up to May 2014 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). We found 14 studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. In this systematic review we present information relating to the effectiveness and safety of the following interventions: metformin compared with placebo/no treatment, metformin compared with weight loss intervention, or metformin compared with cyproterone acetate-ethinylestradiol.

  12. Short-term curative effect of endovascular stent-graft treatment for aortic diseases in China: a systematic review.

    Directory of Open Access Journals (Sweden)

    Siwen Wang

    Full Text Available INTRODUCTION: We analyzed the short-term efficacy of endovascular treatment for aortic diseases by summarizing all available published data on endovascular stent-graft treatment for abdominal aortic aneurysm (AAA, thoracic aortic aneurysm (TAA, type A aortic dissection (type A AD and type B aortic dissection (type B AD in China. METHODS: We performed a systematic analysis of 935 published series on retrograde endovascular treatment for aortic diseases in China from January 1996 to November 2010. Based on the inclusion criteria, 159 studies, involving a total of 5531 patients, were included. RESULTS: There were no significant differences in procedural success among the studies (P>0.05. The rates of overall neurologic complications and stroke were significantly different in all two-group comparisons (P0.05. A significant difference was noted between the 30-day mortality rate of the type A AD patients and the AAA or type B AD patients (P<0.05. CONCLUSION: Endovascular stent-graft is a feasible and safe treatment for aortic diseases, with high procedural success and low incidences of post-procedural complications and short-term mortality. Endovascular treatment for AAA and type B AD is more efficient than for type A AD and TAA.

  13. Carbon source and myc expression influence the antiproliferative actions of metformin.

    Science.gov (United States)

    Javeshghani, Shiva; Zakikhani, Mahvash; Austin, Shane; Bazile, Miguel; Blouin, Marie-José; Topisirovic, Ivan; St-Pierre, Julie; Pollak, Michael N

    2012-12-01

    Epidemiologic and experimental data have led to increased interest in possible roles of biguanides in cancer prevention and/or treatment. Prior studies suggest that the primary action of metformin is inhibition of oxidative phosphorylation, resulting in reduced mitochondrial ATP production and activation of AMPK. In vitro, this may lead to AMPK-dependent growth inhibition if AMPK and its effector pathways are intact or to an energetic crisis if these are defective. We now show that the effect of exposure of several transformed cell lines to metformin varies with carbon source: in the presence of glutamine and absence of glucose, a 75% decrease in cellular ATP and an 80% decrease in cell number is typical; in contrast, when glucose is present, metformin exposure leads to increased glycolysis, with only a modest reduction in ATP level and cell number. Overexpression of myc was associated with sensitization to the antiproliferative effects of metformin, consistent with myc involvement in "glutamine addiction". Our results reveal previously unrecognized factors that influence metformin sensitivity and suggest that metformin-induced increase in glycolysis attenuates the antiproliferative effects of the compound.

  14. The influence of metformin as a radiosensitizer of cells submitted to gamma radiation

    Energy Technology Data Exchange (ETDEWEB)

    Gonçalves, Letícia S.; Pereira, Alline G.; Gerolis, Luanai G.L.; Filho, Jamilson N.R.; Neves, Maria J., E-mail: lsatlergoncalves@gmail.com [Centro de Desenvolvimento da Tecnologia Nuclear (CDTN/CNEN-MG), Belo Horizontge, MG (Brazil). Lab. de Radiobiologia

    2017-07-01

    In recent years, due to the high prevalence of type 2 diabetes, the pharmacological therapy with metformin has become one of the most prescribed medications worldwide, with approximately 150 million people currently in use. Several studies have reflected the relevance of this fact, indicating that this extensively used drug may play another important role: it has been reported that metformin could be responsible for decreasing cancer incidence and mortality in diabetic patients. However, the mechanism by which its antineoplastic effect occurs remains unclear. The term cancer refers to not only one single disease, but to hundreds of them, grouped under the same name. Even in one specific organ, different types of malignant cells can possibly develop. Radiotherapy, one of the most effective ways to combat many cancers, is based on the formation of free radicals through the radiolysis of water molecules on the affected area, caused by ionizing irradiation. The objective of this work was to study if the treatment with metformin can influence the effect caused by ionizing radiation on cells, using the yeast Saccharomyces cerevisiae as an experimental model for cancer. In other words, this work aims to analyze if metformin acts as a radiosensitizer of tumor cells. This can represent a possible strategy as a therapeutic combination to be explored in the war against cancer. (author)

  15. The influence of metformin as a radiosensitizer of cells submitted to gamma radiation

    International Nuclear Information System (INIS)

    Gonçalves, Letícia S.; Pereira, Alline G.; Gerolis, Luanai G.L.; Filho, Jamilson N.R.; Neves, Maria J.

    2017-01-01

    In recent years, due to the high prevalence of type 2 diabetes, the pharmacological therapy with metformin has become one of the most prescribed medications worldwide, with approximately 150 million people currently in use. Several studies have reflected the relevance of this fact, indicating that this extensively used drug may play another important role: it has been reported that metformin could be responsible for decreasing cancer incidence and mortality in diabetic patients. However, the mechanism by which its antineoplastic effect occurs remains unclear. The term cancer refers to not only one single disease, but to hundreds of them, grouped under the same name. Even in one specific organ, different types of malignant cells can possibly develop. Radiotherapy, one of the most effective ways to combat many cancers, is based on the formation of free radicals through the radiolysis of water molecules on the affected area, caused by ionizing irradiation. The objective of this work was to study if the treatment with metformin can influence the effect caused by ionizing radiation on cells, using the yeast Saccharomyces cerevisiae as an experimental model for cancer. In other words, this work aims to analyze if metformin acts as a radiosensitizer of tumor cells. This can represent a possible strategy as a therapeutic combination to be explored in the war against cancer. (author)

  16. Efficacy of Metformin Versus Insulin in the Management of Pregnancy with Diabetes

    International Nuclear Information System (INIS)

    Waheed, S.; Malik, F.P.

    2013-01-01

    Objective: To compare the efficacy of metformin with insulin in the management of pregnancy with diabetes. Study Design: Randomized clinical trial. Place and Duration of Study: Department of Obstetrics and Gynaecology, Maternal and Child Health Centre (MCH), Pakistan Institute of Medical Sciences, Islamabad, from May 2010 to January 2011. Methodology: A total of 68 pregnant patients with diabetes were included in this study. Patients were randomly divided in to two groups of each 34 patients based on table of random numbers. One was labelled as group-A and other was labelled as group-B. Group-A received insulin and group-B received metformin for the management of diabetes. Results: The mean age was 29.82 A+- 4.58 and 29.35 A+- 4.97 years in groups-A and B respectively. Fasting blood sugar level after 1 month was controlled in 22 (64.7%) patients in group-A and in 27 (79.4%) in group-B (p > 0.05). Fasting blood sugar level at term, remained controlled in 30 (88.2%) patients in group-A and 27 (79.4%) in group-B (p > 0.05). Comparison of random blood sugar levels within normal limits after 1 month in 25 (73.5%) in group-A and in 24 (70.6%) in group-B. At term, random blood sugar level was controlled in 28 (82.4%) and 27 (79.4%) patients in group-A and B, respectively. Comparison of post-treatment HBA1C level depicts that diabetes controlled in 27 (79.4%) patients in group-A while in 28 (82.3%) patients of group-B. The efficacy of metformin and insulin in controlling diabetes was equal in two groups. Conclusion: There was no marked difference in efficacy of metformin and insulin in controlling diabetes in pregnant patients in two groups. (author)

  17. Efficacy of metformin versus insulin in the management of pregnancy with diabetes.

    Science.gov (United States)

    Waheed, Seema; Malik, Farhat Perveen; Mazhar, Syeda Batool

    2013-12-01

    To compare the efficacy of metformin with insulin in the management of pregnancy with diabetes. Randomized clinical trial. Department of Obstetrics and Gynaecology, Maternal and Child Health Centre (MCH), Pakistan Institute of Medical Sciences, Islamabad, from May 2010 to January 2011. A total of 68 pregnant patients with diabetes were included in this study. Patients were randomly divided in to two groups of each 34 patients based on table of random numbers. One was labelled as group-A and other was labelled as group-B. Group-A received insulin and group-B received metformin for the management of diabetes. The mean age was 29.82 ± 4.58 and 29.35 ± 4.97 years in groups-A and B respectively. Fasting blood sugar level after 1 month was controlled in 22 (64.7%) patients in group-A and in 27 (79.4%) in group-B (p > 0.05). Fasting blood sugar level at term, remained controlled in 30 (88.2%) patients in group-A and 27 (79.4%) in group-B (p > 0.05). Comparison of random blood sugar levels within normal limits after 1 month in 25 (73.5%) in group-A and in 24 (70.6%) in group-B. At term, random blood sugar level was controlled in 28 (82.4%) and 27 (79.4%) patients in group-A and B, respectively. Comparison of post-treatment HBA1C level depicts that diabetes controlled in 27 (79.4%) patients in group-A while in 28 (82.3%) patients of group-B. The efficacy of metformin and insulin in controlling diabetes was equal in two groups. There was no marked difference in efficacy of metformin and insulin in controlling diabetes in pregnant patients in two groups.

  18. Metformin induces oxidative stress in white adipocytes and raises uncoupling protein 2 levels.

    Science.gov (United States)

    Anedda, Andrea; Rial, Eduardo; González-Barroso, M Mar

    2008-10-01

    Metformin is a drug widely used to treat type 2 diabetes. It enhances insulin sensitivity by improving glucose utilization in tissues like liver or muscle. Metformin inhibits respiration, and the decrease in cellular energy activates the AMP-activated protein kinase that in turn switches on catabolic pathways. Moreover, metformin increases lipolysis and beta-oxidation in white adipose tissue, thereby reducing the triglyceride stores. The uncoupling proteins (UCPs) are transporters that lower the efficiency of mitochondrial oxidative phosphorylation. UCP2 is thought to protect against oxidative stress although, alternatively, it could play an energy dissipation role. The aim of this work was to analyse the involvement of UCP2 on the effects of metformin in white adipocytes. We studied the effect of this drug in differentiating 3T3-L1 adipocytes and found that metformin causes oxidative stress since it increases the levels of reactive oxygen species (ROS) and lowers the aconitase activity. Variations in UCP2 protein levels parallel those of ROS. Metformin also increases lipolysis in these cells although only when the levels of ROS and UCP2 have decreased. Hence, UCP2 does not appear to be needed to facilitate fatty acid oxidation. Furthermore, treatment of C57BL/6 mice with metformin also augmented the levels of UCP2 in epididymal white adipose tissue. We conclude that metformin treatment leads to the overexpression of UCP2 in adipocytes to minimize the oxidative stress that is probably due to the inhibition of respiration caused by the drug.

  19. Metformin for Preventing Gestational Diabetes in Women with Polycystic Ovarian Syndrome

    International Nuclear Information System (INIS)

    Ainuddin, J. A.; Kazi, A.; Aftab, S.; Kamran, A.

    2015-01-01

    Objective:To assess the effect of metformin in controlling Gestational Diabetes Mellitus (GDM) in women with Polycystic Ovarian Syndrome (PCOS). Study Design: Comparative cohort study. Place and Duration of Study: Gynecology Clinics of Mamji Hospital, Karachi, from 2008 to 2010. Methodology: Patients who had been diagnosed Polycystic Ovarian Syndrome (PCOS) with hyperinsulinemia and conceived and continued pregnancy, were divided in two groups; 50 patients received metformin throughout pregnancy and 32 did not. Development of GDM was ascertained in both groups. The patients were followed throughout pregnancy and in puerperium with OGTT as per WHO criteria. Primary outcome measure was development of gestational diabetes mellitus. Comparison of continuous variables was done using student 't' test. For categorical variables, frequency and percentages are reported while, odds ratio is also estimated for GDM during pregnancy. Results: A total of 82 women with PCOS were included in this study, out of whom, 50 patients received metformin treatment while 32 patients did not. Pregnant women with PCOS in both groups were comparable in age, weight, parity and BMI. Mean fasting insulin levels at beginning of study entry were 17.22 ± 2.3 mIU/L and 16.93 ± 2.28 mIU/L in metformin and no metformin group respectively (p=0.589). Mean fasting blood sugar levels were 94.54 mg/dl in metformin and 99.59 mg/dl in no metformin group p < 0.001. A total of 5 (10%) patients in metformin group developed GDM while 11 (34.37% OR 4.71, p = 0.01) developed GDM in no metformin group. Patients not receiving metformin were 4.7 times likely to have GDM (OR: 4.71) compared to those who received it. Conclusion: The frequency of gestational diabetes, was significantly higher in patients with PCOS who had not received metformin compared to those who did. (author)

  20. Metformin for preventing gestational diabetes in women with polycystic ovarian syndrome.

    Science.gov (United States)

    Ainuddin, Jahan Ara; Kazi, Sarah; Aftab, Shazia; Kamran, Ayesha

    2015-04-01

    To assess the effect of metformin in controlling Gestational Diabetes Mellitus (GDM) in women with Polycystic Ovarian Syndrome (PCOS). Comparative cohort study. Gynecology Clinics of Mamji Hospital, Karachi, from 2008 to 2010. Patients who had been diagnosed Polycystic Ovarian Syndrome (PCOS) with hyperinsulinemia and conceived and continued pregnancy, were divided in two groups; 50 patients received metformin throughout pregnancy and 32 did not. Development of GDM was ascertained in both groups. The patients were followed throughout pregnancy and in puerperium with OGTT as per WHO criteria. Primary outcome measure was development of gestational diabetes mellitus. Comparison of continuous variables was done using student 't' test. For categorical variables, frequency and percentages are reported while, odds ratio is also estimated for GDM during pregnancy. A total of 82 women with PCOS were included in this study, out of whom, 50 patients received metformin treatment while 32 patients did not. Pregnant women with PCOS in both groups were comparable in age, weight, parity and BMI. Mean fasting insulin levels at beginning of study entry were 17.22 ± 2.3 mIU/L and 16.93 ± 2.28 mIU/L in metformin and no metformin group respectively (p=0.589). Mean fasting blood sugar levels were 94.54 mg/dl in metformin and 99.59 mg/dl in no metformin group p metformin group developed GDM while 11 (34.37% OR 4.71, p = 0.01) developed GDM in no metformin group. Patients not receiving metformin were 4.7 times likely to have GDM (OR: 4.71) compared to those who received it. The frequency of gestational diabetes, was significantly higher in patients with PCOS who had not received metformin compared to those who did.

  1. Metformin increases pressure pain threshold in lean women with polycystic ovary syndrome.

    Science.gov (United States)

    Kiałka, Marta; Milewicz, Tomasz; Sztefko, Krystyna; Rogatko, Iwona; Majewska, Renata

    2016-01-01

    Despite the strong preclinical rationale, there are only very few data considering the utility of metformin as a potential pain therapeutic in humans. The aim of this study was to determine the association between metformin therapy and pressure pain threshold (PPT) in lean women with polycystic ovary syndrome (PCOS). We hypothesized that metformin therapy in lean PCOS women increases PPT. Twenty-seven lean PCOS women with free androgen index phenotype >5 and 18 lean healthy controls were enrolled in the study. Fifteen of the PCOS women were randomly assigned to be treated with metformin 1,500 mg daily for 6 months. PPT and plasma β-endorphin levels were measured in all women at the beginning of the study and after 6 months of observation. We observed an increase in PPT values measured on deltoid and trapezius muscle in the PCOS with metformin group after 6 months of metformin administration (4.81±0.88 kg/cm(2), PPCOS without treatment group and in controls. We did not observe any significant changes in serum β-endorphin levels in any studied groups during the 6-month observation. We conclude that metformin therapy increases PPT in lean PCOS women, without affecting plasma β-endorphin concentration. Our results may suggest the potential role of metformin in pain therapy. We propose that larger, randomized studies on metformin impact on pain perception should be performed.

  2. Phase II randomized trial of neoadjuvant metformin plus letrozole versus placebo plus letrozole for estrogen receptor positive postmenopausal breast cancer (METEOR)

    International Nuclear Information System (INIS)

    Kim, Jisun; Kim, Lee Su; Han, Sehwan; Nam, Seok Jin; Kang, Han-Sung; Kim, Seung Il; Yoo, Young Bum; Jeong, Joon; Kim, Tae Hyun; Kang, Taewoo; Kim, Sung-Won; Lim, Woosung; Jung, Yongsik; Lee, Jeong Eon; Kim, Ku Sang; Yu, Jong-Han; Chae, Byung Joo; Jung, So-Youn; Kang, Eunyoung; Choi, Su Yun; Moon, Hyeong-Gon; Noh, Dong-Young; Kim, Eun-Kyu; Han, Wonshik; Kim, Min-Kyoon; Paik, Nam-Sun; Jeong, Sang-Seol; Yoon, Jung-han; Park, Chan Heun; Ahn, Sei Hyun

    2014-01-01

    Neoadjuvant endocrine therapy with an aromatase inhibitor has shown efficacy comparable to that of neoadjuvant chemotherapy in patients with postmenopausal breast cancer. Preclinical and clinical studies have shown that the antidiabetic drug metformin has anti-tumor activity. This prospective, multicenter, phase II randomized, placebo controlled trial was designed to evaluate the direct anti-tumor effect of metformin in non-diabetic postmenopausal women with estrogen-receptor (ER) positive breast cancer. Patients meeting the inclusion criteria and providing written informed consent will be randomized to 24 weeks of neoadjuvant treatment with letrozole (2.5 mg/day) and either metformin (2000 mg/day) or placebo. Target accrual number is 104 patients per arm. The primary endpoint will be clinical response rate, as measured by calipers. Secondary endpoints include pathologic complete response rate, breast conserving rate, change in Ki67 expression, breast density change, and toxicity profile. Molecular assays will be performed using samples obtained before treatment, at week 4, and postoperatively. This study will provide direct evidence of the anti-tumor effect of metformin in non-diabetic, postmenopausal patients with ER-positive breast cancer. ClinicalTrials.gov Identifier http://clinicaltrial.gov/ct2/show/NCT01589367?term

  3. BISOPROLOL AND METFORMIN IN PATIENTS WITH ARTERIAL HYPERTENSION AND METABOLIC SYNDROME

    Directory of Open Access Journals (Sweden)

    V. A. Nevzorova

    2007-01-01

    Full Text Available Aim. To compare efficacy of bisoprolol and bisoprolol+metformin combination in patients with arterial hypertension (AH and metabolic syndrome (MS.Material and methods. 20 patients with AH and MS were involved in the study. They were randomized in 2 groups, 10 patients in each group. Patients of the 1st group received bisoprolol. Patients of the 2nd group received combination of bisoprolol and metformin. Blood pressure (BP, body mass index (BMI, carbohydrate metabolism, lipid profile, microalbuminuria (МАU level was determined before, within and at the end of 24-week treatment.Results. Both treatments resulted in similar reduction in BP. Reduction of BMI and insulin plasma concentration was more significant in patients received combined therapy. Both treatments improved lipid profile and reduced MAU.Conclusion. Bisoprolol has positive effect on pathogenic mechanisms of AH and MS. Metformin additionally improves carbohydrate and lipid metabolism.

  4. A pilot randomized, controlled trial of metformin versus insulin in women with type 2 diabetes mellitus during pregnancy.

    Science.gov (United States)

    Refuerzo, Jerrie S; Gowen, Rose; Pedroza, Claudia; Hutchinson, Maria; Blackwell, Sean C; Ramin, Susan

    2015-02-01

    Few studies support oral diabetic treatment in pregnant women with type 2 diabetes mellitus (T2DM). The objective of this study was to compare the effects of metformin versus insulin on achieving glycemic control and improving maternal and neonatal outcomes in pregnant women with T2DM. A pilot randomized, controlled trial was conducted of metformin versus insulin for the treatment of T2DM during pregnancy. The primary outcome was glycemic control measured with hemoglobin A1c metformin and 11 received insulin. All women in both groups achieved glycemic control by delivery (HgbA1c: metformin 5.96 ± 5.88 vs. insulin 6.34 ± 0.92%). There were similar rates of cesarean delivery, birth weights, neonatal intensive care unit admissions, respiratory distress syndrome, and neonatal dextrose treatment between groups. There was one case of fetal macrosomia in the insulin group, one case of shoulder dystocia in the metformin group and no cases of failed metformin therapy. In this pilot study, glycemic control was achieved in women who received metformin and insulin. Larger studies are needed to determine whether metformin can be considered a reasonable alternative to insulin in pregnant women with T2DM. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

  5. The Effect of Metformine on Glucose Control in Patients with Diabetes Type 1

    Directory of Open Access Journals (Sweden)

    A. Ziaee

    2010-07-01

    Full Text Available Introduction & Objective: Metabolic control in adolescents with type 1 DM who are in pubertal period will be impaired, thus finding a therapeutic strategy such as adding metformin to insulin to reduce insulin resistance will be useful in blood glucose control and metabolic state improvement.Materials & Methods: This was a randomized double blind placebo controlled 3-month trial metformin therapy in 32 adolescents with type 1 DM. These patients were divided in two groups of metformin and placebo and treated with metformin and placebo for 3-months. Their HbA1C, FBS, Insulin dosage, TG, Cholesterol, and LDL were measured at the initiation and end of the treatment.Results: After the study there was a significant improvement of FBS and TG in metformin group versus placebo group (P=0.02 and P=0.028 in order. But, there was not significant difference in other variables such as BMI, insulin dosage, HbA1C, Cholesterol and LDL between the two groups.Conclusion: Metformin treatment in teenagers with type1 DM who are in pubertal period will improve the control of FBS and lowers TG but has not any significant effect on HbA1C, BMI, insulin dosage, Cholesterol and LDL.

  6. Short-term, high-dose glucocorticoid treatment does not contribute to reduced bone mineral density in patients with multiple sclerosis

    DEFF Research Database (Denmark)

    Olsson, A.; Oturai, D B; Sørensen, P S

    2015-01-01

    BACKGROUND: Patients with multiple sclerosis (MS) are at increased risk of reduced bone mineral density (BMD). A contributing factor might be treatment with high-dose glucocorticoids (GCs). OBJECTIVES: The objective of this paper is to assess bone mass in patients with MS and evaluate...... the importance of short-term, high-dose GC treatment and other risk factors that affect BMD in patients with MS. METHODS: A total of 260 patients with MS received short-term high-dose GC treatment and had their BMD measured by dual x-ray absorptiometry. BMD was compared to a healthy age-matched reference...... population (Z-scores). Data regarding GCs, age, body mass index (BMI), serum 25(OH)D, disease duration and severity were collected retrospectively and analysed in a multiple linear regression analysis to evaluate the association between each risk factor and BMD. RESULTS: Osteopenia was present in 38...

  7. Cardiovascular and metabolic effects of metformin in patients with type 1 diabetes (REMOVAL)

    DEFF Research Database (Denmark)

    Petrie, John R; Chaturvedi, Nishi; Ford, Ian

    2017-01-01

    BACKGROUND: Metformin might reduce insulin requirement and improve glycaemia in patients with type 1 diabetes, but whether it has cardiovascular benefits is unknown. We aimed to investigate whether metformin treatment (added to titrated insulin therapy) reduced atherosclerosis, as measured by pro...

  8. The pathophysiological basis of the protective effects of metformin in heart failure.

    Science.gov (United States)

    Dziubak, Aleksandra; Wójcicka, Grażyna

    2017-08-24

    Metformin, currently recommended as the drug of first choice in type 2 diabetes mellitus (T2DM), is one of the few antihiperglycemic drugs to reduce cardiovascular risk. Nonetheless, due to the risk of lactic acidosis during metformin therapy, its usage in patients with diabetes and heart failure (HF) is still a matter of debate. The aim of this review is to present data supporting the possibility of using metformin in the treatment of diabetic patients with concomitant heart failure. In the failing heart, metformin through the mechanism related to AMP-activated protein kinase (AMPK) activity, improves free fatty acids (FFA) and glucose metabolism, mitochondrial biogenesis, as well as nitric oxide (NO)-NO synthase pathway. Metformin can also inhibit the generation and accumulation of advanced glycation end products (AGEs) and thereby prevents the development of the adverse structural and functional changes in myocardium.In summary, experimental and clinical data indicate the ability of metformin to prevent the development of the structural and functional changes in myocardium, although further basic research and clinical studies assessing benefits and safety of metformin therapy in patients with HF are required.

  9. PHARMACOGENETICS OF METFORMIN

    DEFF Research Database (Denmark)

    Hougaard Christensen, Mette Marie; Andersen, Charlotte Brasch; Damkier, Per

    Introduction: Genetic polymorphisms in metformin transporters and their impact at the steady state metformin plasma concentrations is evaluated in a large well characterized type 2 diabetes cohort given by South Danish Diabetes Study. SNPs in PMAT, OCT1-2 and MATE 1-2 have been linked to reduced ...

  10. Metformin - a Future Therapy for Neurodegenerative Diseases : Theme: Drug Discovery, Development and Delivery in Alzheimer's Disease Guest Editor: Davide Brambilla.

    Science.gov (United States)

    Markowicz-Piasecka, Magdalena; Sikora, Joanna; Szydłowska, Aleksandra; Skupień, Agata; Mikiciuk-Olasik, Elżbieta; Huttunen, Kristiina M

    2017-12-01

    Type 2 diabetes mellitus (T2DM) is a complex, chronic and progressive metabolic disease, which is characterized by relative insulin deficiency, insulin resistance, and high glucose levels in blood. Esteemed published articles and epidemiological data exhibit an increased risk of developing Alzheimer's disease (AD) in diabetic pateints. Metformin is the most frequently used oral anti-diabetic drug, which apart from hypoglycaemic activity, improves serum lipid profiles, positively influences the process of haemostasis, and possesses anti-inflammatory properties. Recently, scientists have put their efforts in establishing metformin's role in the treatment of neurodegenerative diseases, such as AD, amnestic mild cognitive impairment and Parkinson's disease. Results of several clinical studies confirm that long term use of metformin in diabetic patients contributes to better cognitive function, compared to participants using other anti-diabetic drugs. The exact mechanism of metformin's advantageous activity in AD is not fully understood, but scientists claim that activation of AMPK-dependent pathways in human neural stem cells might be responsible for the neuroprotective activity of metformin. Metformin was also found to markedly decease Beta-secretase 1 (BACE1) protein expression and activity in cell culture models and in vivo, thereby reducing BACE1 cleavage products and the production of Aβ (β-amyloid). Furthermore, there is also some evidence that metformin decreases the activity of acetylcholinesterase (AChE), which is responsible for the degradation of acetylcholine (Ach), a neurotransmitter involved in the process of learning and memory. In regard to the beneficial effects of metformin, its anti-inflammatory and anti-oxidative properties cannot be omitted. Numerous in vitro and in vivo studies have confirmed that metformin ameliorates oxidative damage.

  11. Pediatric polytrauma : Short-term and long-term outcomes

    NARCIS (Netherlands)

    vanderSluis, CK; Kingma, J; Eisma, WH; tenDuis, HJ

    Objective: To assess the short-term and long-term outcomes of pediatric polytrauma patients and to analyze the extent to which short-term outcomes can predict long-term outcomes. Materials and Methods: Ail pediatric polytrauma patients (Injury Severity Score of greater than or equal to 16, less than

  12. Diabetes, pancreatic cancer, and metformin therapy

    Directory of Open Access Journals (Sweden)

    Jun eGong

    2014-11-01

    Full Text Available Pancreatic cancer carries a poor prognosis as most patients present with advanced disease and preferred chemotherapy regimens offer only modest effects on survival. Risk factors include smoking, obesity, heavy alcohol, and chronic pancreatitis. Pancreatic cancer has a complex relationship with diabetes, as diabetes can be both a risk factor for pancreatic cancer and a result of pancreatic cancer. Insulin, insulin-like growth factor-1 (IGF-1, and certain hormones play an important role in promoting neoplasia in diabetics. Metformin appears to reduce risk for pancreatic cancer and improve survival in diabetics with pancreatic cancer primarily by decreasing insulin/IGF signaling, disrupting mitochondrial respiration, and inhibiting the mammalian target of rapamycin (mTOR pathway. Other potential anti-tumorigenic effects of metformin include the ability to downregulate specificity protein transcription factors and associated genes, alter microRNAs, decrease cancer stem cell proliferation, and reduce DNA damage and inflammation. Here, we review the most recent knowledge on risk factors and treatment of pancreatic cancer and the relationship between diabetes, pancreatic cancer, and metformin as a potential therapy.

  13. Chronic Metformin Treatment is Associated with Reduced Myocardial Infarct Size in Diabetic Patients with ST-segment Elevation Myocardial Infarction

    NARCIS (Netherlands)

    Lexis, Chris P. H.; Wieringa, Wouter G.; Hiemstra, Bart; van Deursen, Vincent M.; Lipsic, Erik; van der Harst, Pim; van Veldhuisen, Dirk J.; van der Horst, Iwan C. C.

    Increased myocardial infarct (MI) size is associated with higher risk of developing left ventricular dysfunction, heart failure and mortality. Experimental studies have suggested that metformin treatment reduces MI size after induced ischaemia but human data is lacking. We aimed to investigate the

  14. Metformin - For the dermatologist

    Science.gov (United States)

    Bubna, Aditya Kumar

    2016-01-01

    Metformin though primarily an antidiabetic drug, has found to play an important role in a number of cutaneous disorders. Because of its role in improving hyperinsulinemia, it has proven beneficial in hormonal acne, hidradenitis suppurativa (HS) and acanthosis nigricans. Its antiandrogenic properties further serve as an add-on to the conventional management of hirsutism associated with polycystic ovarian syndrome. Very recently, systemic usage of metformin for psoriasis and cutaneous malignancies has shown promising results. Interestingly, metformin has also been topically used in hyperpigmentary disorders with pertinent levels of improvement and happens to be the most recent addition to the list of dermatologic indications. Though an oral hypoglycemic agent to begin with, metformin today has proven to be a boon for dermatologists. PMID:26997714

  15. A phase Ib study of everolimus combined with metformin for patients with advanced cancer.

    Science.gov (United States)

    Molenaar, Remco J; van de Venne, Tim; Weterman, Mariëtte J; Mathot, Ron A; Klümpen, Heinz-Josef; Richel, Dick J; Wilmink, Johanna W

    2018-02-01

    Background The efficacy to monotherapy with the mTOR inhibitor everolimus in advanced cancer is often limited due to therapy resistance. Combining everolimus with metformin may decrease the chance of therapy resistance. Methods Patients received everolimus and metformin in a 3 + 3 dose-escalation scheme. Objectives were to determine the dose-limiting toxicities (DLTs), maximum tolerated dose, toxic effects, pharmacokinetics and anti-tumour efficacy. Results 9 patients received study treatment for a median duration of 48 days (range: 4-78). 6 patients discontinued due to toxicity and 3 patients because of progressive disease. At the starting dose level of 10 mg everolimus qd and 500 mg metformin bid, 3 out of 5 patients experienced a DLT. After de-escalation to 5 mg everolimus qd and 500 mg metformin bid, considerable toxicity was still observed and patient enrollment was terminated. In pharmacokinetic analyses, metformin was eliminated slower when co-administered with everolimus than as single-agent. After 9 weeks of treatment, 3 patients were still on study and all had stable disease. Conclusion The combination of everolimus and metformin is poorly tolerated in patients with advanced cancer. The pharmacokinetic interaction between everolimus and metformin may have implications for diabetic cancer patients that are treated with these drugs. Our results advocate for future clinical trials with combinations of other mTOR inhibitors and biguanides.

  16. Efficacy and safety of metformin during pregnancy in women with gestational diabetes mellitus or polycystic ovary syndrome: a systematic review.

    Science.gov (United States)

    Lautatzis, Maria-Elena; Goulis, Dimitrios G; Vrontakis, Maria

    2013-11-01

    Metformin is an effective oral anti-hyperglycemic agent that is widely used to manage diabetes mellitus type 2 in the general population and more recently, in pregnancy. However, as metformin crosses the placenta, its use during pregnancy raises concerns regarding potential adverse effects on the mother and fetus. (i) To provide background for the use of metformin during pregnancy through a narrative review and (ii) to critically appraise the published evidence on the efficacy and safety of using metformin during pregnancy through a systematic review. Metformin appears to be effective and safe for the treatment of gestational diabetes mellitus (GDM), particularly for overweight or obese women. However, patients with multiple risk factors for insulin resistance may not meet their treatment goals with metformin alone and may require supplementary insulin. Evidence suggests that there are potential advantages for the use of metformin over insulin in GDM with respect to maternal weight gain and neonatal outcomes. Furthermore, patients are more accepting of metformin than insulin. The use of metformin throughout pregnancy in women with polycystic ovary syndrome reduces the rates of early pregnancy loss and preterm labor and protects against fetal growth restriction. There have been no demonstrable teratogenic effects, intra-uterine deaths or developmental delays with the use of metformin. The publications reviewed in this paper support the efficacy and safety of metformin during pregnancy with respect to immediate pregnancy outcomes. Because there are no guidelines for the continuous use of metformin in pregnancy, the duration of treatment is based on clinical judgment and experience on a case-by-case basis. © 2013.

  17. Metformin compared with insulin in the management of gestational diabetes mellitus: a randomized clinical trial.

    Science.gov (United States)

    Niromanesh, Shirin; Alavi, Azin; Sharbaf, Fatemeh Rahimi; Amjadi, Nooshin; Moosavi, Sanaz; Akbari, Soheila

    2012-12-01

    To evaluate the effect of metformin and insulin in glycemic control and compare pregnancy outcome in women with gestational diabetes mellitus (GDM). This randomized controlled trial was conducted in GDM women with singleton pregnancy and gestational age between 20 and 34 weeks who did not achieve glycemic control on diet were assigned randomly to receive either metformin (n=80) or insulin (n=80). The primary outcomes were maternal glycemic control and birth weight. The secondary outcomes were neonatal and obstetric complications. Two groups were comparable regarding the maternal characteristics. Two groups were similar in mean FBS (P=0.68) and postprandial measurements (P=0.87) throughout GDM treatment. The neonates of metformin group had less rate of birth weight centile >90 than insulin group (RR: 0.5, 95% CI: 0.3-0.9, P=0.012). Maternal weight gain was reduced in the metformin group (P0.05). In metformin group 14% of women needed to supplemental insulin to achieve euglycemia. Metformin is an effective and safe alternative treatment to insulin for women with GDM. This study does not show significant risk of maternal or neonatal adverse outcome with the use of metformin. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  18. Use of metformin and survival of diabetic women with breast cancer

    DEFF Research Database (Denmark)

    Peeters, Paul J H L; Bazelier, Marloes T; Vestergaard, Peter

    2013-01-01

    OBJECTIVE: This study was set out to determine whether metformin use influences survival in breast cancer patients treated with antidiabetic drugs as compared to non-users. RESEARCH DESIGN AND METHODS: We used data from the Danish national registries (1996-2008) to identify adult female patients...... diagnosed with breast cancer who were prescribed antidiabetic medication. We performed multivariate Coxproportional hazard regression to assess all-cause and breast cancer-specific mortality risks associated with metformin exposure. In a secondary analysis, we stratified use of metformin according...... to the cumulative number of prescriptions. RESULTS: Of the 1058 breast cancer patients 349 died during follow-up, with breast cancer listed as the primary cause of death for 152 cases. Compared to non-use, current metformin treatment was associated with a significant reduction in overall mortality (adjusted HR 0...

  19. Short-term efficacy of mandibular advancement splint in treatment of obstructive sleep apnea-hypopnea syndrome

    Directory of Open Access Journals (Sweden)

    Calliandra Moura Pereira de Lima

    2013-06-01

    Full Text Available OBJECTIVE: The aim of the present study was to determine the short-term efficacy of treatment for snoring and obstructive sleep apnea-hypopnea syndrome (OSAHS using a mandibular advancement splint. METHODS: The sample comprised 20 patients (13 men and 7 women; mean age = 48 years; mean body mass index = 27.07 with OSAHS. Polysomnograms were performed before and 60 days after mandibular advancement splint therapy. RESULTS: There was a significant reduction in the apnea-hypopnea index (AHI following treatment (mean pretreatment AHI = 20.89 ± 17.9 versus mean posttreatment AHI = 4.43 ± 3.09 (p < 0.05. The snoring reduced and the sleep efficiency improved, as registered by polysomnograms (p<0.05. CONCLUSIONS: The sleep quality improved in patients using mandibular advancement splint. Further studies evaluating long-term effects are needed.

  20. Compound list: metformin [Open TG-GATEs

    Lifescience Database Archive (English)

    Full Text Available metformin MFM 00053 ftp://ftp.biosciencedbc.jp/archive/open-tggates/LATEST/Human/in..._vitro/metformin.Human.in_vitro.Liver.zip ftp://ftp.biosciencedbc.jp/archive/open-tggates/LATEST/Rat/in_vitr...o/metformin.Rat.in_vitro.Liver.zip ftp://ftp.biosciencedbc.jp/archive/open-tggates/LATEST/Rat/in_vivo/Liver/...Single/metformin.Rat.in_vivo.Liver.Single.zip ftp://ftp.biosciencedbc.jp/archive/

  1. Alleviation of senescence and epithelial-mesenchymal transition in aging kidney by short-term caloric restriction and caloric restriction mimetics via modulation of AMPK/mTOR signaling.

    Science.gov (United States)

    Dong, Dan; Cai, Guang-Yan; Ning, Yi-Chun; Wang, Jing-Chao; Lv, Yang; Hong, Quan; Cui, Shao-Yuan; Fu, Bo; Guo, Ya-Nan; Chen, Xiang-Mei

    2017-03-07

    Renal fibrosis contributes to declining renal function in the elderly. What is unclear however, is whether epithelial-mesenchymal transition (EMT) contributes to this age-related renal fibrosis. Here, we analyzed indicators of EMT during kidney aging and investigated the protective effects and mechanisms of short-term regimens of caloric restriction (CR) or caloric restriction mimetics (CRMs), including resveratrol and metformin. High glucose was used to induce premature senescence and EMT in human primary proximal tubular cells (PTCs) in vitro. To test the role of AMPK-mTOR signaling, siRNA was used to deplete AMPK. Cellular senescence and AMPK-mTOR signaling markers associated with EMT were detected. CR or CRMs treatment alleviated age-related EMT in aging kidneys, which was accompanied by activation of AMPK-mTOR signaling. High glucose induced premature senescence and EMT in PTCs in vitro, which was accompanied by down-regulation of AMPK/mTOR signaling. CRMs alleviated high glucose-induced senescence and EMT via stimulation of AMPK/mTOR signaling. Activation of AMPK/mTOR signaling protected PTCs from high glucose-induced EMT and cellular senescence. Short-term regimens of CR and CRMs alleviated age-related EMT via AMPK-mTOR signaling, suggesting a potential approach to reducing renal fibrosis during aging.

  2. Clinical Effectiveness of Aripiprazole in Short-term Treatment of Tic Disorder in Children and Adolescents: A Naturalistic Study

    Directory of Open Access Journals (Sweden)

    Che-Sheng Ho

    2014-02-01

    Conclusion: Aripiprazole is effective for short-term treatment of TD, especially vocal tics, in children and adolescents with mild adverse effects. However, further double-blind trials against placebo or other medications are needed to verify the efficacy of aripiprazole in the pharmacotherapy of TD.

  3. Double-blind, randomized, clinical trial of metformin as add-on treatment with clozapine in treatment of schizophrenia disorder

    Directory of Open Access Journals (Sweden)

    Paria Hebrani

    2015-01-01

    Full Text Available Background: One of the major causes of death in schizophrenia is a metabolic syndrome. The clozapine has the highest rate of weight gain among antipsychotics. It has been shown that metformin can promote weight loss. We aimed to investigate the effect of metformin as an adjunctive therapy with clozapine to prevent metabolic syndrome in patients with schizophrenia. Materials and Methods: A total of 37 patients consisting metformin group (19 cases and a group of placebo consisting of 18 cases were evaluated. A brief psychiatric rating scale score (BPRS and metabolic profiles was determined for all patients. All of the variables were also determined at 2, 8, 16, and 20 weeks after the onset of the study. Results: The mean age of the group of metformin was 47.2 ± 10.4 compared with 45.8 ± 10.2 for the group of placebo. The difference in mean waist circumference and serum level of triglyceride at baseline compared with the end of study showed a statistically significant difference between two groups (P = 0. 000. A statistically significant difference was also observed in a comparison of mean difference of weight and body mass index at baseline compared with end of study (P = 0. 000. There was a statistically significant difference of fasting blood sugar (P = 0.011 and serum high-density lipoprotein (P = 0.000 between two groups but this difference was not significant for mean BPRS scores, mean systolic and diastolic blood pressure, serum level of triiodothyronine, thyroxin and thyroid stimulating hormone, serum low-density lipoprotein and serum cholesterol. Conclusion: Metformin could be considered an adjunctive therapy with clozapine to prevent metabolic syndrome in schizophrenic patients.

  4. Effect of metformin on early pregnancy loss in women with polycystic ovary syndrome.

    Science.gov (United States)

    Al-Biate, Mawahib A S

    2015-06-01

    To evaluate the effectiveness of metformin therapy in reducing early pregnancy loss in pregnant women with polycystic ovary syndrome (PCOS). This is a prospective cohort study conducted in the Obstetric Department of the Gulf Medical College Hospital in Ajman, UAE, for a period of 3 years. This study involved 106 nondiabetic pregnant women with PCOS who became pregnant while using metformin. They were divided into two groups, namely, the group that received metformin throughout pregnancy (metformin group) and the group that discontinued using the drug once pregnancy started (control group). A comparison was made between the two groups of patients with respect to certain basal characteristics (age, body mass index, previous obstetric outcome, serum glucose with free testosterone). Statistical analysis was performed using Chi-square test to compare the differences between the two groups. There were 56 patients who received metformin during pregnancy (metformin group) compared with 50 patients who did not receive the treatment (control group). The rate of early pregnancy loss in the metformin group was 8.9% (5/56) compared with 36% (18/50) in the control group (p metformin group with a history of previous miscarriage, the rate of pregnancy loss was 45% (35 cases/50 pregnancies). Metformin therapy in pregnant women with PCOS was associated with a significant reduction in the rate of early pregnancy loss. Copyright © 2015. Published by Elsevier B.V.

  5. Spectrophotometric determination of metformin in pharmaceutical preparations, serum and urine using benzoin as derivatizing reagent

    International Nuclear Information System (INIS)

    Alamgir, M.; Hayat, A.

    2014-01-01

    A simple and selective spectrophotometric procedure is described for the determination of Metformin based on derivatization with benzoin. The Beers law was obeyed with 2.50-12.50 meu mol L-1 at 290 nm with coefficient of determination (r2) 0.997. The experimental conditions in term of pH, reaction time and temperature, and addition of derivatizing reagent were examined. The pure metformin-benzoin derivative was prepared and characterized by FT-IR and mass spectroscopic techniques. The method was applied for the determination of metformin from pharmaceutical preparations and serum and urine of volunteers after spiking with metformin. The results were checked by standard addition method. A number of pharmaceutical additives and serum or urine matrix did not affect the determination of metformin. (author)

  6. Fractional carbon dioxide laser for the treatment of facial atrophic acne scars: prospective clinical trial with short and long-term evaluation.

    Science.gov (United States)

    Elcin, Gonca; Yalici-Armagan, Basak

    2017-12-01

    The aim of this study was to evaluate the efficacy and safety of fractional carbon dioxide laser for the treatment of acne scars. Thirty-one participants, 15 female and 16 male, whose mean age was 34.84 ± 10.94 years, were included in this prospective study. The study took place between 2012 and 2016. Participants were evaluated with the "ECCA Grading Scale" before the first session, 3 months (short-term evaluation) and 3 years after the last session (long-term evaluation). Participants received two or three treatment sessions at 4-week intervals, with a 10,600 nm fractional carbon dioxide laser with pulse energies ranging between 100 and 160 mJ, 120 spot type, 75-100 spot/cm 2 density, and 30 W power. Self-assessments by the participants were done 3 months and 3 years after the last session. The mean ECCA score was 107.90 ± 39.38 before the first session, and 82.17 ± 36.23 at the time of short-term evaluation (p = 0.000). The grade of improvement at the short-term evaluation was as follows: no improvement, mild, moderate, and significant improvement for 7 (22.6%), 11 (35.5%), 9 (29%), and 4 (12.9%) of the participants, respectively. Regarding self-assessments, 80.6 and 61.3% of the participants rated themselves as having at least mild improvement at the short-term and the long-term follow-up periods, respectively. The results of this study suggest that fractional carbon dioxide laser is an efficient treatment option for acne scars. Furthermore, self-assessment results show that more than half of the participants still experience at least mild improvement at the end of 3 years.

  7. Long-term associative learning predicts verbal short-term memory performance

    OpenAIRE

    Jones, Gary; Macken, Bill

    2017-01-01

    Studies using tests such as digit span and nonword repetition have implicated short-term memory across a range of developmental domains. Such tests ostensibly assess specialized processes for the short-term manipulation and maintenance of information that are often argued to enable long-term learning. However, there is considerable evidence for an influence of long-term linguistic learning on performance in short-term memory tasks that brings into question the role of a specialized short-term...

  8. Long-term associative learning predicts verbal short-term memory performance.

    Science.gov (United States)

    Jones, Gary; Macken, Bill

    2018-02-01

    Studies using tests such as digit span and nonword repetition have implicated short-term memory across a range of developmental domains. Such tests ostensibly assess specialized processes for the short-term manipulation and maintenance of information that are often argued to enable long-term learning. However, there is considerable evidence for an influence of long-term linguistic learning on performance in short-term memory tasks that brings into question the role of a specialized short-term memory system separate from long-term knowledge. Using natural language corpora, we show experimentally and computationally that performance on three widely used measures of short-term memory (digit span, nonword repetition, and sentence recall) can be predicted from simple associative learning operating on the linguistic environment to which a typical child may have been exposed. The findings support the broad view that short-term verbal memory performance reflects the application of long-term language knowledge to the experimental setting.

  9. DYNAMICS OF THE ANXIETY DISORDERS IN THE COURSE OF SHORT-TERM PSYCHOTHERAPY

    Directory of Open Access Journals (Sweden)

    T.N. Hmylova

    2008-06-01

    Full Text Available The tendency of psychotherapy modern concepts referring to the short-term forms having been taken into account, we carried out the research aimed at the study of short-term form personality-oriented psychotherapy effect on the anxiety disorder dynamics. 103 patients with neurotic disorders were examined in the neurosis and psychotherapy department of the Bekhterev Psychoneurological Research Institute. The findings revealed the situational and personal anxiety level to be objectively decreased in the short-term group psychotherapy course. The short-term group psychotherapy was proved to bean effective method in anxiety disorders treatment considering indications and limitations.

  10. Metformin Ameliorates Dysfunctional Traits of Glibenclamide- and Glucose-Induced Insulin Secretion by Suppression of Imposed Overactivity of the Islet Nitric Oxide Synthase-NO System.

    Directory of Open Access Journals (Sweden)

    Ingmar Lundquist

    Full Text Available Metformin lowers diabetic blood glucose primarily by reducing hepatic gluconeogenesis and increasing peripheral glucose uptake. However, possible effects by metformin on beta-cell function are incompletely understood. We speculated that metformin might positively influence insulin secretion through impacting the beta-cell nitric oxide synthase (NOS-NO system, a negative modulator of glucose-stimulated insulin release. In short-time incubations with isolated murine islets either glibenclamide or high glucose augmented insulin release associated with increased NO production from both neural and inducible NOS. Metformin addition suppressed the augmented NO generation coinciding with amplified insulin release. Islet culturing with glibenclamide or high glucose revealed pronounced fluorescence of inducible NOS in the beta-cells being abolished by metformin co-culturing. These findings were reflected in medium nitrite-nitrate levels. A glucose challenge following islet culturing with glibenclamide or high glucose revealed markedly impaired insulin response. Metformin co-culturing restored this response. Culturing murine islets and human islets from controls and type 2 diabetics with high glucose or high glucose + glibenclamide induced a pronounced decrease of cell viability being remarkably restored by metformin co-culturing. We show here, that imposed overactivity of the beta-cell NOS-NO system by glibenclamide or high glucose leads to insulin secretory dysfunction and reduced cell viability and also, importantly, that these effects are relieved by metformin inhibiting beta-cell NO overproduction from both neural and inducible NOS thus ameliorating a concealed negative influence by NO induced by sulfonylurea treatment and/or high glucose levels. This double-edged effect of glibenclamide on the beta-cellsuggests sulfonylurea monotherapy in type 2 diabetes being avoided.

  11. Regional cerebral blood flow in Alzheimer's disease. Comparison between short and long-term donepezil therapy

    International Nuclear Information System (INIS)

    Ushijima, Yo; Okuyama, Chio; Kubota, Takao; Nakai, Takako; Nishimura, Tsunehiko; Mori, Satoru

    2006-01-01

    Treatment with donepezil improves cognitive function of patients with Alzheimer's disease (AD) when compared to a placebo-controlled group. The purpose of this study was to investigate changes in regional cerebral blood flow (rCBF) of AD patients in short-term and long-term treatment with donepezil. rCBF was measured by N-isopropyl-p- 123 I-iodoamphetamine (IMP) autoradiography method. CBF measurements were performed in 17 AD patients before treatment and after 3 months (short-term therapy) and 1 year (long-term therapy). Regions of interest were set at cerebral cortex and cerebellar hemisphere. We used absolute CBF and relative CBF expressed as ratio to cerebellar CBF. Significant increases in relative rCBF were noted in the frontal, parietal and temporal lobes at the end of short-term therapy. rCBF was decreased after the long-term therapy, whereas rCBF was still increased to a slight extent, as compared with the pre-treatment levels. Absolute rCBF showed minimal change and a tendency to decline. Relative rCBF significantly increased in the short-term donepezil therapy, while following the long-term therapy, rCBF decreased to the pre-treatment level. (author)

  12. Metformin improves defective hematopoiesis and delays tumor formation in Fanconi anemia mice.

    Science.gov (United States)

    Zhang, Qing-Shuo; Tang, Weiliang; Deater, Matthew; Phan, Ngoc; Marcogliese, Andrea N; Li, Hui; Al-Dhalimy, Muhsen; Major, Angela; Olson, Susan; Monnat, Raymond J; Grompe, Markus

    2016-12-15

    Fanconi anemia (FA) is an inherited bone marrow failure disorder associated with a high incidence of leukemia and solid tumors. Bone marrow transplantation is currently the only curative therapy for the hematopoietic complications of this disorder. However, long-term morbidity and mortality remain very high, and new therapeutics are badly needed. Here we show that the widely used diabetes drug metformin improves hematopoiesis and delays tumor formation in Fancd2 -/- mice. Metformin is the first compound reported to improve both of these FA phenotypes. Importantly, the beneficial effects are specific to FA mice and are not seen in the wild-type controls. In this preclinical model of FA, metformin outperformed the current standard of care, oxymetholone, by improving peripheral blood counts in Fancd2 -/- mice significantly faster. Metformin increased the size of the hematopoietic stem cell compartment and enhanced quiescence in hematopoietic stem and progenitor cells. In tumor-prone Fancd2 -/- Trp53 +/- mice, metformin delayed the onset of tumors and significantly extended the tumor-free survival time. In addition, we found that metformin and the structurally related compound aminoguanidine reduced DNA damage and ameliorated spontaneous chromosome breakage and radials in human FA patient-derived cells. Our results also indicate that aldehyde detoxification might be one of the mechanisms by which metformin reduces DNA damage in FA cells. © 2016 by The American Society of Hematology.

  13. Assessment of ovarian stromal blood flow after metformin treatment in women with polycystic ovary syndrome.

    Science.gov (United States)

    Makled, Ahmed K; El Sherbiny, Mohamed; Elkabarity, Rania

    2014-04-01

    To authenticate the effect of metformin treatment on ovarian stromal blood flow in women with polycystic ovary syndrome (PCOS) using 3-dimensional (3D) power Doppler. The current case-control study was conducted at Ain Shams University Maternity Hospital. A total of 60 women diagnosed to have PCOS were included as group 1. Another 40 fertile women who were recruited from outpatient clinic for contraception without PCOS with regular menstrual cycles were included as control group (group 2). All women underwent 3D power Doppler evaluations of ovarian stroma. Anthropometric, hormonal and biochemical criteria were also measured. All women in group 1 received metformin hydrochloride 500 mg tablets, which were started in a step-up maneuver every 5 days, from one to three tablets per day. The same parameters were also measured after the 3 months duration of treatment. A total of 100 women were finally analyzed. At the start of the study, there were no statistically significant differences between group 1 and group 2 and regarding age and body mass index, but the waist/hip ratio and Ferriman-Gallwey scoring were statistically different between the 2 groups. The mean ovarian volume and stromal volume were significantly larger in group 1. 3D power Doppler indices [the vascularization index (VI), the flow index (FI) and the (VFI) vascularization-flow index] were much higher in group 1 than in group 2 (1.38 ± 0.76 vs. 4.69 ± 1.37, P treatment significantly reduce VI, FI and VFI (4.69 ± 1.37 vs. 2.95 ± 1.52, P < 0.05, 32.66 ± 4.37 vs. 29.48 ± 4.98, P < 0.05 and 1.54 ± 0.69 vs. 1.21 ± 0.7 P < 0.05, respectively). Using Receiver operator characteristic, there was no cut-off value of VI, FI or VFI to detect ovulation in women of PCOS. Metformin seems to have a beneficial effect in normal weight PCO women via correcting ovarian stromal blood flow and hormonal profiles.

  14. Metformin targets the metabolic achilles heel of human pancreatic cancer stem cells.

    Directory of Open Access Journals (Sweden)

    Enza Lonardo

    Full Text Available Pancreatic ductal adenocarcinomas contain a subset of exclusively tumorigenic cancer stem cells (CSCs, which are capable of repopulating the entire heterogeneous cancer cell populations and are highly resistant to standard chemotherapy. Here we demonstrate that metformin selectively ablated pancreatic CSCs as evidenced by diminished expression of pluripotency-associated genes and CSC-associated surface markers. Subsequently, the ability of metformin-treated CSCs to clonally expand in vitro was irreversibly abrogated by inducing apoptosis. In contrast, non-CSCs preferentially responded by cell cycle arrest, but were not eliminated by metformin treatment. Mechanistically, metformin increased reactive oxygen species production in CSC and reduced their mitochondrial transmembrane potential. The subsequent induction of lethal energy crisis in CSCs was independent of AMPK/mTOR. Finally, in primary cancer tissue xenograft models metformin effectively reduced tumor burden and prevented disease progression; if combined with a stroma-targeting smoothened inhibitor for enhanced tissue penetration, while gemcitabine actually appeared dispensable.

  15. Metformin Induces Cell Cycle Arrest, Reduced Proliferation, Wound Healing Impairment In Vivo and Is Associated to Clinical Outcomes in Diabetic Foot Ulcer Patients.

    Science.gov (United States)

    Ochoa-Gonzalez, Fatima; Cervantes-Villagrana, Alberto R; Fernandez-Ruiz, Julio C; Nava-Ramirez, Hilda S; Hernandez-Correa, Adriana C; Enciso-Moreno, Jose A; Castañeda-Delgado, Julio E

    2016-01-01

    Several epidemiological studies in diabetic patients have demonstrated a protective effect of metformin to the development of several types of cancer. The underlying mechanisms of such phenomenon is related to the effect of metformin on cell proliferation among which, mTOR, AMPK and other targets have been identified. However, little is known about the role that metformin treatment have on other cell types such as keratinocytes and whether exposure to metformin of these cells might have serious repercussions in wound healing delay and in the development of complications in diabetic patients with foot ulcers or in their exacerbation. HaCaT Cells were exposed to various concentrations of metformin and cell viability was evaluated by a Resazurin assay; Proliferation was also evaluated with a colony formation assay and with CFSE dilution assay by flow cytometry. Cell cycle was also evaluated by flow cytometry by PI staining. An animal model of wound healing was used to evaluate the effect of metformin in wound closure. Also, an analysis of patients receiving metformin treatment was performed to determine the effect of metformin treatment on the outcome and wound area. Statistical analysis was performed on SPSS v. 18 and GraphPad software v.5. Metformin treatment significantly reduces cell proliferation; colony formation and alterations of the cell cycle are observed also in the metformin treated cells, particularly in the S phase. There is a significant increase in the area of the wound of the metformin treated animals at different time points (Pdiabetic foot ulcers at the time of hospitalization. A protective effect of metformin was observed for amputation, probably associated with the anti inflammatory effects reported of metformin. Metformin treatment reduces cell proliferation and reduces wound healing in an animal model and affects clinical outcomes in diabetic foot ulcer patients. Chronic use of this drug should be further investigated to provide evidence of

  16. Short- and long-term memory: differential involvement of neurotransmitter systems and signal transduction cascades

    Directory of Open Access Journals (Sweden)

    MÔNICA R.M. VIANNA

    2000-09-01

    Full Text Available Since William James (1890 first distinguished primary from secondary memory, equivalent to short- and long-term memory, respectively, it has been assumed that short-term memory processes are in charge of cognition while long-term memory is being consolidated. From those days a major question has been whether short-term memory is merely a initial phase of long-term memory, or a separate phenomena. Recent experiments have shown that many treatments with specific molecular actions given into the hippocampus and related brain areas after one-trial avoidance learning can effectively cancel short-term memory without affecting long-term memory formation. This shows that short-term memory and long-term memory involve separate mechanisms and are independently processed. Other treatments, however, influence both memory types similarly, suggesting links between both at the receptor and at the post-receptor level, which should not be surprising as they both deal with nearly the same sensorimotor representations. This review examines recent advances in short- and long-term memory mechanisms based on the effect of intra-hippocampal infusion of drugs acting upon neurotransmitter and signal transduction systems on both memory types.

  17. The administration of metformin during pregnancy reduces polycystic ovary syndrome related gestational complications.

    Science.gov (United States)

    De Leo, V; Musacchio, M C; Piomboni, P; Di Sabatino, A; Morgante, G

    2011-07-01

    To prospectively evaluate the safety of metformin administration during pregnancy in a group of PCOS patients by assessing its effect on the prevalence of gestational complications and neonatal outcome. Our prospective, single centre study included 98 pregnant women with PCOS treated with metformin throughout pregnancy and 110 normal pregnant controls. All PCOS patients were hyperinsulinemic and received metformin (1700-3000 mg/day) before conception and until 37 weeks' gestation. Metformin treatment in the pregnant PCOS patients resulted in significant decrease in miscarriage rate (9.1% vs 20%; pmetformin therapy throughout pregnancy resulted in significant reduction in pregnancy complications with concomitant improved neonatal outcome, with no serious deleterious side effects. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  18. Metformin lowers plasma triglycerides by promoting VLDL-triglyceride clearance by brown adipose tissue in mice.

    Science.gov (United States)

    Geerling, Janine J; Boon, Mariëtte R; van der Zon, Gerard C; van den Berg, Sjoerd A A; van den Hoek, Anita M; Lombès, Marc; Princen, Hans M G; Havekes, Louis M; Rensen, Patrick C N; Guigas, Bruno

    2014-03-01

    Metformin is the first-line drug for the treatment of type 2 diabetes. Besides its well-characterized antihyperglycemic properties, metformin also lowers plasma VLDL triglyceride (TG). In this study, we investigated the underlying mechanisms in APOE*3-Leiden.CETP mice, a well-established model for human-like lipoprotein metabolism. We found that metformin markedly lowered plasma total cholesterol and TG levels, an effect mostly due to a decrease in VLDL-TG, whereas HDL was slightly increased. Strikingly, metformin did not affect hepatic VLDL-TG production, VLDL particle composition, and hepatic lipid composition but selectively enhanced clearance of glycerol tri[(3)H]oleate-labeled VLDL-like emulsion particles into brown adipose tissue (BAT). BAT mass and lipid droplet content were reduced in metformin-treated mice, pointing to increased BAT activation. In addition, both AMP-activated protein kinase α1 (AMPKα1) expression and activity and HSL and mitochondrial content were increased in BAT. Furthermore, therapeutic concentrations of metformin increased AMPK and HSL activities and promoted lipolysis in T37i differentiated brown adipocytes. Collectively, our results identify BAT as an important player in the TG-lowering effect of metformin by enhancing VLDL-TG uptake, intracellular TG lipolysis, and subsequent mitochondrial fatty acid oxidation. Targeting BAT might therefore be considered as a future therapeutic strategy for the treatment of dyslipidemia.

  19. Comparison of the effect between pioglitazone and metformin in treating patients with PCOS:a meta-analysis.

    Science.gov (United States)

    Xu, Yifeng; Wu, Yanxiang; Huang, Qin

    2017-10-01

    Pioglitazone was used to treat patients of PCOS in many researches, but the treatment has not been recognized by public or recommended by all the guidelines. We conducted a meta-analysis of the related literatures to objectively evaluate the clinical effectiveness and safety by comparing pioglitazone with metformin administrated by PCOS patients. Searches were performed in Cochrane Library, EMBASE and PubMed (last updated December 2016). Eleven studies among 486 related articles were identified through searches. Fixed effects and random effects models were used to calculate the overall risk estimates. The results of the meta-analysis suggest that improvement of the menstrual cycle and ovulation in pioglitazone treatment group was better than metformin group [OR = 2.31, 95% CI (1.37, 3.91), P treatment group was better than pioglitazone group [SMD = 0.29, 95% CI (0.0, 0.59), P = 0.048, I 2  = 0.0%]. BMI was more elevated in pioglitazone group than in metformin group [SMD = 0.83, 95% CI (0.24, 1.41), P = 0.006, I 2  = 82.8%]. There were no significant differences of the other data between the two groups. This meta-analysis indicated that pioglitazone ameliorated menstrual cycle and ovulation better than metformin and metformin ameliorated BMI and F-G scores better than pioglitazone in treating patients with PCOS. Pioglitazone might be a good choice for the patients with PCOS who were intolerant or invalid to metformin for the treatment.

  20. Effect of oral contraceptives and/or metformin on GLP-1 secretion and reactive hypoglycemia in PCOS

    DEFF Research Database (Denmark)

    Glintborg, Dorte; Mumm, Hanne; Holst, Jens Juul

    2017-01-01

    CONTEXT: Insulin resistance in polycystic ovary syndrome (PCOS) may increase the risk of reactive hypoglycaemia (RH) and decrease glucagon-like peptide-1 (GLP-1) secretion. The possible effects of treatment with oral contraceptives (OCP) and/or metformin on GLP-1 secretion and risk of RH in PCOS ...... significantly lower in obese vs. lean patients and were inversely associated with BMI. CONCLUSIONS: AUC GLP-1 levels were unchanged during treatment. Increased risk of hypoglycemia during metformin +OCP could be associated with increased insulin secretion.......CONTEXT: Insulin resistance in polycystic ovary syndrome (PCOS) may increase the risk of reactive hypoglycaemia (RH) and decrease glucagon-like peptide-1 (GLP-1) secretion. The possible effects of treatment with oral contraceptives (OCP) and/or metformin on GLP-1 secretion and risk of RH in PCOS......, glucose, insulin, and C-peptide during 5 h OGTT. RESULTS: Fasting GLP-1 levels increased during metformin+OCP vs. OCP treatment, whereas AUC GLP-1 levels were unchanged during medical treatment. The prevalence of reactive hypoglycemia increased from 9/65 to 14/65 after intervention (P

  1. Managing Recurring Obstetric Cholestasis With Metformin.

    Science.gov (United States)

    Elfituri, Abdullatif; Ali, Amanda; Shehata, Hassan

    2016-12-01

    Obstetric cholestasis is a pregnancy-related disorder associated with an adverse pregnancy outcome. It is characterized by generalized pruritus, elevated bile acids, and abnormal liver enzymes. Recent publications show that obstetric cholestasis is associated with, and likely to potentiate, the risk of developing gestational diabetes mellitus. This case describes an unusual pattern of the disease, in which obstetric cholestasis occurred in five consecutive pregnancies with a different course of the disease in the fifth pregnancy. A patient with recurrent cholestasis of pregnancy had worsening disease in her first four pregnancies. In her fifth pregnancy, treatment for gestational diabetes mellitus with metformin was associated with a lowering effect on bile acids and liver enzymes, indicating a possible role for metformin in the management of obstetric cholestasis.

  2. Metformin improves endothelial function and carotid intima media thickness in patients with PCOS.

    Science.gov (United States)

    Kaya, Mehmet Gungor; Yildirim, Sumeyra; Calapkorur, Bekir; Akpek, Mahmut; Unluhizarci, Kursad; Kelestimur, Fahrettin

    2015-05-01

    Oral contraceptive pills (OCP) are widely used for treating women with polycystic ovary syndrome (PCOS). Metformin has beneficial effects on insulin resistance and endothelial functions. The aim of this study was to investigate the effects of treatment with drospirenone/ethinyl estradiol (EE) alone or in combination with metformin on the flow-mediated vasodilatation (FMD) and carotid intima media thickness (CIMT) in women with PCOS. Fifty women with PCOS (mean age 23 ± 5) were randomized to oral treatment of OCP alone (n = 25) or an OCP combination with metformin (n = 25) for 6 months. FMD from the brachial artery and CIMT were calculated. The hormonal profile, HOMA-IR score, basal insulin and glucose levels were studied in both groups. Before and after 6 months' treatment, echocardiographic measurements and laboratory tests were also obtained. After 6 months' treatment we observed a small decrease in FMD in the OCP group (14.9 ± 9.4 versus 14.4 ± 9.9, p = 0.801) and a slight increase in the combination group (14.5 ± 9.1 versus 15.0 ± 8.0, p = 0.715) but neither of them reached significance. CIMT increased in the OCP group (0.048 ± 0.011 to 0.050 ± 0.010 cm, p = 0.433) and decreased slightly in the combination group (0.049 ± 0.012, 0.048 ± 0.011 cm, p = 0.833). We demonstrated that adding metformin to OCP treatment may have beneficial effect on FMD and CIMT that represent vascular function in patients with PCOS. These results suggest that adding metformin to OCP treatment for PCOS could preserve the cardiovascular system and improve it.

  3. Metformin impacts cecal bile acid profiles in mice.

    Science.gov (United States)

    Sillner, Nina; Walker, Alesia; Koch, Wendelin; Witting, Michael; Schmitt-Kopplin, Philippe

    2018-04-15

    Bile acids (BAs) are major components of bile synthesized from cholesterol and take part in the digestion of dietary lipids, as well as having signaling functions. They undergo extensive microbial metabolism inside the gastrointestinal tract. Here, we present a method of ultra-high pressure liquid chromatography coupled to ion trap mass spectrometry for quantification of 45 BAs in mouse cecum. The system was validated in regard to sensitivity with limits of detection and quantification (0.6-24.9 nM), interday accuracy (102.4%), interday precision (15.2%), recovery rate (74.7%), matrix effect (98.2%) and carry-over effect (mice were treated with metformin for 1 day or 14 days. One day of treatment resulted in a significant increase of total BA concentration (2.7-fold increase; db/db metformin 5.32 μmol/g, db/db control mice 1.95 μmol/g), most notable in levels of 7-oxodeoxycholic, 3-dehydrocholic and cholic acid. We observed only minor impact on BA metabolism after 14 days of metformin treatment, compared to the single treatment. Furthermore, healthy wild type mice had elevated concentrations of allocholic and ω-muricholic acid compared to diabetic mice. Our method proved the applicability of profiling BAs in cecum to investigate intestinal BA metabolism in diabetes and pharmacological applications. Copyright © 2018 Elsevier B.V. All rights reserved.

  4. Fixed-dose combinations in type 2 diabetes – role of the canagliflozin metformin combination

    Directory of Open Access Journals (Sweden)

    Fleming JW

    2015-06-01

    Full Text Available Joshua W Fleming, Laurie W Fleming, Courtney S Davis Department of Pharmacy Practice, The University of Mississippi School of Pharmacy, Jackson, MS, USA Abstract: Canagliflozin–metformin is one of the newest combination therapies available for the treatment of type 2 diabetes mellitus (T2DM. Canagliflozin is an inhibitor of the sodium–glucose co-transporter 2 which causes an increase in the urinary excretion of glucose. In the present article, we review the safety and efficacy of canagliflozin and metformin from data obtained from Phase III metformin add-on therapy clinical trials as there are no studies to date that specifically evaluate the combination of metformin and canagliflozin. Trials included in this review were dual-therapy trials of subjects who were already taking background metformin and were assigned to receive canagliflozin, glimepiride, or sitagliptin. The addition of canagliflozin to metformin resulted in a decrease in HbA1c of 0.73%–0.93%. Canagliflozin 100 mg was considered to be non-inferior to glimepiride and sitagliptin 100 mg with the canagliflozin 300 mg dose being statistically superior to sitagliptin and glimepiride. Other advantages of the use of canagliflozin are reduction in weight (3.3–4.0 kg and systolic blood pressure (3.3–4.7 mmHg. The primary disadvantages are potential genital mycotic infections, hypotension, and gastrointestinal side effects from metformin. All things considered, this combination appears to be safe and effective in clinical trials and represents a promising option for the treatment of T2DM. Keywords: type 2 diabetes, fixed-dose combination (FDC, canagliflozin metformin 

  5. Impact of metformin on reproductive tissues: an overview from gametogenesis to gestation

    OpenAIRE

    Bertoldo, Michael J.; Faure, Melanie; Dupont, Joelle; Froment, Pascal

    2014-01-01

    Metformin is an oral anti-hyperglycemic drug that acts as an insulin sensitizer in the treatment of diabetes mellitus type 2. It has also been widely used in the treatment of polycystic ovary syndrome (PCOS) and gestational diabetes. This drug has been shown to activate a protein kinase called 5' AMP-activated protein kinase or AMPK. AMPK is present in many tissues making metformin’s effect multi factorial. However as metformin crosses the placenta, its use during pregnancy raises concerns re...

  6. The utility of metformin therapy in reproductive-aged women with polycystic ovary syndrome (PCOS).

    Science.gov (United States)

    Nathan, Nisha; Sullivan, Shannon D

    2014-01-01

    Metformin, an insulin-sensitizing drug commonly used to treat Type 2 Diabetes Mellitus (T2DM), has been increasingly used off-label for the treatment of polycystic ovary syndrome (PCOS), which affects at least 5-10% of reproductive- age women. With very little risk associated with its use, metformin provides many important benefits to women with PCOS, including regulating menstrual cycles, improving clinical signs of hyperandrogenism, ameliorating metabolic syndrome, inducing ovulation, improving pregnancy rates and pregnancy outcomes, preventing gestational diabetes, and preventing progression to T2DM. Here, we review the indications for metformin in women with PCOS, with a focus on the use of metformin during pre-conception and pregnancy.

  7. High and typical 18F-FDG bowel uptake in patients treated with metformin

    International Nuclear Information System (INIS)

    Gontier, Eric; Bonardel, Gerald; Mantzarides, Marina; Foehrenbach, Herve; Fourme, Emmanuelle; Wartski, Myriam; Pecking, Alain-Paul; Alberini, Jean-Louis; Blondet, Cyrille; Le Stanc, Elise

    2008-01-01

    This prospective and bi-centric study was conducted in order to determine the impact of antidiabetic treatments (AD) on 18 F-FDG bowel uptake in type 2 diabetic patients. Fifty-five patients with previously diagnosed and treated type 2 diabetes mellitus (group 1) were divided in two subgroups: AD treatment including metformin (n=32; group 1a) and AD treatment excluding metformin (n=23; group 1b). The 95 patients without diabetes mellitus made up controls (group 2). 18 F-FDG uptake in small intestine and colon was visually graded and semi-quantitatively measured using the maximum standardized uptake value. 18 F-FDG bowel uptake was significantly increased in AD patients (group 1) as compared to controls (group 2) (p 18 F-FDG uptake in colon and, to a lesser extent, in small intestine. It raises the question of stopping metformin treatment before an 18 F-FDG PET/CT scan is performed for intra-abdominal neoplasic lesion assessment. (orig.)

  8. Treatment with L-citrulline and metformin in Duchenne muscular dystrophy: study protocol for a single-centre, randomised, placebo-controlled trial.

    Science.gov (United States)

    Hafner, Patricia; Bonati, Ulrike; Rubino, Daniela; Gocheva, Vanya; Zumbrunn, Thomas; Gueven, Nuri; Fischer, Dirk

    2016-08-03

    Duchenne muscular dystrophy (DMD) is an X-linked recessive disease that affects 1 in 3500-6000 male births. Despite broad research aiming to improve muscle function as well as heart and brain function, sufficient therapeutic efficacy has not yet been achieved and current therapeutic management is still supportive. In a recent pilot trial, oral treatment with L-arginine and metformin showed consistent changes of muscular metabolism both in vitro and in vivo by raising NO levels and expression of mitochondrial proteins in the skeletal muscle tissue of patients with DMD. This randomised, double-blind, placebo-controlled trial aims to demonstrate the superiority of L-citrulline and metformin therapy over placebo in DMD patients with regard to the Motor Function Measure (MFM) D1 subscore (primary endpoint) as well as additional clinical and subclinical tests. A total of 40-50 ambulant patients with DMD will be recruited at the outpatient department of the University of Basel Children's Hospital (Switzerland), as well as from the DMD patient registries of Switzerland, Germany and Austria. Patients will be randomly allocated to one of the two arms of the study and will receive either a combination of L-citrulline and metformin or placebo for 26 weeks. Co-medication with glucocorticoids is allowed. The primary endpoint is the change of the MFM D1 subscore from baseline to week 26 under L-citrulline and metformin therapy. Secondary endpoints will include the motor function measure (MFM) and its items and subscores, the 6-minute walking test, timed function tests and quantitative muscle testing. Furthermore, quantitative muscle MRI assessment to evaluate the muscle fat fraction as well as safety and biomarker laboratory analyses from blood will be included. For comparison, muscle metabolism and mitochondrial function will be analysed in 10-20 healthy age-matched male children. The aim of this study is to test if a 6-month treatment of a combination of L-citrulline and

  9. Risk of lactic acidosis in type 2 diabetes patients using metformin

    DEFF Research Database (Denmark)

    Aharaz, Abdellatif; Pottegård, Anton; Henriksen, Daniel Pilsgaard

    2018-01-01

    risk of lactic acidosis associated with metformin treatment. Methods This is a population-based combined cohort and case-control study among patients with type 2 diabetes mellitus who were acutely admitted with lactic acidosis at Odense University Hospital, Denmark; in the period from 1st June 2009...... to 1st October 2013. The patients included as cases were all acutely hospitalized with lactic acidosis (pH 2.0 mmol/l). For each case, we identified 24 age- and sex-matched controls sampled from the same cohort with type 2 diabetes mellitus. The use of metformin identified by using......Background Metformin constitutes first-line treatment of type 2 diabetes mellitus. It is presumed to have lactic acidosis as a dangerous, but rare, side effect. Objectives To estimate the incidence rate of lactic acidosis in patients with type 2 diabetes mellitus as well as to estimate the relative...

  10. Low Concentrations of Metformin Selectively Inhibit CD133+ Cell Proliferation in Pancreatic Cancer and Have Anticancer Action

    Science.gov (United States)

    Li, Xiangsheng; Shi, Pengfei; Liu, Tao; Wang, Chunyou

    2013-01-01

    Pancreatic cancer is the fourth leading cause of cancer related deaths in the United States. The prognosis remains dismal with little advance in treatment. Metformin is a drug widely used for the treatment of type II diabetes. Recent epidemiologic data revealed that oral administration of metformin is associated with a reduced risk of pancreatic cancer, suggesting its potential as a novel drug for this disease. Many studies have demonstrated the in vitro anticancer action of metformin, but the typically used concentrations were much higher than the in vivo plasma and tissue concentrations achieved with recommended therapeutic doses of metformin, and low concentrations of metformin had little effect on the proliferation of pancreatic cancer cells. We examined the effect of low concentrations of metformin on different subpopulations of pancreatic cancer cells and found that these selectively inhibited the proliferation of CD133+ but not CD24+CD44+ESA+ cells. We also examined the effect of low concentrations of metformin on cell invasion and in vivo tumor formation, demonstrating in vitro and in vivo anticancer action. Metformin was associated with a reduction of phospho-Erk and phospho-mTOR independent of Akt and AMPK phosphorylation. CD133+ pancreatic cancer cells are considered to be cancer stem cells that contribute to recurrence, metastasis and resistance to adjuvant therapies in pancreatic cancer. Our results provide a basis for combination of metformin with current therapies to improve the prognosis of this disease. PMID:23667692

  11. Treatment Considerations for the Cardiometabolic Signs of Polycystic Ovary Syndrome: A Review of the Literature Since the 2013 Endocrine Society Clinical Practice Guidelines.

    Science.gov (United States)

    Fields, Errol L; Trent, Maria E

    2016-05-01

    Polycystic ovary syndrome is characterized by an excess in androgen levels, ovarian dysfunction, and polycystic ovarian morphology but is also associated with metabolic dysfunction and risk factors for cardiovascular disease. To our knowledge, there are few therapeutic recommendations for these cardiometabolic risk factors and little evidence of their long-term clinical relevance to cardiovascular health. To determine metabolic and/or cardiovascular outcomes in polycystic ovary syndrome treatment literature since the publication of the most recent Endocrine Society clinical practice guidelines in 2013. We searched PubMed using a string of variations of polycystic ovary syndrome, therapy/treatment, and adolescence, and we included English-language original research articles published while the 2013 clinical practice guidelines were disseminated (ie, articles published from January 1, 2011, to June 1, 2015). Articles that appeared relevant based on a review of titles and abstracts were read in full to determine relevancy. References from relevant articles were reviewed for additional studies. Four topic areas emerged: (1) lifestyle modification, (2) metformin vs placebo or estrogen-progestin oral contraceptives, (3) insulin-sensitizing agents, and (4) estrogen-progestin formulations. Most studies assessed the role of metformin as a monotherapy or dual therapy supplement and found significant benefit when including metformin in polycystic ovary syndrome treatment regimens. Studies showed improvements in cardiometabolic risk factors and, in several, androgen excess and cutaneous and menstrual symptoms. Studies were limited by sample size (range, 22-171), few adolescent participants, and short-term outcomes. Findings show potential for metformin and estrogen-progestin dual therapy but warrant longitudinal studies examining outcomes from adolescence through middle age to determine the effect on long-term cardiovascular health.

  12. Extending Metformin Use in Diabetic Kidney Disease: A Pharmacokinetic Study in Stage 4 Diabetic Nephropathy

    Directory of Open Access Journals (Sweden)

    Ajith Munasinghe Dissanayake

    2017-07-01

    Discussion: In our patient cohorts with diabetes and stage 4 chronic kidney disease, treatment with 4 weeks of low-dose metformin was not associated with adverse safety outcomes and revealed stable pharmacokinetics. Our study supports the liberalization of metformin use in this population and supports the use of metformin assays for more individualized dosing.

  13. Metformin influence on hormone levels at birth, in PCOS mothers and their newborns.

    Science.gov (United States)

    Carlsen, S M; Vanky, E

    2010-03-01

    Polycystic ovary syndrome (PCOS) tends to run in families and excess intrauterine androgen exposure has been suggested as one possible cause of PCOS. We wanted to study the relationship between maternal and offspring sex hormone levels and the possible effects of metformin treatment in PCOS pregnancies. We performed a post hoc analysis of a trial in which 40 pregnant women with PCOS were randomized in the first trimester, to use either metformin 850 mg twice daily or placebo until delivery. Maternal venous blood and umbilical arterial and venous blood samples were collected at delivery. Outcome measures were levels of androgens, estrogens and sex hormone binding globulin (SHBG). (i) In newborns, SHBG levels were higher in the metformin group. All other hormones, both in mothers and offspring, were unaffected by metformin treatment. (ii) Mothers, who gave birth to boys, had higher estrone and estradiol levels compared with those who gave birth to girls. (iii) Male newborns had higher levels of testosterone, androstanediol glucuronide and estradiol compared with females. (iv) Positive correlations were found between maternal and newborn levels of androstenedione, dihydrotestosterone and estradiol. Intrauterine metformin exposure seems to result in elevated SHBG levels in newborns. However, at birth, maternal and newborn androgen and estrogen levels are unaffected by metformin use in pregnancy. Although androgen and estrogen levels are higher in male newborns compared with females, maternal and newborn androgen and estrogen levels are highly correlated at birth.

  14. Combined Vildagliptin and Metformin Exert Better Cardioprotection than Monotherapy against Ischemia-Reperfusion Injury in Obese-Insulin Resistant Rats

    Science.gov (United States)

    Apaijai, Nattayaporn; Chinda, Kroekkiat; Palee, Siripong; Chattipakorn, Siriporn; Chattipakorn, Nipon

    2014-01-01

    Background Obese-insulin resistance caused by long-term high-fat diet (HFD) consumption is associated with left ventricular (LV) dysfunction and increased risk of myocardial infarction. Metformin and vildagliptin have been shown to exert cardioprotective effects. However, the effect of these drugs on the hearts under obese-insulin resistance with ischemia-reperfusion (I/R) injury is unclear. We hypothesized that combined vildagliptin and metformin provide better protective effects against I/R injury than monotherapy in obese-insulin resistant rats. Methodology Male Wistar rats were fed either HFD or normal diet. Rats in each diet group were divided into 4 subgroups to receive vildagliptin, metformin, combined vildagliptin and metformin, or saline for 21 days. Ischemia due to left anterior descending artery ligation was allowed for 30-min, followed by 120-min reperfusion. Metabolic parameters, heart rate variability (HRV), LV function, infarct size, mitochondrial function, calcium transient, Bax and Bcl-2, and Connexin 43 (Cx43) were determined. Rats developed insulin resistance after 12 weeks of HFD consumption. Vildagliptin, metformin, and combined drugs improved metabolic parameters, HRV, and LV function. During I/R, all treatments improved LV function, reduced infarct size and Bax, increased Bcl-2, and improved mitochondrial function in HFD rats. However, only combined drugs delayed the time to the first VT/VF onset, reduced arrhythmia score and mortality rate, and increased p-Cx43 in HFD rats. Conclusion Although both vildagliptin and metformin improved insulin resistance and attenuate myocardial injury caused by I/R, combined drugs provided better outcomes than single therapy by reducing arrhythmia score and mortality rate. PMID:25036861

  15. Combined vildagliptin and metformin exert better cardioprotection than monotherapy against ischemia-reperfusion injury in obese-insulin resistant rats.

    Directory of Open Access Journals (Sweden)

    Nattayaporn Apaijai

    Full Text Available BACKGROUND: Obese-insulin resistance caused by long-term high-fat diet (HFD consumption is associated with left ventricular (LV dysfunction and increased risk of myocardial infarction. Metformin and vildagliptin have been shown to exert cardioprotective effects. However, the effect of these drugs on the hearts under obese-insulin resistance with ischemia-reperfusion (I/R injury is unclear. We hypothesized that combined vildagliptin and metformin provide better protective effects against I/R injury than monotherapy in obese-insulin resistant rats. METHODOLOGY: Male Wistar rats were fed either HFD or normal diet. Rats in each diet group were divided into 4 subgroups to receive vildagliptin, metformin, combined vildagliptin and metformin, or saline for 21 days. Ischemia due to left anterior descending artery ligation was allowed for 30-min, followed by 120-min reperfusion. Metabolic parameters, heart rate variability (HRV, LV function, infarct size, mitochondrial function, calcium transient, Bax and Bcl-2, and Connexin 43 (Cx43 were determined. Rats developed insulin resistance after 12 weeks of HFD consumption. Vildagliptin, metformin, and combined drugs improved metabolic parameters, HRV, and LV function. During I/R, all treatments improved LV function, reduced infarct size and Bax, increased Bcl-2, and improved mitochondrial function in HFD rats. However, only combined drugs delayed the time to the first VT/VF onset, reduced arrhythmia score and mortality rate, and increased p-Cx43 in HFD rats. CONCLUSION: Although both vildagliptin and metformin improved insulin resistance and attenuate myocardial injury caused by I/R, combined drugs provided better outcomes than single therapy by reducing arrhythmia score and mortality rate.

  16. Anti-proliferative effect of metformin on a feline injection site sarcoma cell line independent of Mtor inhibition.

    Science.gov (United States)

    Pierro, J; Saba, C; McLean, K; Williams, R; Karpuzoglu, E; Prater, R; Hoover, K; Gogal, R

    2017-10-01

    Metformin is an oral hypoglycemic drug that has been shown to inhibit cancer cell proliferation via up-regulation of AMPK (AMP-activated protein kinase), and possibly inhibition of mTOR (mammalian target of rapamycin). The purpose of this study was to evaluate the effects of metformin on a feline injection site sarcoma cell line. Cells from a feline injection site sarcoma cell line were treated with metformin at varied concentrations. A dose-dependent decrease in cell viability following metformin treatment was observed, with an IC50 of 8.0mM. Using flow cytometry, the mechanism of cell death was determined to be apoptosis or necrosis. To evaluate the role of mTOR inhibition in metformin-induced cell death, Western blot was performed. No inhibition of mTOR or phosphorylated mTOR was found. Although metformin treatment leads to apoptotic or necrotic cell death in feline injection site sarcoma cells, the mechanism does not appear to be mediated by mTOR inhibition. Copyright © 2017 Elsevier Ltd. All rights reserved.

  17. Fenofibrate plus Metformin Produces Cardioprotection in a Type 2 Diabetes and Acute Myocardial Infarction Model

    Directory of Open Access Journals (Sweden)

    Víctor Hugo Oidor-Chan

    2016-01-01

    Full Text Available We investigated whether fenofibrate, metformin, and their combination generate cardioprotection in a rat model of type 2 diabetes (T2D and acute myocardial infarction (AMI. Streptozotocin-induced diabetic- (DB- rats received 14 days of either vehicle, fenofibrate, metformin, or their combination and immediately after underwent myocardial ischemia/reperfusion (I/R. Fenofibrate plus metformin generated cardioprotection in a DBI/R model, reported as decreased coronary vascular resistance, compared to DBI/R-Vehicle, smaller infarct size, and increased cardiac work. The subchronic treatment with fenofibrate plus metformin increased, compared with DBI/R-Vehicle, total antioxidant capacity, manganese-dependent superoxide dismutase activity (MnSOD, guanosine triphosphate cyclohydrolase I (GTPCH-I expression, tetrahydrobiopterin : dihydrobiopterin (BH4 : BH2 ratio, endothelial nitric oxide synthase (eNOS activity, nitric oxide (NO bioavailability, and decreased inducible NOS (iNOS activity. These findings suggest that PPARα activation by fenofibrate + metformin, at low doses, generates cardioprotection in a rat model of T2D and AMI and may represent a novel treatment strategy to limit I/R injury in patients with T2D.

  18. Effect of metformin and oral contraceptives on polycystic ovary syndrome and IVF cycles.

    Science.gov (United States)

    Kalem, M N; Kalem, Z; Gurgan, T

    2017-07-01

    The aim of this study is to investigate the effect of metformin and/or OC added to the treatment of PCOS patients at our clinic on IVF outcome. This study is a retrospective study that assesses the data of PCOS patients who received IVF between 2005 and 2015 at a private IVF center. The study included 496 PCOS cases aged between 24 and 40. Participants diagnosed with PCOS were divided into 4 groups according to the use of metformin and OC prior to the IVF cycle: 11.1% were in the metformin group, 31.3% in the OC group, 14.9% in the Metformin + OC group, and 42.7% in the control group. No difference was found in the total gonadotropin dose and duration of stimulation between the groups. Clinical pregnancy rates and implantation rates were similar in all groups, although the numbers of oocytes, mature oocytes, fertilized oocytes, and transferred embryos were lower in the treatment groups received metformin compared to the OC group and control group. There was no significant difference in the presence of OHSS and the singleton and multiple pregnancies between the four groups. The present study established no positive role of metformin and OC use in increasing the treatment success in IVF/ICSI cycles in PCOS patients. It would be appropriate to limit the use of these agents with special indications such as decreasing insulin resistance or synchronizing follicular cohort.

  19. Effects of vildagliptin relative to sulfonylureas in Muslim patients with type 2 diabetes fasting during Ramadan: influence of age and treatment with/without metformin in the VIRTUE study

    Science.gov (United States)

    Hassoun, Ahmed AK; Pathan, Md Faruque; Medlej, Rita C; Alarouj, Monira; Shaltout, Inass; Chawla, Manoj S; Knap, Ditte; Vaz, Julius A

    2016-01-01

    Background VIRTUE was a prospective, observational study assessing the effectiveness and safety of vildagliptin vs sulfonylureas (SUs) (both as monotherapy and in combination with metformin) in patients with type 2 diabetes mellitus who fasted during Ramadan. A post hoc analysis was carried out to assess the effect of treatment with/without metformin and age (Ramadan. Secondary end points included change from baseline in glycated hemoglobin (HbA1c), body weight, and safety. Results Overall, 684 patients received vildagliptin and 631 received SUs. Most patients received dual therapy with metformin (n=1,148) and were aged fasting during Ramadan. PMID:27555791

  20. Metformin and Ara-a Effectively Suppress Brain Cancer by Targeting Cancer Stem/Progenitor Cells

    Directory of Open Access Journals (Sweden)

    Tarek H. Mouhieddine

    2015-11-01

    Full Text Available Background: Gliomas and neuroblastomas pose a great health burden worldwide with a poor and moderate prognosis, respectively. Many studies have tried to find effective treatments for these primary malignant brain tumors. Of interest, the AMP-activated protein kinase (AMPK pathway was found to be associated with tumorigenesis and tumor survival, leading to many studies on AMPK drugs, especially Metformin, and their potential role as anti-cancer treatments. Cancer stem cells (CSCs are a small population of slowly-dividing, treatment-resistant, undifferentiated cancer cells that are being discovered in a multitude of cancers. They are thought to be responsible for replenishing the tumor with highly proliferative cells and increasing the risk of recurrence. Methods: Metformin and 9-β-d-Arabinofuranosyl Adenine (Ara-a were used to study the role of the AMPK pathway in vitro on U251 (glioblastoma and SHSY-5Y (neuroblastoma cell lines.Results: We found that both drugs are able to decrease the survival of U251 and SH-SY5Y cell lines in a 2D as well as a 3D culture model. Metformin and Ara-a significantly decreased the invasive ability of these cancer cell lines. Treatment with these drugs decreased the sphere-forming units (SFU of U251 cells, with Ara-a being more efficient, signifying the extinction of the CSC population. However, if treatment is withdrawn before all SFUs are extinguished, the CSCs regain some of their sphere-forming capabilities in the case of Metformin but not Ara-a treatment. Conclusion: Metformin and Ara-a have proved to be effective in the treatment of glioblastomas and neuroblastomas, in vitro, by targeting their cancer stem/progenitor cell population, which prevents recurrence.

  1. Trends in metformin utilisation and dose appropriateness in Australia.

    Science.gov (United States)

    Moon, J; Kumar, S S; Graham, G G; Baysari, M T; Williams, K M; Chen, W; Viardot, A; Greenfield, J R; Day, R O

    2016-12-01

    The study aimed to (1) determine the trends in the utilisation of metformin in Australia, (2) determine the appropriateness of metformin dosing in an Australian teaching hospital and (3) gather the opinions of prescribers on the relationship between metformin dose and renal function. National prescription data between 1990 and 2012 were accessed. A retrospective audit (2008-2012) of metformin doses and patient renal function (20 % random sample of all in-patients prescribed metformin) was conducted at St Vincent's Hospital (SVH), Sydney. Prescribers of metformin were interviewed (semi-structured; consultants at SVH) or surveyed (Australian endocrinologists) to gather their understanding of metformin dosing in relation to renal function. Metformin utilisation increased fivefold nationally between 1995 and 2012. Metformin tended to be under-dosed in SVH patients with normal renal function (83.5 %) and over-dosed in patients with impaired renal function (estimated glomerular filtration rate (eGFR) metformin doses needed to be reduced in renal impairment. Most endocrinologists (61 %) were comfortable prescribing metformin down to eGFRs around 30 mL/min. The use of metformin increased greatly over the period of the study. Metformin is prescribed frequently for patients with eGFR values below the minimal level approved in the product label (60 mL/min). While prescribers expressed their understanding of the need to reduce metformin doses in patients with renal impairment, we found that metformin doses were higher than appropriate in patients with impaired renal function. Metformin may be used safely when renal function is poor provided dosage is appropriately reduced.

  2. Metformin induces apoptosis through AMPK-dependent inhibition of UPR signaling in ALL lymphoblasts.

    Directory of Open Access Journals (Sweden)

    Gilles M Leclerc

    Full Text Available The outcome of patients with resistant phenotypes of acute lymphoblastic leukemia (ALL or those who relapse remains poor. We investigated the mechanism of cell death induced by metformin in Bp- and T-ALL cell models and primary cells, and show that metformin effectively induces apoptosis in ALL cells. Metformin activated AMPK, down-regulated the unfolded protein response (UPR demonstrated by significant decrease in the main UPR regulator GRP78, and led to UPR-mediated cell death via up-regulation of the ER stress/UPR cell death mediators IRE1α and CHOP. Using shRNA, we demonstrate that metformin-induced apoptosis is AMPK-dependent since AMPK knock-down rescued ALL cells, which correlated with down-regulation of IRE1α and CHOP and restoration of the UPR/GRP78 function. Additionally rapamycin, a known inhibitor of mTOR-dependent protein synthesis, rescued cells from metformin-induced apoptosis and down-regulated CHOP expression. Finally, metformin induced PIM-2 kinase activity and co-treatment of ALL cells with a PIM-1/2 kinase inhibitor plus metformin synergistically increased cell death, suggesting a buffering role for PIM-2 in metformin's cytotoxicity. Similar synergism was seen with agents targeting Akt in combination with metformin, supporting our original postulate that AMPK and Akt exert opposite regulatory roles on UPR activity in ALL. Taken together, our data indicate that metformin induces ALL cell death by triggering ER and proteotoxic stress and simultaneously down-regulating the physiologic UPR response responsible for effectively buffering proteotoxic stress. Our findings provide evidence for a role of metformin in ALL therapy and support strategies targeting synthetic lethal interactions with Akt and PIM kinases as suitable for future consideration for clinical translation in ALL.

  3. Massage therapy has short-term benefits for people with common musculoskeletal disorders compared to no treatment: a systematic review.

    Science.gov (United States)

    Bervoets, Diederik C; Luijsterburg, Pim A J; Alessie, Jeroen J N; Buijs, Martijn J; Verhagen, Arianne P

    2015-07-01

    Is massage therapy effective for people with musculoskeletal disorders compared to any other treatment or no treatment? Systematic review of randomised clinical trials. People with musculoskeletal disorders. Massage therapy (manual manipulation of the soft tissues) as a stand-alone intervention. The primary outcomes were pain and function. The 26 eligible randomised trials involved 2565 participants. The mean sample size was 95 participants (range 16 to 579) per study; 10 studies were considered to be at low risk of bias. Overall, low-to-moderate-level evidence indicated that massage reduces pain in the short term compared to no treatment in people with shoulder pain and osteoarthritis of the knee, but not in those with low back pain or neck pain. Furthermore, low-to-moderate-level evidence indicated that massage improves function in the short term compared to no treatment in people with low back pain, knee arthritis or shoulder pain. Low-to-very-low-level evidence from single studies indicated no clear benefits of massage over acupuncture, joint mobilisation, manipulation or relaxation therapy in people with fibromyalgia, low back pain and general musculoskeletal pain. Massage therapy, as a stand-alone treatment, reduces pain and improves function compared to no treatment in some musculoskeletal conditions. When massage is compared to another active treatment, no clear benefit was evident. Copyright © 2015 Australian Physiotherapy Association. Published by Elsevier B.V. All rights reserved.

  4. The effect of short-term corticosteroid treatment on the CT appearance of experimental brain abscesses

    International Nuclear Information System (INIS)

    Enzmann, D.R.; Britt, R.H.; Placone, R.C. Jr.; Obana, W.; Lyons, B.; Yeager, A.S.

    1982-01-01

    The effect of short-term corticosteroid treatment on contrast enhancement was investigated in an experimental brain abscess model. The degree of enhancement was reduced in the cerebritis stage, unaffected in the capsule stage, and intermediate in the transitional stage. The area and pattern of enhancement were also altered in the cerebritis stage. Although the magnitude of the entire cerebritis time-density curve (extended for 60 minutes) was decreased by the steroids, its configuration was unchanged. Prior to steroid administration, the 10- and 60-minute components of the curve discriminated between cerebritis and capsule stages, with the latter exhibiting a far lower 60-minute value. Implications for treatment of brain abscesses are discussed

  5. Is It Time to Change the Type 2 Diabetes Treatment Paradigm? No! Metformin Should Remain the Foundation Therapy for Type 2 Diabetes.

    Science.gov (United States)

    Inzucchi, Silvio E

    2017-08-01

    Most treatment guidelines, including those from the American Diabetes Association/European Association for the Study of Diabetes and the International Diabetes Federation, suggest metformin be used as the first-line therapy after diet and exercise. This recommendation is based on the considerable body of evidence that has accumulated over the last 30 years, but it is also supported on clinical grounds based on metformin's affordability and tolerability. As such, metformin is the most commonly used oral antihyperglycemic agent in the U.S. However, based on the release of newer agents over the recent past, some have suggested that the modern approach to disease management should be based upon identification of its etiology and correcting the underlying biological disturbances. That is, we should use interventions that normalize or at least ameliorate the recognized derangements in physiology that drive the clinical manifestation of disease, in this circumstance, hyperglycemia. Thus, it is argued that therapeutic interventions that target glycemia but do not correct the underlying pathogenic disturbances are unlikely to result in a sustained benefit on the disease process. In our field, there is an evolving debate regarding the suggested first step in diabetes management and a call for a new paradigm. Given the current controversy, we provide a Point-Counterpoint debate on this issue. In the point narrative that precedes the counterpoint narrative below, Drs. Abdul-Ghani and DeFronzo provide their argument that a treatment approach for type 2 diabetes based upon correcting the underlying pathophysiological abnormalities responsible for the development of hyperglycemia provides the best therapeutic strategy. Such an approach requires a change in the recommendation for first-line therapy from metformin to a GLP-1 receptor agonist. In the counterpoint narrative below, Dr. Inzucchi argues that based on the medical community's extensive experience and the drug

  6. Repositioning chloroquine and metformin to eliminate cancer stem cell traits in pre-malignant lesions.

    Science.gov (United States)

    Vazquez-Martin, Alejandro; López-Bonetc, Eugeni; Cufí, Sílvia; Oliveras-Ferraros, Cristina; Del Barco, Sonia; Martin-Castillo, Begoña; Menendez, Javier A

    2011-01-01

    Ideal oncology drugs would be curative after a short treatment course if they could eliminate epithelium-originated carcinomas at their non-invasive, pre-malignant stages. Such ideal molecules, which are expected to molecularly abrogate all the instrumental mechanisms acquired by migrating cancer stem cells (CSCs) to by-pass tumour suppressor barriers, might already exist. We here illustrate how system biology strategies for repositioning existing FDA-approved drugs may accelerate our therapeutic capacity to eliminate CSC traits in pre-invasive intraepithelial neoplasias. First, we describe a signalling network signature that overrides bioenergetics stress- and oncogene-induced senescence (OIS) phenomena in CSCs residing at pre-invasive lesions. Second, we functionally map the anti-malarial chloroquine and the anti-diabetic metformin ("old drugs") to their recently recognized CSC targets ("new uses") within the network. By discussing the preclinical efficacy of chloroquine and metformin to inhibiting the genesis and self-renewal of CSCs we finally underscore the expected translational impact of the "old drugs-new uses" repurposing strategy to open a new CSC-targeted chemoprevention era. Copyright © 2011 Elsevier Ltd. All rights reserved.

  7. Metformin-associated respiratory alkalosis.

    Science.gov (United States)

    Bryant, Sean M; Cumpston, Kirk; Lipsky, Martin S; Patel, Nirali; Leikin, Jerrold B

    2004-01-01

    We present an 84-year-old man with a history of chronic obstructive pulmonary disease, type 2 diabetes, hypertension, glaucoma, and bladder cancer who presented to the emergency department after the police found him disoriented and confused. Metformin therapy began 3 days before, and he denied any overdose or suicidal ideation. Other daily medications included glipizide, fluticasone, prednisone, aspirin, furosemide, insulin, and potassium supplements. In the emergency department, his vital signs were significant for hypertension (168/90), tachycardia (120 bpm), and Kussmaul respirations at 24 breaths per minute. Oxygen saturation was 99% on room air, and a fingerstick glucose was 307 mg/dL. He was disoriented to time and answered questions slowly. Metformin was discontinued, and by day 3, the patient's vital signs and laboratory test results normalized. He has been asymptomatic at subsequent follow-up visits. Metformin-associated lactic acidosis is a well-known phenomenon. Respiratory alkalosis may be an early adverse event induced by metformin prior to the development of lactic acidosis.

  8. Short-term versus continuous antimicrobial therapy for asymptomatic bacteriuria in pregnancy.

    Science.gov (United States)

    Whalley, P J; Cunningham, F G

    1977-03-01

    Asymptomatic bacteriuria was identified in 300 pregnant women prior to the 28th week of gestation. In one group of 200 women short-term treatment with either nitrofurantoin or sulfamethizole was given for 14 days, and in another group of 100 women continuous therapy with one of these drugs was given for the remainder of gestation. Weekly urine cultures were obtained from all the women. Of the women treated with short-term therapy, 65% were abacteriuric for the remainder of pregnancy following one course of therapy, 24% became abacteriuric but subsequently relapsed, 2% had reinfection after becoming abacteriuric, and 9% demonstrated no response. Following treatment with a second course of short-term therapy, another 19% of these women were cured for the remainder of their pregnancy, and 3.5% responded to a third course. In the continuous therapy group, 88% of the women became abacteriuric for the remainder of the gestation, 3% demonstrated relapse, 2% developed reinfection, and 7% had no response to the first drug given. These data demonstrate that short-term administration of antimicrobials, when combined with surveillance for recurrent bacteriuria, is effective for the management of the pregnant woman with asymptomatic bacteriuria.

  9. Use of metformin and risk of kidney cancer in patients with type 2 diabetes.

    Science.gov (United States)

    Tseng, Chin-Hsiao

    2016-01-01

    The anticancer effect of metformin has been reported in the literature but requires additional confirmation in epidemiologic studies. With respect to kidney cancer scarce data are available. This study investigates whether metformin use in patients with type 2 diabetes mellitus (T2DM) might affect kidney cancer risk. The reimbursement database of the National Health Insurance in Taiwan was used. T2DM patients aged ≥ 40 years and newly treated with either metformin (n=171,753, "ever users of metformin") or other antidiabetic drugs (n=75,499, "never users of metformin") within 1998-2002 were followed for at least 6 months for kidney cancer until 31 December 2009. The treatment effect was estimated by Cox regression using propensity score weighting by inverse probability of treatment weighting approach. Hazard ratios were estimated for ever versus never users, and for tertiles of cumulative duration of metformin therapy. During follow-up, 917 ever users and 824 never users developed kidney cancer, with respective incidence of 80.09 and 190.30 per 100,000 person-years. The hazard ratio (95% confidence intervals) for ever versus never users is 0.279 (0.254-0.307); and is 0.598 (0.535-0.668), 0.279 (0.243-0.321) and 0.104 (0.088-0.124), respectively, for the first, second, and third tertile of cumulative duration of 45.8 months. In subgroup analyses, the lower risk of kidney cancer associated with metformin use is consistently observed in both sexes, and in patients with or without concomitant use of other antidiabetic drugs. Metformin use is associated with a decreased risk of kidney cancer in patients with T2DM. Copyright © 2015 Elsevier Ltd. All rights reserved.

  10. Metformin modifies the exercise training effects on risk factors for cardiovascular disease in impaired glucose tolerant adults

    Science.gov (United States)

    Malin, Steven K.; Nightingale, Joy; Choi, Sung-Eun; Chipkin, Stuart R.; Braun, Barry

    2012-01-01

    Impaired glucose tolerant (IGT) adults are at elevated risk for cardiovascular disease (CVD). Exercise or metformin reduce CVD risk, but the efficacy of combining treatments is unclear. To determine the effects of exercise training plus metformin, compared to each treatment alone, on CVD risk factors in IGT adults. Subjects were assigned to: placebo (P), metformin (M), exercise plus placebo (EP), or exercise plus metformin (EM) (8/group). In a double-blind design, P or 2000mg/d of M were administered for 12 weeks and half performed aerobic and resistance training 3 days/week for approximately 60 minutes/day at 70% pre-training heart rate peak. Outcomes included: adiposity, blood pressure (BP), lipids and high sensitivity C-reactive protein (hs-CRP). Z-scores were calculated to determine metabolic syndrome severity. M and EM, but not EP, decreased body weight compared to P (p metabolic syndrome Z-score compared to baseline (EP; trend p = 0.07 and EM or M; p exercise and/or metformin improve some CVD risk factors, only training or metformin alone lowered hs-CRP and BP. Thus, metformin may attenuate the effects of training on some CVD risk factors and metabolic syndrome severity in IGT adults. PMID:23505172

  11. Self-reported immature defense style as a predictor of outcome in short-term and long-term psychotherapy.

    Science.gov (United States)

    Laaksonen, Maarit A; Sirkiä, Carlos; Knekt, Paul; Lindfors, Olavi

    2014-07-01

    Identification of pretreatment patient characteristics predictive of psychotherapy outcome could help to guide treatment choices. This study evaluates patients' initial level of immature defense style as a predictor of the outcome of short-term versus long-term psychotherapy. In the Helsinki Psychotherapy Study, 326 adult outpatients with mood or anxiety disorder were randomized to individual short-term (psychodynamic or solution-focused) or long-term (psychodynamic) psychotherapy. Their defense style was assessed at baseline using the 88-item Defense Style Questionnaire and classified as low or high around the median value of the respective score. Both specific (Beck Depression Inventory [BDI], Hamilton Depression Rating Scale [HDRS], Symptom Check List Anxiety Scale [SCL-90-Anx], Hamilton Anxiety Rating Scale [HARS]) and global (Symptom Check List Global Severity Index [SCL-90-GSI], Global Assessment of Functioning Scale [GAF]) psychiatric symptoms were measured at baseline and 3-7 times during a 3-year follow-up. Patients with high use of immature defense style experienced greater symptom reduction in long-term than in short-term psychotherapy by the end of the 3-year follow-up (50% vs. 34%). Patients with low use of immature defense style experienced faster symptom reduction in short-term than in long-term psychotherapy during the first year of follow-up (34% vs. 19%). Knowledge of patients' initial level of immature defense style may potentially be utilized in tailoring treatments. Further research on defense styles as outcome predictors in psychotherapies of different types is needed.

  12. Comparison of short-term effects between interventional embolization treatment and iodine-131 therapy for graves'hyperthyroidism

    International Nuclear Information System (INIS)

    Zhu Gaohong; Zhao Wei; Yuan Weihong; Wang Bailing; Yi Gengfa; Yang Shumin

    2010-01-01

    Objective: To compare the short-term effects between interventional arterial embolization and iodine-131 therapy in treating Graves' disease. Methods: A total of 84 patients with Graves' disease (GD), confirmed by clinical data and laboratory tests, were divided into two groups: interventional group (n = 42) receiving arterial embolization and iodine-131 group (n = 42)receiving iodine-131 therapy. Before and after the treatment thyroid angiography and SPECT / CT imaging were performed to determine the shape and size of the thyroid, and radioimmunoassay method was used to measure serum levels of FT3, FT4, TSH and TRAb at 3, 6 and 12 months after the therapy. The results were compared and statistically analyzed. The occurrence of complications was observed. Results: No statistically significant difference in short-term therapeutic effects was found between interventional group and iodine-131 group. The occurrence of early severe complication was much higher in interventional group than that in iodine-131 group, while the occurrence of hypothyroidism was obviously higher in iodine-131 group than that in interventional group. Conclusion: Both interventional embolization and iodine-131 therapy have reliable effect for the treatment of Graves' disease. Iodine-131 therapy may be used in patients who plan to receive initial treatment or in patients who failed to effectively respond to other kinds of therapies, while interventional embolization may be employed in patients who are not able to receive surgery or in patients who have failed to respond to anti-thyroid drug treatment, or in patients whose iodine-131 intake rate is too low to undergo iodine-131 therapy, especially in patients with refractory and intractable hyperthyroidism. Interventional embolization can be regarded as an alternative treatment for Graves' disease. (authors)

  13. Effect of Metformin on Potassium-adapted and Non- adapted ...

    African Journals Online (AJOL)

    determined. Results: The blood glucose of the potassium-adapted diabetic group was not significantly reduced on treatment ... whom dietary carbohydrate restriction has not controlled .... significantly different from the metformin-treated group.

  14. Metformin and breast cancer: basic knowledge in clinical context.

    Science.gov (United States)

    Pizzuti, Laura; Vici, Patrizia; Di Lauro, Luigi; Sergi, Domenico; Della Giulia, Marina; Marchetti, Paolo; Maugeri-Saccà, Marcello; Giordano, Antonio; Barba, Maddalena

    2015-05-01

    Although preclinical work is vital in unraveling the molecular tenets which apply to metformin action in breast cancer, it is by nature unable to capture the host's response to metformin in terms of insulin-mediated effects and related changes in the hormonal and metabolic asset at the systemic level. The latter might sound seemingly paradoxical when considering the inveterate use of metformin in dysmetabolisms and pathologic conditions with underlying hormonal disruption. Bridging the gap between the molecular target and characteristics of breast cancer patients may help lab-based experiments and clinical work converge into one or more well characterized sub-populations instead of a sub optimally selected one. An appropriate patient selection is the main key to the most suitable outcome interpretation and amelioration, in an attempt to meet our patients needs midway between overestimation of benefits and efficacy dilution for any given intervention and/or co-intervention. Copyright © 2015 Elsevier Ltd. All rights reserved.

  15. Clomiphene citrate, metformin or a combination of both as the first line ovulation induction drug for Asian Indian women with polycystic ovarian syndrome: A randomized controlled trial

    Directory of Open Access Journals (Sweden)

    Sujata Kar

    2015-01-01

    Full Text Available Aim: To compare clomiphene citrate (CC, metformin or the combination of CC and metformin as the first line ovulation induction drug in Asian Indian women with polycystic ovary syndrome (PCOS. Methods: One hundred and five newly diagnosed, treatment naive PCOS women were recruited. They were randomized into any of the three groups: Group I (CC 50-150 mg/day, Group II (metformin 1700 mg/day, and Group III (CC + metformin in similar dosage to Groups I and II. Patients underwent follicular monitoring and advice on timed intercourse. The study period was 6 months, or till pregnant, or till CC resistant. Primary outcome studied was live birth rate (LBR. Secondary outcomes were ovulation rate, pregnancy rate, and early pregnancy loss rate. Results: There was no significant difference among the groups in baseline characteristics and biochemical parameters. LBR was 41.6%, 37.5%, and 28.1%, respectively in Groups III, II, and I. Group III (CC + metformin had the highest ovulation (83.3%, pregnancy (50%, and LBRs (41.6%. Group II (metformin was as good as Group I (CC in all the outcomes. CC + metformin (Group III had statistically significantly higher ovulation rate as compared to CC alone (Group I (P = 0.03; odds ratio: 95% confidence interval: 3.888 [1.08-13.997]. Conclusion: Thus, our study shows that metformin was as good as CC in terms of "LBR" and the combination of CC and metformin gave the highest ovulation and LBR.

  16. Pregnancies following the use of sequential treatment of metformin and incremental doses of letrozole in clomiphen-resistant women with polycystic ovary syndrome

    Directory of Open Access Journals (Sweden)

    Jafar Alavy Toussy

    2012-01-01

    Full Text Available Background: Clomiphen citrate (CC is the first line therapy for women with infertility and poly cystic ovary syndrome( PCOS. However, 20-25% of women are resistant to CC and do not ovulate. Objective: The objective of this study was to evaluate the efficacy of sequential treatment of metformin and incremental doses of letrozole in induction of ovulation in cases of CC-resistant PCOS patients. Materials and Methods: In this prospective before-after study, we enrolled 106 anovulatory PCOS women who failed to ovulate with CC alone from Amir-Almomenin University Hospital in Semnan, Iran. After an initial 6-8 weeks of metformin treatment, they received 2.5 mg letrozole daily on days 3-7 after menes. If they did not ovulate with 2.5 mg letrozole, the doses were increased to 5 to 7.5 mg daily in subsequent cycles. The main outcomes were ovulatory rate, pregnancy rate and cumulative pregnancy rate. Results: 13.33% of patients conceived with metformin alone. Ovulation occurred in 83 out of remaining 91 patients (91.2%. 78.02% of patients responded to lower doses of letrozole. Cumulative pregnancy rate was 60/ 105 (57.14%.Conclusion: We suggest that treatment in CC-resistant PCOS patients should begin at first with lower doses of letrozole and could increase to the higher dose depending on the patient response before considering more aggressive therapeutic alternatives such as gonadotropins.

  17. Metformin reduces hyper-reactivity of platelets from patients with polycystic ovary syndrome by improving mitochondrial integrity.

    Science.gov (United States)

    Randriamboavonjy, Voahanginirina; Mann, W Alexander; Elgheznawy, Amro; Popp, Rüdiger; Rogowski, Paul; Dornauf, Imke; Dröse, Stefan; Fleming, Ingrid

    2015-08-31

    Polycystic ovary syndrome (PCOS) is associated with decreased fertility, insulin resistance and an increased risk of developing cardiovascular disease. Treating PCOS patients with metformin improves fertility and decreases cardiovascular complications. Given that platelet activation contributes to both infertility and cardiovascular disease development, we assessed platelet reactivity in PCOS patients and the consequences of metformin treatment. Compared to washed platelets from healthy donors, platelets from PCOS patients demonstrated enhanced reactivity and impaired activation of the AMP-activated kinase (AMPK). PCOS platelets also demonstrated enhanced expression of mitochondrial proteins such as the cytochrome c reductase, ATP synthase and the voltage-dependent anion channel-1. However, mitochondrial function was impaired as demonstrated by a decreased respiration rate. In parallel, the phosphorylation of dynamin-related protein-1 (Drp-1) on Ser616 was increased while that on Ser637 decreased. The latter changes were accompanied by decreased mitochondrial size. In insulin-resistant PCOS patients (HOMA-IR> 2) metformin treatment (1.7 g per day for 4 weeks to 6 months) improved insulin sensitivity, restored mitochondrial integrity and function and normalised platelet aggregation. Treatment was without effect in PCOS patients with HOMA-IRtreatment of megakaryocytes with metformin enhanced mitochondrial content and in the same cells metformin enhanced the phosphorylation of the Drp-1 on Ser637 via an AMPKα1-dependent mechanism. In conclusion, the improvement of mitochondrial integrity and platelet reactivity may contribute to the beneficial effects of metformin on cardiovascular disease.

  18. Pregnancy outcomes and the effect of metformin treatment in women with polycystic ovary syndrome: an overview.

    Science.gov (United States)

    Ghazeeri, Ghina S; Nassar, Anwar H; Younes, Zeina; Awwad, Johnny T

    2012-06-01

    This article is a review of the literature assessing pregnancy outcomes and the effect of metformin treatment among women with polycystic ovary syndrome (PCOS). A review of research published in English was undertaken using PubMed and MEDLINE databases. The weight of the available evidence suggests that pregnant women with PCOS are at an increased risk of developing gestational diabetes, hypertensive disorders of pregnancy, preterm birth and early pregnancy loss. Obesity is a contributory factor for the increased risk of gestational diabetes in this group of women and is estimated to affect 5-40% of pregnant women with PCOS. The prevalence of other obstetric complications is estimated at 10-30% for gestational hypertension, 8-15% for pre-eclampsia and 6-15% for preterm birth. The association between PCOS and early pregnancy loss may not be direct, wherein the presence of PCOS-associated hyperinsulinemia, leading to hyperandrogenemia, has been implicated in the pathophysiology of early pregnancy loss. Apart from the role of metformin in improving the metabolic consequences accompanying PCOS, it has been shown to improve pregnancy rates in women with PCOS who are resistant to clomiphene citrate. In conclusion, pregnancy in women with PCOS is associated with adverse obstetric outcomes (multiple adverse obstetric risk). Whether metformin should be administered throughout pregnancy still remains controversial. Further prospective studies that foster a larger number of participants and adjust for all potentially confounding factors are needed. © 2012 The Authors Acta Obstetricia et Gynecologica Scandinavica© 2012 Nordic Federation of Societies of Obstetrics and Gynecology.

  19. Metformin prevents and reverses inflammation in a non-diabetic mouse model of nonalcoholic steatohepatitis.

    Directory of Open Access Journals (Sweden)

    Yuki Kita

    Full Text Available BACKGROUND: Optimal treatment for nonalcoholic steatohepatitis (NASH has not yet been established, particularly for individuals without diabetes. We examined the effects of metformin, commonly used to treat patients with type 2 diabetes, on liver pathology in a non-diabetic NASH mouse model. METHODOLOGY/PRINCIPAL FINDINGS: Eight-week-old C57BL/6 mice were fed a methionine- and choline-deficient plus high fat (MCD+HF diet with or without 0.1% metformin for 8 weeks. Co-administration of metformin significantly decreased fasting plasma glucose levels, but did not affect glucose tolerance or peripheral insulin sensitivity. Metformin ameliorated MCD+HF diet-induced hepatic steatosis, inflammation, and fibrosis. Furthermore, metformin significantly reversed hepatic steatosis and inflammation when administered after the development of experimental NASH. CONCLUSIONS/SIGNIFICANCE: These histological changes were accompanied by reduced hepatic triglyceride content, suppressed hepatic stellate cell activation, and the downregulation of genes involved in fatty acid metabolism, inflammation, and fibrogenesis. Metformin prevented and reversed steatosis and inflammation of NASH in an experimental non-diabetic model without affecting peripheral insulin resistance.

  20. Genetic Variants in Transcription Factors Are Associated With the Pharmacokinetics and Pharmacodynamics of Metformin

    Science.gov (United States)

    Goswami, S; Yee, SW; Stocker, S; Mosley, JD; Kubo, M; Castro, R; Mefford, JA; Wen, C; Liang, X; Witte, J; Brett, C; Maeda, S; Simpson, MD; Hedderson, MM; Davis, RL; Roden, DM; Giacomini, KM; Savic, RM

    2014-01-01

    One-third of type 2 diabetes patients do not respond to metformin. Genetic variants in metformin transporters have been extensively studied as a likely contributor to this high failure rate. Here, we investigate, for the first time, the effect of genetic variants in transcription factors on metformin pharmacokinetics (PK) and response. Overall, 546 patients and healthy volunteers contributed their genome-wide, pharmacokinetic (235 subjects), and HbA1c data (440 patients) for this analysis. Five variants in specificity protein 1 (SP1), a transcription factor that modulates the expression of metformin transporters, were associated with changes in treatment HbA1c (P < 0.01) and metformin secretory clearance (P < 0.05). Population pharmacokinetic modeling further confirmed a 24% reduction in apparent clearance in homozygous carriers of one such variant, rs784888. Genetic variants in other transcription factors, peroxisome proliferator–activated receptor-α and hepatocyte nuclear factor 4-α, were significantly associated with HbA1c change only. Overall, our study highlights the importance of genetic variants in transcription factors as modulators of metformin PK and response. PMID:24853734

  1. The effect of metformin on monocyte secretory function in simvastatin-treated patients with impaired fasting glucose.

    Science.gov (United States)

    Krysiak, Robert; Okopien, Bogusław

    2013-01-01

    This study was designed to investigate whether metformin affects monocyte secretory function in patients with impaired fasting glucose receiving chronic statin therapy. The study included 48 patients with impaired fasting glucose treated for at least three months with simvastatin (40 mg daily). These patients were randomized to either metformin (3 g daily) or placebo, which was administered together with simvastatin for 90 days. Plasma lipids, glucose homeostasis markers, monocyte cytokine release and plasma C-reactive protein levels were determined before randomization and at the end of the treatment. Compared to placebo, metformin reduced monocyte release of tumor necrosis factor-α, interleukin-1β, interleukin-6, monocyte chemoattractant protein-1 and interleukin-8, as well as decreased plasma C-reactive protein levels, which were accompanied by an improvement in insulin sensitivity. The obtained results suggest that metformin may inhibit monocyte secretory function and reduce systemic inflammation in statin-treated patients with prediabetes. Impaired fasting glucose patients with high cardiovascular risk may receive the greatest benefits from concomitant treatment with a statin and metformin. Copyright © 2013 Elsevier Inc. All rights reserved.

  2. Response of stream invertebrates to short-term salinization: A mesocosm approach

    International Nuclear Information System (INIS)

    Cañedo-Argüelles, Miguel; Grantham, Theodore E.; Perrée, Isabelle; Rieradevall, Maria; Céspedes-Sánchez, Raquel; Prat, Narcís

    2012-01-01

    Salinization is a major and growing threat to freshwater ecosystems, yet its effects on aquatic invertebrates have been poorly described at a community-level. Here we use a controlled experimental setting to evaluate short-term stream community responses to salinization, under conditions designed to replicate the duration (72 h) and intensity (up to 5 mS cm −1 ) of salinity pulses common to Mediterranean rivers subjected to mining pollution during runoff events. There was a significant overall effect, but differences between individual treatments and the control were only significant for the highest salinity treatment. The community response to salinization was characterized by a decline in total invertebrate density, taxon richness and diversity, an increase in invertebrate drift and loss of the most sensitive taxa. The findings indicate that short-term salinity increases have a significant impact on the stream invertebrate community, but concentrations of 5 mS cm −1 are needed to produce a significant ecological response. - Highlights: ► Short-term salinization has a significant impact on the aquatic invertebrates. ► A significant short-term ecological response is registered at 5 mS cm −1 . ► Salinization causes a decline in invertebrate density, richness and diversity. ► Biotic quality indices decline with increasing salinity and exposure time. - Short-term salinization in a stream mesocosm caused a significant response in the aquatic invertebrate community and led to declines in biological quality indices.

  3. Body weight reduction and metformin: Roles in polycystic ovary syndrome.

    Science.gov (United States)

    Al-Nozha, Omar; Habib, Fawziah; Mojaddidi, Moaz; El-Bab, Mohamed Fath

    2013-04-01

    Polycystic ovary syndrome (PCOS) is a common problem in women at fertile age. A prospective study was conducted to clarify the pathophysiological responses during an application of insulin sensitizer, metformin and weight reduction therapy at the Gynecology Center in Ohud hospital, in AL-Madinah AL-Munawarah, Kingdom of Saudi Arabia. Twenty healthy women served as controls and 180 PCOS women divided into three groups participated in the study. First group was treated with Clomid citrate 100mg/day from the 2nd day of menses to the 6th day plus gonadotrophin from day three to the 13th. Group II was treated as group I plus 850mg metformin twice a day and group III was treated as group I plus weight reduction. Clinical symptoms, menstrual pattern, hirsutism, blood glucose, body mass index, waist-to-hip ratio, insulin, hormonal, and lipid profiles were assessed pre- and post treatment. Insulin resistance was calculated. PCOS women had significantly higher values than the healthy women in most of the measurements. Metformin and weight reduction therapy resulted in a significant decrease in the fasting insulin, glucose/insulin ratio and HOMA-IR. Metformin and weight reduction therapy resulted in a significant decrease in the lipid parameters, testosterone, LH/FSH ratio, SHBG, and prolactin levels. HOMA-IR was significantly higher in women with PCOS. HOMA-IR was positively correlated with testosterone, estradiol, TG, total cholesterol and LDL-cholesterol parameters, and negatively correlated with HDL-cholesterol and FSH levels. Metformin therapy and weight reduction had favorable influences on the basic metabolic and hormonal profiles in women with PCOS and that metformin and lifestyle modification (weight reduction via diet restriction or exercise) resulted in a significantly greater weight loss than hormonal therapy alone. Metformin and weight reduction therapy decreased also hyperandrogenism and insulin resistance. Copyright © 2013 Elsevier Ireland Ltd. All rights

  4. Metformin enhances tamoxifen-mediated tumor growth inhibition in ER-positive breast carcinoma

    International Nuclear Information System (INIS)

    Ma, Ji; Zhang, Jian; Liu, Wenchao; Guo, Yan; Chen, Suning; Zhong, Cuiping; Xue, Yan; Zhang, Yuan; Lai, Xiaofeng; Wei, Yifang; Yu, Shentong

    2014-01-01

    Tamoxifen, an endocrine therapy drug used to treat breast cancer, is designed to interrupt estrogen signaling by blocking the estrogen receptor (ER). However, many ER-positive patients are low reactive or resistant to tamoxifen. Metformin is a widely used anti-diabetic drug with noteworthy anti-cancer effects. We investigated whether metformin has the additive effects with tamoxifen in ER-positive breast cancer therapy. The efficacy of metformin alone and in combination with tamoxifen against ER-positive breast cancer was analyzed by cell survival, DNA replication activity, plate colony formation, soft-agar, flow cytometry, immunohistochemistry, and nude mice model assays. The involved signaling pathways were detected by western blot assay. When metformin was combined with tamoxifen, the concentration of tamoxifen required for growth inhibition was substantially reduced. Moreover, metformin enhanced tamoxifen-mediated inhibition of proliferation, DNA replication activity, colony formation, soft-agar colony formation, and induction of apoptosis in ER-positive breast cancer cells. In addition, these tamoxifen-induced effects that were enhanced by metformin may be involved in the bax/bcl-2 apoptotic pathway and the AMPK/mTOR/p70S6 growth pathway. Finally, two-drug combination therapy significantly inhibited tumor growth in vivo. The present work shows that metformin and tamoxifen additively inhibited the growth and augmented the apoptosis of ER-positive breast cancer cells. It provides leads for future research on this drug combination for the treatment of ER-positive breast cancer

  5. Metformin improved health-related quality of life in ethnic Chinese women with polycystic ovary syndrome.

    Science.gov (United States)

    Huang-TzOu; Chen, Pei-Chi; Wu, Meng-Hsing; Lin, Chung-Ying

    2016-08-24

    Few studies have assessed whether the amelioration of the clinical signs of polycystic ovary syndrome (PCOS) achieved by treatment leads to improvement in the health-related quality of life (HRQoL) of patients. This study was aimed to examine the HRQoL of ethnic Chinese women with PCOS who received metformin treatment. This prospective study was conducted at a medical center in Taiwan. Study participants aged 18-45 years were diagnosed as having PCOS according to the Rotterdam criteria, and all received metformin treatment. Their HRQoL was assessed using generic (WHOQOL-Bref) and PCOS-specific (Chi-PCOSQ) instruments. Mixed effect models were used to examine the effects of metformin on repeatedly measured HRQoL. Additional analyses using stratified patients characteristics (overweight vs. normal; hyperandrogenism vs. non-hyperandrogenism) were done. We recruited 109 participants (56 % were overweight, 80 % had hyperandrogenism). Among the domain scores of WHOQOL-Bref, the psychological domain score was the lowest one (12.64 ± 2.2, range 4-20). Weight (3.25 ± 1.59, range 1-7) and infertility (3.38 ± 1.93, range 1-7) domain scores were relatively low among the domain scores of Chi-PCOSQ. Overweight and hyperandrogenic patients had significantly lower HRQoL as compared with those of normal weight and non-hyperandrogenic patients, respectively. Metformin significantly improved the physical domain of WHOQOL-Bref (p = 0.01), and the infertility (p = 0.043) and acne and hair loss aspects (p = 0.008) of PCOS-specific HRQoL. In the subgroup analysis, significantly improved HRQoL following metformin treatment appeared for only overweight and hyperandrogenism subgroups. Metformin might improve health-related quality of life of polycystic ovary syndrome women by ameliorating psychological disturbances due to acne, hair loss and infertility problems, especially for overweight and hyperandrogenic patients.

  6. Metformin and thiazolidinedione use in Medicare patients with heart failure.

    Science.gov (United States)

    Masoudi, Frederick A; Wang, Yongfei; Inzucchi, Silvio E; Setaro, John F; Havranek, Edward P; Foody, JoAnne M; Krumholz, Harlan M

    2003-07-02

    According to package inserts, metformin is contraindicated in diabetic patients receiving drug treatment for heart failure therapy, and thiazolidinediones are not recommended in diabetic patients with symptoms of advanced heart failure. Little is known about patterns of use of these antihyperglycemic drugs in diabetic patients with heart failure. To determine the proportions of patients hospitalized with heart failure and concomitant diabetes treated with metformin or thiazolidinediones. Serial cross-sectional measurements using data from retrospective medical record abstraction. Nongovernmental acute care hospitals in the United States. Two nationally representative samples of Medicare beneficiaries hospitalized with the primary diagnosis of heart failure and concomitant diabetes between April 1998 and March 1999 and between July 2000 and June 2001. The prescription of either metformin or a thiazolidinedione at hospital discharge. In the 1998-1999 sample (n = 12 505), 7.1% of patients were discharged with a prescription for metformin, 7.2% with a prescription for a thiazolidinedione, and 13.5% with a prescription for either drug. In the 2000-2001 sample (n = 13 158), metformin use increased to 11.2%, thiazolidinedione use to 16.1%, and use of either drug to 24.4% (Puse of metformin and thiazolidinediones is common and has increased rapidly in Medicare beneficiaries with diabetes and heart failure in direct contrast with explicit warnings against this practice by the Food and Drug Administration. Further studies to establish the safety and effectiveness of this practice are needed to ensure optimal care of patients with diabetes and heart failure.

  7. Metformin treatment is associated with a low risk of mortality in diabetic patients with heart failure: a retrospective nationwide cohort study

    DEFF Research Database (Denmark)

    Andersson, C; Olesen, JB; Hansen, PR

    2010-01-01

    The safety of metformin in heart failure has been questioned because of a perceived risk of life-threatening lactic acidosis, though recent studies have not supported this concern. We investigated the risk of all-cause mortality associated with individual glucose-lowering treatment regimens used...

  8. Simvastatin and metformin inhibit cell growth in hepatitis C virus infected cells via mTOR increasing PTEN and autophagy.

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    José A Del Campo

    Full Text Available Hepatitis C virus (HCV infection has been related to increased risk of development of hepatocellular carcinoma (HCC while metformin (M and statins treatment seemed to protect against HCC development. In this work, we aim to identify the mechanisms by which metformin and simvastatin (S could protect from liver cancer. Huh7.5 cells were infected with HCV particles and treated with M+S. Human primary hepatocytes were treated with M+S. Treatment with both drugs inhibited Huh7.5 cell growth and HCV infection. In non-infected cells S increased translational controlled tumor protein (TCTP and phosphatase and tensin homolog (PTEN proteins while M inhibited mammalian target of rapamycin (mTOR and TCTP. Simvastatin and metformin co-administered down-regulated mTOR and TCTP, while PTEN was increased. In cells infected by HCV, mTOR, TCTP, p62 and light chain 3B II (LC3BII were increased and PTEN was decreased. S+M treatment increased PTEN, p62 and LC3BII in Huh7.5 cells. In human primary hepatocytes, metformin treatment inhibited mTOR and PTEN, but up-regulated p62, LC3BII and Caspase 3. In conclusion, simvastatin and metformin inhibited cell growth and HCV infection in vitro. In human hepatocytes, metformin increased cell-death markers. These findings suggest that M+S treatment could be useful in therapeutic prevention of HCV-related hepatocellular carcinoma.

  9. Metformin increases pressure pain threshold in lean women with polycystic ovary syndrome

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    Kiałka M

    2016-08-01

    Full Text Available Marta Kiałka,1 Tomasz Milewicz,1 Krystyna Sztefko,2 Iwona Rogatko,2 Renata Majewska3 1Department of Gynecological Endocrinology, Jagiellonian University, Medical College, Kraków, Poland; 2Department of Clinical Biochemistry, Jagiellonian University, Medical College, Kraków, Poland; 3Department of Epidemiology, Chair of Epidemiology and Preventive Medicine, Jagiellonian University Medical College, Kraków, Poland Background: Despite the strong preclinical rationale, there are only very few data considering the utility of metformin as a potential pain therapeutic in humans. The aim of this study was to determine the association between metformin therapy and pressure pain threshold (PPT in lean women with polycystic ovary syndrome (PCOS. We hypothesized that metformin therapy in lean PCOS women increases PPT. Materials and methods: Twenty-seven lean PCOS women with free androgen index phenotype >5 and 18 lean healthy controls were enrolled in the study. Fifteen of the PCOS women were randomly assigned to be treated with metformin 1,500 mg daily for 6 months. PPT and plasma β-endorphin levels were measured in all women at the beginning of the study and after 6 months of observation. Results: We observed an increase in PPT values measured on deltoid and trapezius muscle in the PCOS with metformin group after 6 months of metformin administration (4.81±0.88 kg/cm², P<0.001 on deltoid muscle, and 5.71±1.16 kg/cm² on trapezius muscle. We did not observe any significant changes in PPT values in the PCOS without treatment group and in controls. We did not observe any significant changes in serum β-endorphin levels in any studied groups during the 6-month observation. Conclusion: We conclude that metformin therapy increases PPT in lean PCOS women, without affecting plasma β-endorphin concentration. Our results may suggest the potential role of metformin in pain therapy. We propose that larger, randomized studies on metformin impact on pain

  10. Short-Term Effects of Kinesiotaping on Pain and Joint Alignment in Conservative Treatment of Hallux Valgus.

    Science.gov (United States)

    Karabicak, Gul Oznur; Bek, Nilgun; Tiftikci, Ugur

    2015-10-01

    The main aim of this study was to measure short-term effects of kinesiotaping on pain and joint alignment in the conservative treatment of hallux valgus. Twenty-one female patients diagnosed with a total of 34 feet with hallux valgus (13 bilateral, 6 right, and 2 left) participated in this study. Kinesiotaping was implemented after the first assessment and renewed in days 3, 7, and 10. The main outcome measures were pain, as assessed using visual analog scale, and hallux adduction angle, as measured by goniometry. Secondary outcome measure was patients' functional status, as measured by Foot Function Index and the hallux valgus scale of the American Orthopaedic Foot and Ankle Society (AOFAS). The radiographic results were also measured before and after 1 month of treatment. The Wilcoxon test was used to compare the differences between initial and final scores of AOFAS, as well as FFI scales and hallux valgus angle assessment scores. There was a significant reduction in goniometric measurement of hallux valgus angle (P = .001). There was a significant reduction in pain intensity (P = .001) and AOFAS and Foot Function Index scores at the end of the treatment (P = .001 and P = .001, respectively). There was a significant difference between radiographic results in 1-month control (P = .009). For this group of female patients, pain and joint alignment were improved after a 10-day kinesiotape implementation in patients with hallux valgus. The findings showed short-term decreased pain and disability in hallux valgus deformity. Copyright © 2015 National University of Health Sciences. Published by Elsevier Inc. All rights reserved.

  11. Dispositional optimism as predictor of outcome in short- and long-term psychotherapy.

    Science.gov (United States)

    Heinonen, Erkki; Heiskanen, Tiia; Lindfors, Olavi; Härkäpää, Kristiina; Knekt, Paul

    2017-09-01

    Dispositional optimism predicts various beneficial outcomes in somatic health and treatment, but has been little studied in psychotherapy. This study investigated whether an optimistic disposition differentially predicts patients' ability to benefit from short-term versus long-term psychotherapy. A total of 326 adult outpatients with mood and/or anxiety disorder were randomized into short-term (solution-focused or short-term psychodynamic) or long-term psychodynamic therapy and followed up for 3 years. Dispositional optimism was assessed by patients at baseline with the self-rated Life Orientation Test (LOT) questionnaire. Outcome was assessed at baseline and seven times during the follow-up, in terms of depressive (BDI, HDRS), anxiety (SCL-90-ANX, HARS), and general psychiatric symptoms (SCL-90-GSI), all seven follow-up points including patients' self-reports and three including interview-based measures. Lower dispositional optimism predicted faster symptom reduction in short-term than in long-term psychotherapy. Higher optimism predicted equally rapid and eventually greater benefits in long-term, as compared to short-term, psychotherapy. Weaker optimism appeared to predict sustenance of problems early in long-term therapy. Stronger optimism seems to best facilitate engaging in and benefiting from a long-term therapy process. Closer research might clarify the psychological processes responsible for these effects and help fine-tune both briefer and longer interventions to optimize treatment effectiveness for particular patients and their psychological qualities. Weaker dispositional optimism does not appear to inhibit brief therapy from effecting symptomatic recovery. Patients with weaker optimism do not seem to gain added benefits from long-term therapy, but instead may be susceptible to prolonged psychiatric symptoms in the early stages of long-term therapy. © 2016 The British Psychological Society.

  12. Effect of 12-month treatment with metformin and/or oral contraceptives on health-related quality of life in polycystic ovary syndrome.

    Science.gov (United States)

    Altinok, Magda Lambaa; Ravn, Pernille; Andersen, Marianne; Glintborg, Dorte

    2018-04-16

    Health-related quality of life (HRQoL) is impaired in polycystic ovary syndrome (PCOS), but the effect of treatment with metformin (M) and/or oral contraceptives (OCP) is undetermined. To assess changes in HRQoL during 12-month randomized treatment with M, OCP or M + OCP in PCOS. Ninety women with PCOS were randomized to treatment with M, OCP or M + OCP. HRQoL was evaluated by a PCOS-specific visual analog scale (PCOS-VAS) regarding 1: Facial hair, 2: Body hair, 3: Acne, 4: Irregular menses, 5: Weight and 6: PCOS in general, and Short Form 36 (SF-36). PCOS-VAS1(facial hair) improved during treatment with OCP (n = 23) compared to M (n = 19), and during M + OCP (n = 23) compared to M treatment, whereas changes in PCOS-VAS2-6 and SF-36 scores were comparable between the three medical intervention groups. Pooled data (n = 65) showed improved PCOS-VAS scores during treatment (all p PCOS-VAS were unassociated with changes in BMI or FG-scores despite significant weight-loss during treatment with M (-3.0 kg (-10.3; 0.6)) and M + OCP (-1.9 kg (-4.9; 0.1)) and decreased FG-score during M + OCP treatment (median (quartiles)). PCOS-VAS scores improved significantly and to the same extent during treatment with M, OCP or M + OCP.

  13. Role of metformin in oxaliplatin-induced peripheral neuropathy in patients with stage III colorectal cancer: randomized, controlled study.

    Science.gov (United States)

    El-Fatatry, Basma Mahrous; Ibrahim, Osama Mohamed; Hussien, Fatma Zakaria; Mostafa, Tarek Mohamed

    2018-06-21

    Peripheral sensory neuropathy is the most prominently reported adverse effect of oxaliplatin. The purpose of this study was to evaluate metformin role in oxaliplatin-induced neuropathy. From November 2014 to May 2016, 40 patients with stage III colorectal cancer completed 12 cycles of FOLFOX-4 regimen. Twenty patients in the control arm received FOLFOX-4 regimen only, and 20 patients in the metformin arm, received the same regimen along with metformin 500 mg three times daily. The metformin efficacy was evaluated using National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE version 4.0), a12-item neurotoxicity questionnaire (Ntx-12) from the validated Functional Assessment of Cancer Therapy/Gynecologic Oncology Group and, the brief pain inventory short form "worst pain" item. In addition to neurotensin, malondialdehyde and interleukin-6 serum levels assessment. At the end of the 12th cycle, there were less patients with grade 2 and 3 neuropathy in metformin arm as compared to control arm. (60 versus 95%, P = 0.009) In addition, metformin arm showed significantly higher total scores of Ntx-12 questionnaire than control arm (24.0 versus 19.2, P < 0.001). Furthermore, the mean pain score in metformin arm was significantly lower than those of control arm, (6.7 versus 7.3, P = 0.005). Mean serum levels of malondialdehyde and neurotensin were significantly lower in metformin arm after the 6th and the 12th cycles. Metformin may be a promising drug in protecting colorectal cancer patients against oxaliplatin-induced chronic peripheral sensory neuropathy.

  14. Effects of Metformin on Tissue Oxidative and Dicarbonyl Stress in Transgenic Spontaneously Hypertensive Rats Expressing Human C-Reactive Protein.

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    Hana Malínská

    Full Text Available Inflammation and oxidative and dicarbonyl stress play important roles in the pathogenesis of type 2 diabetes. Metformin is the first-line drug of choice for the treatment of type 2 diabetes because it effectively suppresses gluconeogenesis in the liver. However, its "pleiotropic" effects remain controversial. In the current study, we tested the effects of metformin on inflammation, oxidative and dicarbonyl stress in an animal model of inflammation and metabolic syndrome, using spontaneously hypertensive rats that transgenically express human C-reactive protein (SHR-CRP. We treated 8-month-old male transgenic SHR-CRP rats with metformin (5 mg/kg/day mixed as part of a standard diet for 4 weeks. A corresponding untreated control group of male transgenic SHR-CRP rats were fed a standard diet without metformin. In a similar fashion, we studied a group of nontransgenic SHR treated with metformin and an untreated group of nontransgenic SHR controls. In each group, we studied 6 animals. Parameters of glucose and lipid metabolism and oxidative and dicarbonyl stress were measured using standard methods. Gene expression profiles were determined using Affymetrix GeneChip Arrays. Statistical significance was evaluated by two-way ANOVA. In the SHR-CRP transgenic strain, we found that metformin treatment decreased circulating levels of inflammatory response marker IL-6, TNFα and MCP-1 while levels of human CRP remained unchanged. Metformin significantly reduced oxidative stress (levels of conjugated dienes and TBARS and dicarbonyl stress (levels of methylglyoxal in left ventricles, but not in kidneys. No significant effects of metformin on oxidative and dicarbonyl stress were observed in SHR controls. In addition, metformin treatment reduced adipose tissue lipolysis associated with human CRP. Possible molecular mechanisms of metformin action-studied by gene expression profiling in the liver-revealed deregulated genes from inflammatory and insulin signaling

  15. Successful metformin treatment of insulin resistance is associated with down-regulation of the kynurenine pathway

    International Nuclear Information System (INIS)

    Muzik, Otto; Burghardt, Paul; Yi, Zhengping; Kumar, Ajay; Seyoum, Berhane

    2017-01-01

    Context: An extensive body of literature indicates a relationship between insulin resistance and the up-regulation of the kynurenine pathway, i.e. the preferential conversion of tryptophan to kynurenine, with subsequent overproduction of diabetogenic downstream metabolites, such as kynurenic acid. Case description: We have measured the concentration of kynurenine pathway metabolites (kynurenines) in the brain and pancreas of two young (27 and 28 yrs) insulin resistant, normoglycemic subjects (M-values 2 and 4 mg/kg/min, respectively) using quantitative C-11-alpha-methyl-tryptophan PET/CT imaging. Both subjects underwent a preventive 12-week metformin treatment regimen (500 mg daily) prior to the PET/CT study. Whereas treatment was successful in one of the subject (M-value increased from 2 to 12 mg/kg/min), response was poor in the other subjects (M-value changed from 4 to 5 mg/kg/min). Brain and pancreas concentrations of kynurenines observed in the responder were similar to that in a healthy control subject, whereas kynurenines determined in the non-responder were about 25% higher and similar to those found in a severely insulin resistant patient. Consistent with this outcome, M-values were negatively correlated with both kynurenic acid levels (R 2  = 0.68, p = 0.09) as well as with the kynurenine to tryptophan ratio (R 2  = 0.63, p = 0.11). Conclusion: The data indicates that kynurenine pathway metabolites are increased in subjects with insulin resistance prior to overt manifestation of hyperglycemia. Moreover, successful metformin treatment leads to a normalization of tryptophan metabolism, most likely as a result of decreased contribution from the kynurenine metabolic pathway.

  16. Carbohydrate restricted diet in conjunction with metformin and liraglutide is an effective treatment in patients with deteriorated type 2 diabetes mellitus: Proof-of-concept study

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    Müller Jürgen E

    2011-12-01

    Full Text Available Abstract Background Type 2 diabetes mellitus is a chronic progressive disease. During the course of the disease intensive treatment is often necessary resulting in multiple interventions including administration of insulin. Although dietary intervention is highly recommended, the clinical results of the widely prescribed diets with low fat content and high carbohydrates are disappointing. In this proof-of-concept study, we tested the effect of dietary carbohydrate-restriction in conjunction with metformin and liraglutide on metabolic control in patients with type 2 diabetes. Methods Forty patients with type 2 diabetes already being treated with two oral anti-diabetic drugs or insulin treatment and who showed deterioration of their glucose metabolism (i.e. HbA1c >7.5, were treated. A carbohydrate-restricted diet and a combination of metformin and liraglutide were instituted, after stopping either insulin or oral anti-diabetic drugs (excluding metformin. After enrollment, the study patients were scheduled for follow-up visits at one, two, three and six months. Primary outcome was glycemic control, measured by HbA1c at six months. Secondary outcomes were body weight, lipid-profile and treatment satisfaction. Results Thirty-five (88% participants completed the study. Nearly all participating patients experienced a drop in HbA1c and body weight during the first three months, an effect which was maintained until the end of the study at six months. Seventy-one percent of the patients reached HbA1c values below 7.0%. The range of body weight at enrollment was extreme, reaching 165 kg as the highest initial value. The average weight loss after 6 months was 10%. Most patients were satisfied with this treatment. During the intervention no significant change of lipids was observed. Most patients who were on insulin could maintain the treatment without insulin with far better metabolic control. Conclusions Carbohydrate restriction in conjunction with

  17. Pharmacokinetic comparison using two tablets of an evogliptin/metformin XR 2.5/500 mg fixed dose combination vs. 1 tablet each of evogliptin 5 mg and metformin XR 1,000 mg
.

    Science.gov (United States)

    Yoon, Sumin; Rhee, Su-Jin; Park, Sang-In; Yoon, Seo Hyun; Cho, Joo-Youn; Jang, In-Jin; Lee, SeungHwan; Yu, Kyung-Sang

    2017-06-01

    The aim of this study was to compare the pharmacokinetic (PK) characteristics of evogliptin and metformin following the administration of 2 evogliptin/metformin extended-release (XR) 2.5/500 mg FDC tablets with the coadministration of separate evogliptin 5-mg and metformin XR 1,000-mg tablets (separate formulations). A randomized, two-period, two-sequence crossover study was conducted. Subjects were randomly assigned to receive 2 FDC tablets or the individual tablets, followed by a 14-day washout period and the administration of the alternate treatment. Blood samples were collected predose and up to 72 hours postdose for each period. PK parameters including Cmax and AUClast were calculated. The geometric mean ratios (GMRs) and the 90% confidence intervals (CIs) between FDC and the separate formulations were calculated for the Cmax and AUClast of evogliptin and metformin. 33 subjects completed the study. The GMR (90% CI) values of Cmax and AUClast for evogliptin were 1.011 (0.959 - 1.066) and 1.010 (0.977 - 1.043), respectively. The GMR (90% CI) values of Cmax and AUClast for metformin were 0.892 (0.827 - 0.963) and 0.893 (0.841 - 0.947), respectively. There was no significant difference between the FDC and separate formulations regarding the occurrence of adverse events. All drug-related adverse events were considered to be mild and resolved without any treatment. Two FDC tablets of evogliptin/metformin XR 2.5/500 mg showed a similar PK profile to the separate formulations of evogliptin 5 mg and metformin XR 1,000 mg. All of the 90% CIs of GMR satisfied the regulatory bioequivalence criteria of 0.800 - 1.250.
.

  18. The value of short-term pain relief in predicting the long-term outcome of 'indirect' cervical epidural steroid injections.

    Science.gov (United States)

    Joswig, Holger; Neff, Armin; Ruppert, Christina; Hildebrandt, Gerhard; Stienen, Martin Nikolaus

    2018-05-01

    The predictive value of short-term arm pain relief after 'indirect' cervical epidural steroid injection (ESI) for the 1-month treatment response has been previously demonstrated. It remained to be answered whether the long-term response could be estimated by the early post-interventional pain course as well. Prospective observational study, following a cohort of n = 45 patients for a period of 24 months after 'indirect' ESI for radiculopathy secondary to a single-level cervical disk herniation (CDH). Arm and neck pain on the visual analog scale (VAS), health-related quality of life with the Short Form-12 (SF-12), and functional outcome with the Neck Pain and Disability (NPAD) Scale were assessed. Any additional invasive treatment after a single injection (second injection or surgery) defined treatment outcome as 'non-response'. At 24 months, n = 30 (66.7%) patients were responders and n = 15 (33.3%) were non-responders. Non-responders exited the follow-up at 1 month (n = 10), at 3 months (n = 4), and at 6 months (n = 1). No patients were injected again or operated on between the 6- and 24-month follow-up. Patients with favorable treatment response at 24 months had significantly lower VAS arm pain (p  50% short term pain reduction was not a reliable predictor of the 24-month responder status. SF-12 and NPAD scores were better among treatment responders in the long term. Patients who require a second injection or surgery after 'indirect' cervical ESI for a symptomatic CDH do so within the first 6 months. Short-term pain relief cannot reliably predict the long-term outcome.

  19. Rapid effects of estrogens on short-term memory: Possible mechanisms.

    Science.gov (United States)

    Paletta, Pietro; Sheppard, Paul A S; Matta, Richard; Ervin, Kelsy S J; Choleris, Elena

    2018-06-01

    Estrogens affect learning and memory through rapid and delayed mechanisms. Here we review studies on rapid effects on short-term memory. Estradiol rapidly improves social and object recognition memory, spatial memory, and social learning when administered systemically. The dorsal hippocampus mediates estrogen rapid facilitation of object, social and spatial short-term memory. The medial amygdala mediates rapid facilitation of social recognition. The three estrogen receptors, α (ERα), β (ERβ) and the G-protein coupled estrogen receptor (GPER) appear to play different roles depending on the task and brain region. Both ERα and GPER agonists rapidly facilitate short-term social and object recognition and spatial memory when administered systemically or into the dorsal hippocampus and facilitate social recognition in the medial amygdala. Conversely, only GPER can facilitate social learning after systemic treatment and an ERβ agonist only rapidly improved short-term spatial memory when given systemically or into the hippocampus, but also facilitates social recognition in the medial amygdala. Investigations into the mechanisms behind estrogens' rapid effects on short term memory showed an involvement of the extracellular signal-regulated kinase (ERK) and the phosphoinositide 3-kinase (PI3K) kinase pathways. Recent evidence also showed that estrogens interact with the neuropeptide oxytocin in rapidly facilitating social recognition. Estrogens can increase the production and/or release of oxytocin and other neurotransmitters, such as dopamine and acetylcholine. Therefore, it is possible that estrogens' rapid effects on short-term memory may occur through the regulation of various neurotransmitters, although more research is need on these interactions as well as the mechanisms of estrogens' actions on short-term memory. Copyright © 2018 Elsevier Inc. All rights reserved.

  20. Efficacy of acarbose and metformin in newly diagnosed type 2 diabetes patients stratified by HbA1c levels.

    Science.gov (United States)

    Zhang, Jin-Ping; Wang, Na; Xing, Xiao-Yan; Yang, Zhao-Jun; Wang, Xin; Yang, Wen-Ying

    2016-07-01

    The aim of the present study was to investigate whether the therapeutic efficacy of acarbose and metformin is correlated with baseline HbA1c levels in Chinese patients with newly diagnosed type 2 diabetes mellitus (T2DM). Data for 711 subjects were retrieved from the MARCH (Metformin and AcaRbose in Chinese as initial Hypoglycemic treatment) trial database and reviewed retrospectively. Patients were grouped according to baseline HbA1c levels (8%) and the results for these three groups were compared between acarbose and metformin treatments. Acarbose and metformin treatment significantly improved T2DM-associated parameters (weight, fasting plasma glucose [FPG], postprandial glucose [PPG], glucagon-like peptide-1 [GLP-1], HOMA-IR, and total cholesterol) across all HbA1c levels. Acarbose decreased PPG and HOMA-β significantly more than metformin, but only in subjects with lower baseline HbA1c (PPG in the HbA1c levels (P HbA1c groups (all P HbA1c levels, whereas metformin induced greater reductions in FPG. These results may help guide selection of initial therapy based on baseline HbA1c. © 2015 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd.

  1. Short-term Preoperative Octreotide for Thyrotropin-secreting Pituitary Adenoma

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    Hong-Juan Fang

    2017-01-01

    Conclusions: OCT can control hormone levels and damage the ultrastructure of tumor cells and organelles. Short-term response to OCT may be related to SSTR5 expression. Preoperative SST analog treatment for TSHoma could be considered as a combination therapy.

  2. A Pilot Study of Randomized, Head-to-Head of Metformin Versus Topiramate in Obese People With Schizophrenia.

    Science.gov (United States)

    Peng, Po-Jui; Ho, Pei-Shen; Tsai, Chia-Kuang; Huang, San-Yuan; Liang, Chih-Sung

    A number of research studies support the weight loss effects of metformin and topiramate for obese people with schizophrenia. However, only a few studies have addressed the sustainability of the body weight reduction after discontinuation of these drugs. Moreover, head-to-head studies are still lacking. The study aims to evaluate and compare the efficacy of metformin and topiramate in weight reduction and weight maintenance after discontinuation of these drugs in obese people with schizophrenia. Twenty-two obese inpatients with schizophrenia were recruited and randomized into the metformin group (n = 11; daily dose, 1000 mg) and the topiramate group (n = 11; daily dose, 100 mg). A head-to-head, fixed-dose, and single-blinded design was used. Ten obese patients with schizophrenia of similar sex as that of the treated group were included as the control group. After a 4-month treatment, the metformin group showed a body weight reduction of 3.8 kg, and the topiramate group showed a reduction of 2.7 kg. However, the reduction could be sustained only in the metformin group at 3 and 9 months after metformin discontinuation. Interestingly, 3 months after treatment discontinuation, leptin levels showed a reduction in both metformin (baseline, 25.3 ± 14.7, week 7: 5.7 ± 3.7 ng/mL) and topiramate (baseline: 28.4 ± 16.1, week 7: 9.2 ± 15.5 ng/mL) groups. The trend of weight changes supports the superiority of metformin at 1000 mg/d over topiramate at 100 mg/d in weight reduction and weight maintenance.

  3. Glucose homeostasis in rainbow trout fed a high-carbohydrate diet: metformin and insulin interact in a tissue-dependent manner.

    Science.gov (United States)

    Polakof, S; Moon, T W; Aguirre, P; Skiba-Cassy, S; Panserat, S

    2011-01-01

    Carnivorous fish species such as the rainbow trout (Oncorhynchus mykiss) are considered to be "glucose intolerant" because of the prolonged hyperglycemia experienced after intake of a carbohydrate-enriched meal. In the present study, we use this species to study glucose homeostasis in fish chronically infused with the hypoglycemic agents, insulin, and metformin, and fed with a high proportion of carbohydrates (30%). We analyzed liver, skeletal muscle, and white adipose tissue (WAT), which are insulin- and metformin-specific targets at both the biochemical and molecular levels. Trout infused with the combination of insulin and metformin can effectively utilize dietary glucose at the liver, resulting in lowered glycemia, increased insulin sensitivity, and glucose storage capacity, combined with reduced glucose output. However, in both WAT and skeletal muscle, we observed decreased insulin sensitivity with the combined insulin + metformin treatment, resulting in the absence of changes at the metabolic level in the skeletal muscle and an increased potential for glucose uptake and storage in the WAT. Thus, the poor utilization by rainbow trout of a diet with a high proportion of carbohydrate can at least be partially improved by a combined treatment with insulin and metformin, and the glucose intolerance observed in this species could be, in part, due to some of the downstream components of the insulin and metformin signaling pathways. However, the predominant effects of metformin treatment on the action of insulin in these three tissues thought to be involved in glucose homeostasis remain exclusive in this species.

  4. What are the differences between long-term, short-term, and working memory?

    Science.gov (United States)

    Cowan, Nelson

    2008-01-01

    In the recent literature there has been considerable confusion about the three types of memory: long-term, short-term, and working memory. This chapter strives to reduce that confusion and makes up-to-date assessments of these types of memory. Long- and short-term memory could differ in two fundamental ways, with only short-term memory demonstrating (1) temporal decay and (2) chunk capacity limits. Both properties of short-term memory are still controversial but the current literature is rather encouraging regarding the existence of both decay and capacity limits. Working memory has been conceived and defined in three different, slightly discrepant ways: as short-term memory applied to cognitive tasks, as a multi-component system that holds and manipulates information in short-term memory, and as the use of attention to manage short-term memory. Regardless of the definition, there are some measures of memory in the short term that seem routine and do not correlate well with cognitive aptitudes and other measures (those usually identified with the term "working memory") that seem more attention demanding and do correlate well with these aptitudes. The evidence is evaluated and placed within a theoretical framework depicted in Fig. 1.

  5. (Metformin-κ2N,N′(salicylato-κ2O,O′copper(II trihydrate

    Directory of Open Access Journals (Sweden)

    Sandra Julieta Gutiérrez Ojeda

    2018-02-01

    Full Text Available The hydrous title complex [systematic name: (1,1-dimethylbiguanide-κ2N2,N4(2-oxidobenzoato-κ2O,O′copper(II trihydrate], [Cu(C7H4O3(C4H11N5]·3H2O, was synthesized electrolytically from an ethanolic solution of metformin hydrochloride, acetylsalicylic acid, Pepto-Bismol and a copper sacrificial anode. Diffraction data were collected at 0.56 Å resolution, allowing the accurate determination of H-atom positions in the neutral metformin ligand. Both imine groups in metformin have very similar N=C bond lengths, 1.2978 (17 and 1.3033 (17 Å, and the salicylate dianion behaves as a chelating ligand. The coordination sphere of the copper(II cation deviates marginally from a square-planar arrangement. In the crystal, short Cu...Cu separations of 3.5476 (3 Å are observed, along with classical hydrogen-bonding interactions.

  6. Metformin: Midlife maturity, maiden charm

    Directory of Open Access Journals (Sweden)

    Sanjay Kalra

    2012-01-01

    Full Text Available Metformin is one of the most commonly prescribed drugs for management of Type 2 diabetes mellitus. It has been in use for almost five decades. Now, pharmacological properties of this agent are being exapted for use in a number of other indications. New facets of its personality are coming up, generating more interest of the scientific community in this "middle-aged" molecule. This article explores the role of metformin in cardioprotection and its hepatoprotective properties. Nephroprotective, protection against excess body fat and gonadoprotective actions, properties have also been discussed. Additionally, this manuscript briefly reviews the thyroid stimulating hormone (TSH-lowering properties in diabetic and non-diabetic patients, besides reviewing its actions on different types of cancers. Some of these actions may become approved indications for use of metformin following generation of new evidence. Metformin still has many unexplored dimensions that deserve further exploration.

  7. Metformin reduces insulin resistance and the tendency toward hyperglycaemia and dyslipidaemia in dogs with hyperadrenocorticism

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    Diego Daniel Miceli

    2018-05-01

    Full Text Available Hypercortisolism induces a state of insulin resistance that can occur concurrently with fasting hyperglycaemia, dyslipidaemia and diabetes mellitus. Metformin reduces hepatic glucose production and insulin resistance of the skeletal muscle and adipose tissue. The aim of this study was to evaluate the effects of metformin on the control of metabolic disorders of dogs with hyperadrenocorticism (HAC. Twenty-three dogs with HAC were randomly divided into two groups, consisting of a control group and a metformin group (10 mg metformin/kg/12 h. Both groups received the same treatment for HAC. At baseline and 3 months, blood glucose, total cholesterol, triglycerides and insulin concentrations, in addition to urinary cortisol:creatinine ratio, Homeostatic Model Assessment (HOMA for insulin sensitivity and β-cell function were measured. Dogs treated with metformin showed significantly reduced glycaemia, cholesterolaemia and triglyceridaemia. They also presented reduced hyperinsulinism and insulin resistance, as well as improved pancreatic β-cell function. The implementation of metformin as an adjuvant therapy is effective for the normalisation of metabolic disorders of dogs with HAC.

  8. Combined therapeutic effect and molecular mechanisms of metformin and cisplatin in human lung cancer xenografts in nude mice

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    Yu-Qin Chen

    2015-01-01

    Full Text Available Objective: This work was aimed at studying the inhibitory activity of metformin combined with the commonly used chemotherapy drug cisplatin in human lung cancer xenografts in nude mice. We also examined the combined effects of these drugs on the molecular expression of survivin, matrix metalloproteinase-2 (MMP-2, vascular endothelial growth factor-C (VEGF-C, and vascular endothelial growth factorreceptor-3 (VEGFR-3 to determine the mechanism of action and to explore the potential applications of the new effective drug therapy in lung cancer. Materials and Methods: The nude mice model of lung cancer xenografts was established, and mice were randomly divided into the metformin group, the cisplatin group, the metformin + cisplatin group, and the control group. The animals were killed 42 days after drug administration, and the tumor tissues were then sampled to detect the messenger ribonucleic acid (mRNA and protein expression levels of survivin, MMP-2, VEGF-C, and VEGFR-3 by immunohistochemistry and reverse transcription polymerase chain reaction (RT-PCR. Results: The protein and mRNA expression levels of survivin, MMP-2, VEGF-C, and VEGFR-3 in the cisplatin group and the combined treatment group were lower than that in the control group (P < 0.05. In the metformin group, the expression of MMP-2 protein and mRNA was lower than that in the control group (P < 0.05. The protein and mRNA expression levels of survivin, MMP-2, VEGF-C, and VEGFR-3 in the combined treatment group were lower than that in the cisplatin group and the metformin group (P < 0.05. Conclusions: Metformin inhibited the expression of MMP-2, cisplatin and the combined treatment inhibited the expression of survivin, MMP-2, VEGF-C, and VEGFR-3, and the combined treatment of metformin with cisplatin resulted in enhanced anti-tumor efficacy.

  9. Variations in Metformin Prescribing for Type 2 Diabetes.

    Science.gov (United States)

    Goldberg, Tiffany; Kroehl, Miranda E; Suddarth, Kathleen Heist; Trinkley, Katy E

    2015-01-01

    Reasons for suboptimal metformin prescribing are unclear, but may be due to perceived risk of lactic acidosis. The purpose of this study is to describe provider attitudes regarding metformin prescribing in various patient situations. An anonymous, electronic survey was distributed electronically to 76 health care providers across the nation. The 14-item survey contained demographic questions and questions related to prescribing of metformin for T2DM in various patient situations, including suboptimal glycemic control, alcohol use, history of lactic acidosis, and varying degrees of severity for certain health conditions, including renal and hepatic dysfunction, chronic obstructive pulmonary disease, and heart failure. There were a total of 100 respondents. For suboptimal glycemic control, most providers (75%) would increase metformin from 1500 to 2000 mg daily; however, 25% would add an alternate agent, such as a sulfonylurea (18%) or dipeptidyl peptidase-4 inhibitor (7%). Although 51% of providers would stop metformin based on serum creatinine thresholds, the remainder would rely on glomerular filtration rate thresholds of <60 mL/min (15%), <30 mL/min (33%), or <15 mL/min (1%) to determine when to stop metformin. For heart failure, 45% of providers would continue metformin as currently prescribed regardless of severity. Most providers would adjust metformin for varying severity of hepatic dysfunction (74%) and alcohol abuse (40%). Despite evidence supporting the cardiovascular benefits of metformin, provider attitudes toward prescribing metformin are suboptimal in certain patient situations and vary greatly by provider. © Copyright 2015 by the American Board of Family Medicine.

  10. Is metformin ready for prime time in pregnancy? Probably not yet.

    Science.gov (United States)

    Fantus, I George

    2015-01-01

    Metformin is one of the most commonly used drugs to treat type 2 diabetes and is safe and effective. Its main mechanism of action is thought to be the activation of AMP-activated protein kinase (AMPK) via inhibition of mitochondrial ATP generation. Recent use of metformin as an 'insulin sensitizer' in women with polycystic ovarian syndrome to increase fertility has been successful and resulted in the chance observation that continued use during pregnancy appeared to be safe. There are few studies of metformin in animal models of diabetic pregnancy. However, some data have implicated fetal AMPK activation in neural tube defects. While a recent report suggests that metformin may not activate fetal AMPK, which is reassuring, studies in pregnant woman with gestational diabetes and type 2 diabetes, which are ongoing, require completion before we can conclude that its use in pregnancy is safe. Furthermore, follow-up of the offspring will be critical to determine whether such treatment decreases or increases the development of obesity and diabetes. Copyright © 2014 John Wiley & Sons, Ltd.

  11. Additive glucose-lowering effects of glucagon-like peptide-1 and metformin in type 2 diabetes

    DEFF Research Database (Denmark)

    Zander, M; Taskiran, M; Toft-Nielsen, M B

    2001-01-01

    ) alternating with GLP-1 (continuous subcutaneous infusion of 2.4 pmol x kg(-1) x min(-1)) alternating with a combination of metformin and GLP-1 for 48 h. Under fixed energy intake, we examined the effects on plasma glucose, insulin, C-peptide, glucagon, and appetite. RESULTS: Fasting plasma glucose (day 2...... this study to investigate the effect of a combination therapy with GLP-1 and metformin, which could theoretically be additive, in type 2 diabetic patients. RESEARCH DESIGN AND METHODS: In a semiblinded randomized crossover study, seven patients received treatment with metformin (1,500 mg daily orally......) and 11.7 +/- 0.8 (GLP-1) to 9.8 +/- 0.5 (combination) (P = 0.02, no difference between GLP-1 and metformin). Insulin levels were similar between the three regimens, but glucagon levels were significantly reduced with GLP-1 compared with metformin (P = 0.0003). Combination therapy had no additional effect...

  12. Effect of oral contraceptives and/or metformin on GLP-1 secretion and reactive hypoglycaemia in polycystic ovary syndrome

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    Dorte Glintborg

    2017-06-01

    Full Text Available Context: Insulin resistance in polycystic ovary syndrome (PCOS may increase the risk of reactive hypoglycaemia (RH and decrease glucagon-like peptide-1 (GLP-1 secretion. The possible effects of treatment with oral contraceptives (OCP and/or metformin on GLP-1 secretion and risk of RH in PCOS is undetermined. Setting: Outpatient clinic. Patients and interventions: Randomized, controlled clinical trial. Ninety women with PCOS were randomized to 12-month treatment with OCP (150 mg desogestrel + 30 mg ethinylestradiol, metformin (2 g/day or metformin + OCP. Five-hour oral glucose tolerance tests (5-h OGTT measuring fasting and area under the curve (AUC for GLP-1, glucose, insulin and C-peptide were performed before and after the intervention period. Sixty-five women completed the study and 34 weight-matched healthy women were included as controls. Main outcome measures: Changes in GLP-1, glucose, insulin and C-peptide during 5-h OGTT. Results: Fasting GLP-1 levels increased during metformin + OCP vs OCP treatment, whereas AUC GLP-1 levels were unchanged during medical treatment. The prevalence of reactive hypoglycemia increased from 9/65 to 14/65 after intervention (P < 0.01 and was more common after treatment with metformin + OCP (increase from 3/23 to 6/23, P = 0.01. Reactive hypoglycaemia was associated with higher insulin and C-peptide levels during 5-h OGTT, but was unassociated with BMI and AUC GLP-1. GLP-1 levels were comparable in PCOS vs controls. AUC GLP-1 levels were significantly lower in obese vs lean patients and were inversely associated with BMI. Conclusions: AUC GLP-1 levels were unchanged during treatment. Increased risk of hypoglycemia during metformin + OCP could be associated with increased insulin secretion.

  13. Metformin versus chromium picolinate in clomiphene citrate-resistant patients with PCOs: A double-blind randomized clinical trial

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    Sedigheh Amooee

    2013-01-01

    Full Text Available Background: Chromium picolinate could be effective in clomiphen citrate resistant PCOS patients. Objective: To compare the effects of chromium picolinate vs. metformin in clomiphen citrate resistant PCOS patients. Materials and Methods: The present randomized clinical trial was performed on 92 women with clomiphen citrate-resistant PCOS at the clinics which were affiliated to Shiraz University of Medical Sciences, Shiraz, Iran. The subjects were randomly assigned to two groups receiving either chromium picolinate (200μg daily or metformin (1500mg daily for 3 months. Anthropometric and hormonal profile were measured and compared both before and after the treatment. Ovulation and pregnancy rate was measured in the two study groups, as well. Results: Chromium picolinate significantly decreased fasting blood sugar (FBS after 3 months of treatment (p=0.042. In the same way, the serum levels of fasting insulin had significantly decreased leading to an increase in insulin sensitivity as measured by QUICKI index (p=0.014. In comparison to the patients who received chromium picolinate, those who received metformin had significantly lower levels of testosterone (p=0.001 and free testosterone (p=0.001 after 3 months of treatment. Nevertheless, no significant difference was found between the two study groups regarding ovulation (p=0.417 and pregnancy rates (p=0.500. Conclusion: Chromium picolinate decreased FBS and insulin levels and, thus, increased insulin sensitivity in clomiphene citrate-resistance PCOS women. These effects were comparable with metformin; however, metformin treatment was associated with decreased hyperandrogenism. Overall, chromium picolinate was better tolerated compared to metformin; nonetheless, the two study groups were not significantly different regarding ovulation and pregnancy rates.

  14. Metformin: A Hopeful Promise in Aging Research

    Science.gov (United States)

    Novelle, Marta G.; Ali, Ahmed; Diéguez, Carlos; Bernier, Michel; de Cabo, Rafael

    2016-01-01

    Even though the inevitable process of aging by itself cannot be considered a disease, it is directly linked to life span and is the driving force behind all age-related diseases. It is an undisputable fact that age-associated diseases are among the leading causes of death in the world, primarily in industrialized countries. During the last several years, an intensive search of antiaging treatments has led to the discovery of a variety of drugs that promote health span and/or life extension. The biguanide compound metformin is widely used for treating people with type 2 diabetes and appears to show protection against cancer, inflammation, and age-related pathologies. Here, we summarize the recent developments about metformin use in translational aging research and discuss its role as a potential geroprotector. PMID:26931809

  15. Effects of metformin treatment on luteal phase progesterone concentration in polycystic ovary syndrome

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    Meenakumari K.J.

    2004-01-01

    Full Text Available The causes of luteal phase progesterone deficiency in polycystic ovary syndrome (PCOS are not known. To determine the possible involvement of hyperinsulinemia in luteal phase progesterone deficiency in women with PCOS, we examined the relationship between progesterone, luteinizing hormone (LH and insulin during the luteal phase and studied the effect of metformin on luteal progesterone levels in PCOS. Patients with PCOS (19 women aged 18-35 years were treated with metformin (500 mg three times daily for 4 weeks prior to the test cycle and throughout the study period, and submitted to ovulation induction with clomiphene citrate. Blood samples were collected from control (N = 5, same age range as PCOS women and PCOS women during the late follicular (one sample and luteal (3 samples phases and LH, insulin and progesterone concentrations were determined. Results were analyzed by one-way analysis of variance (ANOVA, Duncan's test and Karl Pearson's coefficient of correlation (r. The endocrine study showed low progesterone level (4.9 ng/ml during luteal phase in the PCOS women as compared with control (21.6 ng/ml. A significant negative correlation was observed between insulin and progesterone (r = -0.60; P < 0.01 and between progesterone and LH (r = -0.56; P < 0.05 concentrations, and a positive correlation (r = 0.83; P < 0.001 was observed between LH and insulin. The study further demonstrated a significant enhancement in luteal progesterone concentration (16.97 ng/ml in PCOS women treated with metformin. The results suggest that hyperinsulinemia/insulin resistance may be responsible for low progesterone levels during the luteal phase in PCOS. The luteal progesterone level may be enhanced in PCOS by decreasing insulin secretion with metformin.

  16. In vitro and in vivo anti-tumor effect of metformin as a novel therapeutic agent in human oral squamous cell carcinoma

    International Nuclear Information System (INIS)

    Luo, Qingqiong; Hu, Dan; Hu, Shuiqing; Yan, Ming; Sun, Zujun; Chen, Fuxiang

    2012-01-01

    Metformin, which is widely used as an antidiabetic agent, has recently been reported to reduce cancer risk and improve prognosis in certain malignancies. However, the specific mechanisms underlying the effect of metformin on the development and progression of several cancers including oral squamous cell carcinoma (OSCC) remain unclear. In the present study, we investigated the effects of metformin on OSCC cells in vitro and in vivo. OSCC cells treated with or without metformin were counted using a hemocytometer. The clonogenic ability of OSCC cells after metformin treatment was determined by colony formation assay. Cell cycle progression and apoptosis were assessed by flow cytometry, and the activation of related signaling pathways was examined by immunoblotting. The in vivo anti-tumor effect of metformin was examined using a xenograft mouse model. Immunohistochemistry and TUNEL staining were used to determine the expression of cyclin D1 and the presence of apoptotic cells in tumors from mice treated with or without metformin. Metformin inhibited proliferation in the OSCC cell lines CAL27, WSU-HN6 and SCC25 in a time- and dose-dependent manner, and significantly reduced the colony formation of OSCC cells in vitro. Metformin induced an apparent cell cycle arrest at the G0/G1 phase, which was accompanied by an obvious activation of the AMP kinase pathway and a strongly decreased activation of mammalian target of rapamycin and S6 kinase. Metformin treatment led to a remarkable decrease of cyclin D1, cyclin-dependent kinase (CDK) 4 and CDK6 protein levels and phosphorylation of retinoblastoma protein, but did not affect p21 or p27 protein expression in OSCC cells. In addition, metformin induced apoptosis in OSCC cells, significantly down-regulating the anti-apoptotic proteins Bcl-2 and Bcl-xL and up-regulating the pro-apoptotic protein Bax. Metformin also markedly reduced the expression of cyclin D1 and increased the numbers of apoptotic cells in vivo, thus inhibiting

  17. Hyperreactivity of Blood Leukocytes in Patients with NAFLD to Ex Vivo Lipopolysaccharide Treatment Is Modulated by Metformin and Phosphatidylcholine but Not by Alpha Ketoglutarate.

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    Agnieszka Zwolak

    Full Text Available Toll-like receptor 4 and proinflammatory cytokines play a central role in the progression of nonalcoholic fatty liver disease. We investigated IL-1, IL-6 and TNFα production and toll-like receptor 4 in both--obese and lean patients with non-alcoholic fatty liver disease who met different sets of metabolic syndrome criteria and linked the results with the disease burden.95 subjects were divided into four groups depending on the following criteria: presence or absence of metabolic syndrome and/or non-alcoholic fatty liver disease, glucose tolerance (prediabetes or normoglycemia and BMI value (obese or lean. We determined the levels of IL-1β, IL-6, TNFα, and monocyte toll-like receptor 4 expression in fresh blood as well as in blood cultures treated with lipopolysaccharide with or without metformin, alphaketoglutarate or phosphatidylcholine supplementation.The blood leukocytes of patients with non-alcoholic fatty liver disease are hypersensitive to lipopolysaccharide treatment and produce elevated levels of pro-inflammatory cytokines in response to ex vivo treatment with lipopolysaccharide. Moreover, they overexpress toll-like receptor-4. Hyperreactivity was typical mainly for obese patients with non-alcoholic fatty liver disease together with metabolic syndrome and decreased with the severity of disease. Metformin was the most effective in attenuation of hyperreactivity in all groups of patients with non-alcoholic fatty liver disease, but in obese patients the effectiveness of metformin was weaker than in lean. The reduction of cytokine level by metformin was accompanied by the decrease in toll-like receptor-4 expression. phosphatidylcholine also attenuated hyperreactivity to lipopolysaccharide but mainly in obese patients. Alpha ketoglutarate did not modulate cytokines' level and toll-like receptor 4 expression in non-alcoholic fatty liver disease patients.Metformin and phosphatidylcholine attenuated lipopolysaccharide induced toll

  18. Short-term, high-dose glucocorticoid treatment does not contribute to reduced bone mineral density in patients with multiple sclerosis.

    Science.gov (United States)

    Olsson, A; Oturai, D B; Sørensen, P S; Oturai, P S; Oturai, A B

    2015-10-01

    Patients with multiple sclerosis (MS) are at increased risk of reduced bone mineral density (BMD). A contributing factor might be treatment with high-dose glucocorticoids (GCs). The objective of this paper is to assess bone mass in patients with MS and evaluate the importance of short-term, high-dose GC treatment and other risk factors that affect BMD in patients with MS. A total of 260 patients with MS received short-term high-dose GC treatment and had their BMD measured by dual x-ray absorptiometry. BMD was compared to a healthy age-matched reference population (Z-scores). Data regarding GCs, age, body mass index (BMI), serum 25(OH)D, disease duration and severity were collected retrospectively and analysed in a multiple linear regression analysis to evaluate the association between each risk factor and BMD. Osteopenia was present in 38% and osteoporosis in 7% of the study population. Mean Z-score was significantly below zero, indicating a decreased BMD in our MS patients. Multiple linear regression analysis showed no significant association between GCs and BMD. In contrast, age, BMI and disease severity were independently associated with both lumbar and femoral BMD. Reduced BMD was prevalent in patients with MS. GC treatment appears not to be the primary underlying cause of secondary osteoporosis in MS patients. © The Author(s), 2015.

  19. Treatment with metformin and a dipeptidyl peptidase-4 inhibitor elevates apelin levels in patients with type 2 diabetes mellitus

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    Fan YJ

    2015-08-01

    Full Text Available Yujuan Fan,* Yu Zhang,* Xuesong Li,* Hui Zheng, Yuping Song, Ning Zhang, Chunfang Shen, Xiaofang Fan, Fengdong Ren, Jiayi Shen, Guoguang Ren, Jialin Yang Department of Endocrinology, Central Hospital of Minhang District, Minhang Hospital affiliated to Fudan University, Shanghai, People’s Republic of China *These authors contributed equally to this work Background: The objective of this study was to assess the effects of metformin monotherapy or combined treatment with a dipeptidyl peptidase-4 inhibitor (vildagliptin on apelin levels in patients with type 2 diabetes mellitus. Methods: Twenty-five patients with poor glycemic control (glycosylated hemoglobin >6.5% [48 mmol/mol] taking 1,000 mg of metformin daily and 25 healthy controls matched for age and body mass index were enrolled in this study. Anthropometric parameters, glycemic and lipid profile, insulin resistance (homeostasis model assessment of insulin resistance index, and apelin levels were measured at baseline and at 12-week and 24-week visits. Results: At baseline, apelin levels were higher in the T2DM patients than in the controls (1.93±1.81 ng/mL versus 6.09±4.90 ng/mL; P<0.05. After 12 weeks, when vildagliptin was added, fasting blood glucose and glycosylated hemoglobin decreased, and apelin levels increased further (from 6.09±4.90 ng/mL to 24.23±12.59 ng/mL; P<0.05. Follow-up at 24 weeks showed no further improvement in the glycemic profile and no further increase in apelin levels. Conclusion: Both metformin and vildagliptin favorably changed glycemic indices and apelin levels. For patients inadequately controlled on a low dose of metformin, addition of vildagliptin may be helpful. Keywords: glucagon-like peptides, glucose-dependent insulinotropic polypeptide, antidiabetic drug, adipocytokine

  20. Low concentrations of metformin selectively inhibit CD133⁺ cell proliferation in pancreatic cancer and have anticancer action.

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    Shanmiao Gou

    Full Text Available Pancreatic cancer is the fourth leading cause of cancer related deaths in the United States. The prognosis remains dismal with little advance in treatment. Metformin is a drug widely used for the treatment of type II diabetes. Recent epidemiologic data revealed that oral administration of metformin is associated with a reduced risk of pancreatic cancer, suggesting its potential as a novel drug for this disease. Many studies have demonstrated the in vitro anticancer action of metformin, but the typically used concentrations were much higher than the in vivo plasma and tissue concentrations achieved with recommended therapeutic doses of metformin, and low concentrations of metformin had little effect on the proliferation of pancreatic cancer cells. We examined the effect of low concentrations of metformin on different subpopulations of pancreatic cancer cells and found that these selectively inhibited the proliferation of CD133⁺ but not CD24⁺CD44⁺ESA⁺ cells. We also examined the effect of low concentrations of metformin on cell invasion and in vivo tumor formation, demonstrating in vitro and in vivo anticancer action. Metformin was associated with a reduction of phospho-Erk and phospho-mTOR independent of Akt and AMPK phosphorylation. CD133⁺ pancreatic cancer cells are considered to be cancer stem cells that contribute to recurrence, metastasis and resistance to adjuvant therapies in pancreatic cancer. Our results provide a basis for combination of metformin with current therapies to improve the prognosis of this disease.

  1. Metformin therapy prevents early pregnancy loss in polycystic ovarian syndrome

    International Nuclear Information System (INIS)

    Hassan, J.A.; Anbareen, T.

    2011-01-01

    Background: The study was done to compare the early pregnancy loss rate in women with polycystic ovarian syndrome who received or did not receive metformin in pregnancy. Study type, settings and duration: A case control interventional study carried out at Civil Hospital Karachi, Hamdard University Hospital and Private Gynaecology clinics from January 2005 to July 2008. Subjects and Methods Eighty two non diabetic patients with polycystic ovarian syndrome who became pregnant were included in the study. A questionnaire was filled for all patients that included information on basic demography and mean age, parity, weight. Fasting blood sugar and serum insulin levels were done for all these women. Only patients with raised insulin levels (more than 10 mu/l) were included in the study and all were offered to use oral metformin throughout pregnancy as 500 mg three times a day with folic acid supplements 5 mg once daily. Those who agreed to take the drug throughout pregnancy and to comply with the therapy were taken as cases, while those who did not agree to take the medicine acted as controls. Patients with other causes of recurrent pregnancy loss were excluded from the study. All pregnancies were followed using serial ultrasound examination to see any pregnancy loss in the two groups. Eighty two cases of polycystic ovaries with pregnancy were seen during the study period. All cases had raised serum insulin levels. Fifty patients agreed to take metformin through out pregnancy while, 32 cases did not agree to take metformin during pregnancy and thus acted as controls. The two groups did not differ in mean age, parity, weight and mean fasting blood sugar levels. Fasting insulin levels were high in metformin group (18.40 mu/l ) than in controls (12.53 mu/l). Missed abortion rate was significantly lower (12%) in metformin group than in controls (28%) (p<0.028). No congenital anomalies were found in both the groups on ultrasound at 16-19 weeks. Metformin treatment during

  2. Metformin therapy prevents early pregnancy loss in polycystic ovarian syndrome

    Energy Technology Data Exchange (ETDEWEB)

    Hassan, J A; Anbareen, T [Dow University of Health Sciences, Karachi (Pakistan). Dept. of Gynae; Anbareen, T [Hamdard University Hospital, Karachi (Pakistan)

    2011-01-15

    Background: The study was done to compare the early pregnancy loss rate in women with polycystic ovarian syndrome who received or did not receive metformin in pregnancy. Study type, settings and duration: A case control interventional study carried out at Civil Hospital Karachi, Hamdard University Hospital and Private Gynaecology clinics from January 2005 to July 2008. Subjects and Methods Eighty two non diabetic patients with polycystic ovarian syndrome who became pregnant were included in the study. A questionnaire was filled for all patients that included information on basic demography and mean age, parity, weight. Fasting blood sugar and serum insulin levels were done for all these women. Only patients with raised insulin levels (more than 10 mu/l) were included in the study and all were offered to use oral metformin throughout pregnancy as 500 mg three times a day with folic acid supplements 5 mg once daily. Those who agreed to take the drug throughout pregnancy and to comply with the therapy were taken as cases, while those who did not agree to take the medicine acted as controls. Patients with other causes of recurrent pregnancy loss were excluded from the study. All pregnancies were followed using serial ultrasound examination to see any pregnancy loss in the two groups. Eighty two cases of polycystic ovaries with pregnancy were seen during the study period. All cases had raised serum insulin levels. Fifty patients agreed to take metformin through out pregnancy while, 32 cases did not agree to take metformin during pregnancy and thus acted as controls. The two groups did not differ in mean age, parity, weight and mean fasting blood sugar levels. Fasting insulin levels were high in metformin group (18.40 mu/l ) than in controls (12.53 mu/l). Missed abortion rate was significantly lower (12%) in metformin group than in controls (28%) (p<0.028). No congenital anomalies were found in both the groups on ultrasound at 16-19 weeks. Metformin treatment during

  3. The Demonstration of Short-Term Consolidation.

    Science.gov (United States)

    Jolicoeur, Pierre; Dell'Acqua, Roberto

    1998-01-01

    Results of seven experiments involving 112 college students or staff using a dual-task approach provide evidence that encoding information into short-term memory involves a distinct process termed short-term consolidation (STC). Results suggest that STC has limited capacity and that it requires central processing mechanisms. (SLD)

  4. No Decreased Risk of Gastrointestinal Cancers in Users of Metformin in The Netherlands; A Time-Varying Analysis of Metformin Exposure

    NARCIS (Netherlands)

    de Jong, Roy G; Burden, Andrea M; de Kort, Sander; van Herk-Sukel, Myrthe P; Vissers, Pauline A; Janssen, Paddy K; Haak, Harm R; Masclee, Ad A; de Vries, Frank; Janssen-Heijnen, Maryska L

    2017-01-01

    Previous studies on metformin use and gastrointestinal (GI) cancer risk have yielded inconclusive results on metformin's chemoprotective effects. We aimed to evaluate GI cancer risk in users of metformin in The Netherlands using a time-varying approach in a large population-based database. A cohort

  5. Metformin and pioglitazone combination therapy ameliorate polycystic ovary syndrome through AMPK/PI3K/JNK pathway

    Science.gov (United States)

    Wu, Yuanyuan; Li, Pengfen; Zhang, Dan; Sun, Yingpu

    2018-01-01

    Polycystic ovary syndrome (PCOS) is a common gynecological endocrine disorder, which results in health problems such as menstrual disorders, hyperandrogenism and persistent anovulation. Hyperandrogenism and insulin resistance are the basic characteristics of PCOS. To investigate the combined effect of metformin and pioglitazone on POCS and the potential mechanisms, a rat model of PCOS was established by intramuscular injection of estradiol valerate (EV). The effect of metformin and pioglitazone monotherapy or combination therapy in control rats and PCOS rats was evaluated, involving the testosterone level, follicular development and insulin resistance. The potential mechanism for the therapeutic effect of metformin and pioglitazone on POCS was explored through using three inhibitors of the 5′adenosine monophosphate-activated protein kinase (AMPK)/phosphoinositide-3 kinase (PI3K)/c-Jun N-terminal kinase (JNK) pathway (Compound C, Wortmannin and SP600125). The results showed that EV-induced PCOS rats demonstrated hyperandrogenemia, hyperinsulinemia and follicular dysplasia. Metformin or pioglitazone monotherapy significantly suppressed the high level of testosterone, reduced the raised percentage of cystic follicles and primary follicles, promoted the number of early antral follicles, and markedly decreased the high concentration of fasting insulin and homeostatic model assessment for insulin resistance index in PCOS rats. In addition, metformin and pioglitazone combination therapy demonstrated greater efficacy than its individual components. Furthermore, individual or joint treatment with metformin and pioglitazone affected the phosphorylation level of JNK in PCOS rats. Compound C and Wortmannin eliminated the effect of metformin and pioglitazone combination therapy on improving the follicular growth in PCOS rats, whereas SP600125 treatment enhanced this combination therapy effect. These data suggested that metformin and pioglitazone combination therapy

  6. Clinical utility in the treatment of type 2 diabetes with the saxagliptin/metformin fixed combination

    Directory of Open Access Journals (Sweden)

    Panagoulias GS

    2014-02-01

    Full Text Available George S Panagoulias,1 John Doupis2,3 11st Department of Propaedeutic and Internal Medicine, Athens University Medical School, Laiko General Hospital, Athens, Greece; 2Salamis Naval Hospital, Athens, Greece; 3Diabetes Division, Iatriko Paleou Falirou Medical Center, Athens, Greece Abstract: Fixed-dose combination (FDC products represent a widely accepted approach to type 2 diabetes treatment, given that monotherapies sometimes fail to meet the treatment targets – obtaining a sustained reduction in micro- and macrovascular complications. Saxagliptin (SAXA/metformin (MET FDC tablets can be used either alone or in combination with glyburide, thiazolidinediones, or insulin. It has been proven that the SAXA/MET combination leads to a significant improvement in glycemic control compared to placebo in patients with type 2 diabetes that is inadequately controlled with MET alone. In addition, this FDC has been proven to be safe for people with diabetes mellitus and established cardiovascular disease, elderly patients, and patients with impaired renal function (>30 mL/minute, with dosage modification. Patient compliance, adherence, and persistence to the therapeutic regimen has been shown to be very good, while the titration of each compound according to the patient's profile is easy, given the availability of different formulations. The SAXA/MET FDC is a patient-friendly, dosage-flexible, and hypoglycemia-safe regimen with very few adverse events and a neutral or even favorable effect on body weight. It achieves significant glycosylated hemoglobin A1c reduction helping the patient to achieve his/her individual glycemic goals. Keywords: DPP-4 inhibitors, saxagliptin, metformin, fixed-dose combination products, FDC products

  7. Conversion of short-term to long-term memory in the novel object recognition paradigm.

    Science.gov (United States)

    Moore, Shannon J; Deshpande, Kaivalya; Stinnett, Gwen S; Seasholtz, Audrey F; Murphy, Geoffrey G

    2013-10-01

    It is well-known that stress can significantly impact learning; however, whether this effect facilitates or impairs the resultant memory depends on the characteristics of the stressor. Investigation of these dynamics can be confounded by the role of the stressor in motivating performance in a task. Positing a cohesive model of the effect of stress on learning and memory necessitates elucidating the consequences of stressful stimuli independently from task-specific functions. Therefore, the goal of this study was to examine the effect of manipulating a task-independent stressor (elevated light level) on short-term and long-term memory in the novel object recognition paradigm. Short-term memory was elicited in both low light and high light conditions, but long-term memory specifically required high light conditions during the acquisition phase (familiarization trial) and was independent of the light level during retrieval (test trial). Additionally, long-term memory appeared to be independent of stress-mediated glucocorticoid release, as both low and high light produced similar levels of plasma corticosterone, which further did not correlate with subsequent memory performance. Finally, both short-term and long-term memory showed no savings between repeated experiments suggesting that this novel object recognition paradigm may be useful for longitudinal studies, particularly when investigating treatments to stabilize or enhance weak memories in neurodegenerative diseases or during age-related cognitive decline. Copyright © 2013 Elsevier Inc. All rights reserved.

  8. Short-term Mobility and Increased Partnership Concurrency among Men in Zimbabwe.

    Directory of Open Access Journals (Sweden)

    Susan Cassels

    Full Text Available Migration has long been understood as an underlying factor for HIV transmission, and sexual partner concurrency has been increasingly studied as an important component of HIV transmission dynamics. However, less work has examined the role of short-term mobility in sexual partner concurrency using a network approach. Short-term mobility may be a risk for HIV for the migrant's partner as well either through the partner's risk behaviors while the migrant is away, such as the partner having additional partners, or via exposure to the return migrant.Using data from the 2010-11 Zimbabwe Demographic and Health Survey, weighted generalized linear regression models were used to investigate the associations between short-term mobility and partnership concurrency at the individual and partnership levels.At the individual level, we find strong evidence of an association between short-term mobility and concurrency. Men who traveled were more likely to have concurrent partnerships compared to men who did not travel and the relationship was non-linear: each trip was associated with a 2% higher probability of concurrency, with a diminishing risk at 60 trips (p<0.001. At the partnership level, short-term mobility by the male only or both partners was associated with male concurrency. Couples in which the female only traveled exhibited less male concurrency.Short-term mobility has the ability to impact population-level transmission dynamics by facilitating partnership concurrency and thus onward HIV transmission. Short-term migrants may be an important population to target for HIV testing, treatment, or social and behavioral interventions to prevent the spread of HIV.

  9. Comparison of newborn outcomes in women with gestational diabetes mellitus treated with metformin or insulin: A randomised blinded trial

    Directory of Open Access Journals (Sweden)

    Elahe Mesdaghinia

    2013-01-01

    Conclusions: Considering data from this study, metformin is efficient to control hyperglycemia in pregnancy. It is suggested performing more studies to evaluate long term side effects of metformin in pregnancy with higher sample size and longer follow-up of newborns.

  10. L-Carnitine for the treatment of a calcium channel blocker and metformin poisoning.

    Science.gov (United States)

    St-Onge, Maude; Ajmo, Ian; Poirier, Diane; Laliberté, Martin

    2013-09-01

    The object of the current communication is to discuss the theory and the evidence for the use of L-carnitine in calcium channel blocker and metformin poisonings. A 68-year-old male known for hypertension and type II diabetes was admitted to the critical care unit of a community hospital following an overdose of amlodipine and metformin. The patient was intubated, ventilated, and hemodynamically supported with vasopressors. Despite calcium, glucagon, high-dose insulin (HDI), and lipid emulsion for calcium channel blocker and bicarbonate for metabolic acidosis, the patient remained hemodynamically unstable. The patient was considered too unstable to initiate continuous renal replacement therapy; and without access to extracorporeal life support, the administration of L-carnitine was administered as a last resort. One hour after L-carnitine, the norepinephrine requirements started to decrease, the patient began to improve and was subsequently extubated successfully without apparent sequelae in less than 4 days. L-Carnitine combined with HDI may have helped with the calcium channel blocker (CCB) poisoning by decreasing insulin resistance, promoting intracellular glucose transport, facilitating the metabolism of free fatty acids, and increasing calcium channel sensitivity. It may have also stimulated oxidative utilization of glucose instead of converting pyruvate into lactate and contributed to decrease lactate production with metformin poisoning.

  11. Antitumor effects of metformin via indirect inhibition of protein phosphatase 2A in patients with endometrial cancer.

    Directory of Open Access Journals (Sweden)

    Shinsuke Hanawa

    Full Text Available Metformin, an antidiabetic drug, inhibits the endometrial cancer cell growth in vivo by improving the insulin resistance; however, its mechanism of action is not completely understood. Protein phosphatase 2A (PP2A is a serine/threonine phosphatase associated with insulin resistance and type 2 diabetes, and its inhibition restores the insulin resistance. This study investigated the antitumor effect of metformin on endometrial cancer with a focus on PP2A.Metformin (1,500-2,250 mg/day was preoperatively administered to patients with endometrial cancer for 4 to 6 weeks. Expression of the PP2A regulatory subunits, 4 (PPP2R4 and B (PP2A-B, was evaluated using real-time polymerase chain reaction (RT-PCR and immunohistochemistry (IHC using paired specimens obtained before and after metformin treatment. The effect of PPP2R4 inhibition with small interfering RNA was evaluated in the endometrial cancer cell lines HEC265 and HEC1B. P values of < .05 were considered statistically significant.Preoperative metformin treatment significantly reduced the expression of PP2A-B, as determined using IHC, and the mRNA expression of PPP2R4, as determined using RT-PCR, in the patients with endometrial cancer. However, metformin could not directly alter the PPP2R4 mRNA levels in the endometrial cancer cell lines in vitro. PPP2R4 knockdown reduced the proliferation and induced the apoptosis by activating caspases 3/7 in HEC265 and HEC1B cells.Downregulation of the PP2A-B subunit, including PPP2R4, is an important indirect target of metformin. Inhibition of PP2A may be an option for the treatment of endometrial cancer patients with insulin resistance.This trial is registered with UMIN-CTR (number UMIN000004852.

  12. Metabolic acidosis: expected and fatal adverse effects of metformin and empagliflozin: a case series and literature review

    Directory of Open Access Journals (Sweden)

    Miriam Čupić

    2016-09-01

    Full Text Available Metformin, a well-known first-line diabetes therapy, and the recently developed sodium- glucose co-transporter 2 (SGLT2 inhibitor empagliflozin are widely used oral antihyperglycemic drugs in the long-term treatment of type 2 diabetes mellitus (T2DM. Metabolic acidosis is a potentially fatal adverse effect (AE of these drugs with a high mortality rate. However, the reported incidence of metabolic acidosis in clinical practice has been proven to be very low. Nevertheless, it should be considered that the event rates are based on confounded data and spontaneous case reports. Metformin increases plasma lactate levels by inhibiting mitochondrial respiration, which, accompanied by elevated plasma metformin concentrations (in renal impairment and a secondary event that further disrupts lactate production (e.g., hypoperfusion, sepsis, typically leads to metformin-associated lactic acidosis (MALA. At the same time, SGLT2 inhibitors are thought to promote ketogenesis and precipitate ketoacidosis by their extra-pancreatic glucuretic mode of action. The present article describes 3 patients suffering from severe metabolic acidosis caused by metformin or empagliflozin, presents similar cases reported in the literature, and assesses the possible etiopathogenesis of the metabolic derangement. Diabetic patients should be educated about the importance of regular fluid and food intake as well as regular blood and urine glucose and ketone self-checkups, whereas physicians should be more aware that the key to an effective use of all glucose-lowering medication is appropriate patient selection, counseling, and follow-up. It is a good clinical sense which will ensure that physicians are able to translate pharmaceutical advances into clinical benefits for patients with T2DM.

  13. Pharmacokinetics of metformin in patients with gastrointestinal intolerance

    DEFF Research Database (Denmark)

    Mccreight, Laura J.; Stage, Tore B.; Connelly, Paul

    2018-01-01

    AIMS: Metformin intolerance symptoms are gastrointestinal in nature, but the underlying mechanism is poorly understood. The aim of this study was to assess potential causes of metformin intolerance including: altered metformin uptake from the intestine; increased anaerobic glucose utilisation and...

  14. Termination of short term melatonin treatment in children with delayed Dim Light Melatonin Onset: effects on sleep, health, behavior problems, and parenting stress

    NARCIS (Netherlands)

    van Maanen, Annette; Meijer, Anne Marie; Smits, Marcel G.; Oort, Frans J.

    2011-01-01

    To investigate the effects of termination of short term melatonin treatment on sleep, health, behavior, and parenting stress in children with delayed Dim Light Melatonin Onset. Forty-one children (24 boys, 17 girls; mean age=9.43 years) entered melatonin treatment for 3 weeks and then discontinued

  15. Dopamine Modulation of Reunion Behavior in Short and Long Term Marmoset Pairs

    Directory of Open Access Journals (Sweden)

    Sarah B. Carp

    2018-05-01

    Full Text Available One major neurobiological substrate regulating social processes is dopamine (DA. DA is implicated in social behavior in species as diverse as fish and birds, and has an established role in regulating relationships between mates in socially monogamous rodents. Marmoset monkeys display traits associated with social monogamy including high rates of affiliation, biparental care, distress upon separation, and aggression toward strangers; several of these behavioral patterns change throughout the development of relationships. This temporal change may represent changing demands, as pairs are likely to jointly face new experiences (e.g., parenthood throughout pairing. We investigated the role of DA and pairing length on social behavior during reunion after separation from the mate. Marmosets were removed from their home environment and treated with agonists and antagonists for the D1 and D2 receptor subtypes. They were exposed to a novel environment containing an opposite-sex stranger and their pair mate, and then reunited with their mate in the home enclosure. Marmosets in long term pairs exhibited higher levels of food sharing during reunion than marmosets in short term pairs, with females in long term pairs sharing food more than males; no sex difference was observed in short term pairs. Subjects in short term pairs spent more time grooming their mate than receiving grooming during reunion, while marmosets in long term pairs displayed similar amounts of both initiated and received grooming. DA treatment altered pair-level behavior. When females received either a D2 agonist or antagonist, short term pairs spent less time in proximity, compared to when males received the same treatments. In long term pairs, treatment of females with either a D1 agonist or antagonist resulted in pairs spending less time in social proximity than when males were treated. These findings suggest that the function of the DA system in mate behavior may be similar between

  16. Short-term use of antiepileptic drugs is neurotoxic to the immature brain

    Directory of Open Access Journals (Sweden)

    Yu Liu

    2015-01-01

    Full Text Available Previous studies have shown that the long-term use of antiepileptic drugs can cause nervous system damage. However, short-term antiepileptic drug treatment is frequently given to infants, especially neonates, to control seizure. Whether the short-term use of antiepileptic drugs is neurotoxic remains unclear. In the present study, immature rats, 3-21 days of age, were intraperitoneally injected with phenobarbital and/or topiramate for 3 consecutive days. Hematoxylin-eosin and immunohistochemical staining revealed that phenobarbital and topiramate, individually or in combination, were cytotoxic to hippocampal CA1 neurons and inhibited the expression of GluR1 and NR2B, excitatory glutamate receptor subunits. Furthermore, the combination of the two drugs caused greater damage than either drug alone. The results demonstrate that the short-term use of antiepileptic drugs damages neurons in the immature brain and that the combined use of antiepileptic drugs exacerbates damage. Our findings suggest that clinicians should consider the potential neurotoxic risk associated with the combined use of antiepileptic drugs in the treatment of seizure.

  17. Safety and otoprotection of metformin in radiation-induced sensorineural hearing loss in the guinea pig.

    Science.gov (United States)

    Mujica-Mota, Mario A; Salehi, Pezhman; Devic, Slobodan; Daniel, Sam J

    2014-05-01

    There is currently no treatment available to prevent radiation-induced sensorineural hearing loss. Metformin has antineoplastic effects and is able to regulate the mitochondrial production of reactive oxygen species after cellular stress, which is one of the mechanisms involved in apoptosis after radiation damage. The objective of this study was to determine the safety and radioprotective properties of metformin against radiation-induced cochlear damage both in vitro and in vivo. In vitro and prospective animal study. Animal Care Facilities of the Montreal Children's Hospital Research Institute. Cultured auditory hair cells (HEI-OC1) were exposed to different concentrations of metformin to determine its safety. Cells were incubated with different metformin concentrations and subjected to radiation. Cell viability after experiments was determined with the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay. Sixteen guinea pigs were divided in 2 groups: drinking tap water (n = 8) and drinking water containing metformin (n = 8). The animals were unilaterally irradiated for 20 days (total dose 70 Gy), and the ears were divided in 4 groups: control (n = 8), irradiated (n = 8), metformin (n = 8), and experimental (n = 8). Auditory brainstem responses were assessed before and 1, 6, and 16 weeks after completion of radiotherapy. Metformin was not cytotoxic or radioprotective in cultured auditory hair cells. Experimental ears had less hearing loss than radiated ones; however, differences were not statistically significant (P > .05). Metformin is not ototoxic or radioprotective in vitro or in vivo. Ears solely subjected to metformin had better hearing thresholds than the rest of the groups.

  18. Short-term ecological consequences of collaborative restoration treatments in ponderosa pine forests of Colorado

    Science.gov (United States)

    Briggs, Jenny S.; Fornwalt, Paula J.; Feinstein, Jonas A.

    2017-01-01

    Ecological restoration treatments are being implemented at an increasing rate in ponderosa pine and other dry conifer forests across the western United States, via the USDA Forest Service’s Collaborative Forest Landscape Restoration (CFLR) program. In this program, collaborative stakeholder groups work with National Forests (NFs) to adaptively implement and monitor ecological restoration treatments intended to offset the effects of many decades of anthropogenic stressors. We initiated a novel study to expand the scope of treatment effectiveness monitoring efforts in one of the first CFLR landscapes, Colorado’s Front Range. We used a Before/After/Control/Impact framework to evaluate the short-term consequences of treatments on numerous ecological properties. We collected pre-treatment and one year post-treatment data on NF and partner agencies’ lands, in 66 plots distributed across seven treatment units and nearby untreated areas. Our results reflected progress toward several treatment objectives: treated areas had lower tree density and basal area, greater openness, no increase in exotic understory plants, no decrease in native understory plants, and no decrease in use by tree squirrels and ungulates. However, some findings suggested the need for adaptive modification of both treatment prescriptions and monitoring protocols: treatments did not promote heterogeneity of stand structure, and monitoring methods may not have been robust enough to detect changes in surface fuels. Our study highlights both the effective aspects of these restoration treatments, and the importance of initiating and continuing collaborative science-based monitoring to improve the outcomes of broad-scale forest restoration efforts.

  19. Metformin inhibits cell cycle progression of B-cell chronic lymphocytic leukemia cells.

    Science.gov (United States)

    Bruno, Silvia; Ledda, Bernardetta; Tenca, Claudya; Ravera, Silvia; Orengo, Anna Maria; Mazzarello, Andrea Nicola; Pesenti, Elisa; Casciaro, Salvatore; Racchi, Omar; Ghiotto, Fabio; Marini, Cecilia; Sambuceti, Gianmario; DeCensi, Andrea; Fais, Franco

    2015-09-08

    B-cell chronic lymphocytic leukemia (CLL) was believed to result from clonal accumulation of resting apoptosis-resistant malignant B lymphocytes. However, it became increasingly clear that CLL cells undergo, during their life, iterative cycles of re-activation and subsequent clonal expansion. Drugs interfering with CLL cell cycle entry would be greatly beneficial in the treatment of this disease. 1, 1-Dimethylbiguanide hydrochloride (metformin), the most widely prescribed oral hypoglycemic agent, inexpensive and well tolerated, has recently received increased attention for its potential antitumor activity. We wondered whether metformin has apoptotic and anti-proliferative activity on leukemic cells derived from CLL patients. Metformin was administered in vitro either to quiescent cells or during CLL cell activation stimuli, provided by classical co-culturing with CD40L-expressing fibroblasts. At doses that were totally ineffective on normal lymphocytes, metformin induced apoptosis of quiescent CLL cells and inhibition of cell cycle entry when CLL were stimulated by CD40-CD40L ligation. This cytostatic effect was accompanied by decreased expression of survival- and proliferation-associated proteins, inhibition of signaling pathways involved in CLL disease progression and decreased intracellular glucose available for glycolysis. In drug combination experiments, metformin lowered the apoptotic threshold and potentiated the cytotoxic effects of classical and novel antitumor molecules. Our results indicate that, while CLL cells after stimulation are in the process of building their full survival and cycling armamentarium, the presence of metformin affects this process.

  20. What are the differences between long-term, short-term, and working memory?

    OpenAIRE

    Cowan, Nelson

    2008-01-01

    In the recent literature there has been considerable confusion about the three types of memory: long-term, short-term, and working memory. This chapter strives to reduce that confusion and makes up-to-date assessments of these types of memory. Long- and short-term memory could differ in two fundamental ways, with only short-term memory demonstrating (1) temporal decay and (2) chunk capacity limits. Both properties of short-term memory are still controversial but the current literature is rath...

  1. Clinical holistic medicine (mindful, short-term psychodynamic psychotherapy complemented with bodywork) in the treatment of experienced physical illness and chronic pain.

    Science.gov (United States)

    Ventegodt, Søren; Thegler, Suzette; Andreasen, Tove; Struve, Flemming; Enevoldsen, Lars; Bassaine, Laila; Torp, Margrethe; Merrick, Joav

    2007-03-02

    We investigated the treatment effect of psychodynamic short-term therapy complemented with bodywork on patients who presented with physical illness at the Research Clinic for Holistic Medicine in Copenhagen. Psychodynamic short-term therapy was complemented with bodywork (Marion Rosen) to help patients confront old emotional pain from childhood trauma(s). Patients were measured with a five-item quality of life and health questionnaire (QOL5), a one-item questionnaire of self-assessed quality of life (QOL1), and four questions on self-rated ability to love and to function sexually, socially, and at work (ability to sustain a full-time job). Most of the patients had chronic pain that could not be alleviated with drugs. Results showed that 31 patients with the experience of being severely physically ill (mostly from chronic pain), in spite of having consulted their own general practitioner, entered the study. The holistic approach and body therapy accelerated the therapy dramatically and no significant side effects were detected. After the intervention, 38.7% did not feel ill (1.73 treatment responders, the treatment seemingly provided lasting benefits.

  2. Effect of Metformin on Adult Hippocampal Neurogenesis: Comparison with Donepezil and Links to Cognition.

    Science.gov (United States)

    Ahmed, Sara; Mahmood, Zahra; Javed, Aneela; Hashmi, Shoaib Naiyer; Zerr, Inga; Zafar, Saima; Zahid, Saadia

    2017-05-01

    Recent studies have uncovered evidence suggesting that interference with hippocampal adult neurogenesis contributes to neurodegeneration in Alzheimer's disease (AD). Evidence supporting that AD is a metabolic disease with derangements in brain glucose utilization implies the use of anti-diabetics as an alternate therapeutic strategy. The present study drew comparison between the pro-neurogenic potential of metformin and donepezil in AlCl 3 -induced mouse model of neurodegeneration. Morris water maze task and subsequent immunohistochemical evaluation for NeuN was conducted. Expression of neurogenesis markers and hippocampal proteome analysis was determined by qRT-PCR and SDS-PAGE, respectively, followed by ESI-QTOFF MS/MS identification. The results demonstrated impaired spatial memory and differential expression of eight proteins in the AlCl 3 group as compared to the controls. Interestingly, treatment with metformin normalized the proteome profile and expression levels of neurogenesis markers along with improvement in the spatial memory. Moreover, as compared to donepezil, metformin-treated mice exhibited an enhanced number of post-mitotic NeuN-positive neurons. It is suggested that underlying molecular mechanisms of metformin-mediated adult hippocampal neurogenesis may have implications in treatment of neurodegenerative disorders.

  3. [Safety and short-term efficacy of renal sympathetic denervation in the treatment of resistant hypertension].

    Science.gov (United States)

    Jiang, Xiong-jing; Liang, Tuo; Dong, Hui; Peng, Meng; Ma, Wen-jun; Guan, Ting; Zhang, Hui-min; Bian, Jin; Xu, Bo; Gao, Run-lin

    2012-12-11

    Transcatheter renal sympathetic denervation (RDN) is a novel technology/therapy in treating resistant hypertension. The present study aims to evaluate the safety and short-term efficacy of RDN for the treatment of resistant hypertension in a Chinese population. This prospective single-center pilot study was the first one conducted in China with Medtronic Ardian Symplicity Catheter System. Eight patients (6 males and 2 females) with resistant hypertension underwent RDN at our hospital from February to April 2012. All patients were followed up at one month and three months post-RDN. Blood pressure, use of antihypertensive medications, renal function and complications were recorded and analyzed. At one month and three months post-RDN, 24-hour ambulatory blood pressure monitoring showed mean systolic blood pressure and diastolic blood pressure decreased 10 (0 - 18) 13 (3 - 19) and 8 (-2 - 15), 9 (2 - 16) mm Hg throughout 24 hours respectively (P renal function (P > 0.05). No complications were observed. The preliminary results revealed that RDN was safe and effective for the treatment of resistant hypertension in the Chinese population during a 3-month follow-up. Further large and long-term studies are warranted.

  4. The role of metformin in ovulation induction: Current status

    OpenAIRE

    Elnashar, Aboubakr Mohamed

    2011-01-01

    To define the exact role of metformin in ovulation induction, it is crucial to distinguish three different indications: naïve PCOS, CC-resistant PCOS and ART. In naïve PCOS: metformin as compared to placebo has been shown to improve ovulation rates, but metformin did not exert significant advantage over CC with respect to cumulative ovulation, pregnancy or live-birth rates. The combined approach of metformin plus CC is not better than CC or metformin monotherapy in naïve PCOS. In CC-resistant...

  5. Metformin Therapy for Fanconis Anemia

    Science.gov (United States)

    2017-08-01

    AWARD NUMBER: W81XWH-16-1-0300 TITLE: Metformin Therapy for Fanconis Anemia PRINCIPAL INVESTIGATOR: Markus Grompe CONTRACTING ORGANIZATION... Anemia 5a. CONTRACT NUMBER 5b. GRANT NUMBER W81XWH-16-1-0300 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Markus Grompe 5d. PROJECT NUMBER 5e. TASK...298 (Rev. 8-98) Prescribed by ANSI Std. Z39.18 This award pertains to the treatment of the inherited bone marrow failure syndrome Fanconi’s Anemia

  6. Metformin Lowers Serum Cobalamin without Changing Other Markers of Cobalamin Status: A Study on Women with Polycystic Ovary Syndrome

    Directory of Open Access Journals (Sweden)

    Ebba Nexo

    2013-07-01

    Full Text Available Treatment with the anti-diabetic drug metformin is followed by a decline in plasma cobalamin, but it is unsettled whether this denotes an impaired cobalamin status. This study has explored changes in the markers of cobalamin status in women with Polycystic Ovary Syndrome treated with metformin (1.5–2.5 g per day (n = 29 or placebo (n = 23 for six months. Serum samples were collected before and after two, four, and six months of treatment. We found serum cobalamin to decline and reach significant lower levels after six months of treatment (p = 0.003. Despite the decline in serum cobalamin, we observed no reductions in the physiological active part of cobalamin bound to transcobalamin (holotranscobalamin, or increase in the metabolic marker of cobalamin status, methylmalonic acid. Instead, the non-functional part of circulating cobalamin bound to haptocorrin declined (p = 0.0009. Our results have two implications: The data questions whether metformin treatment induces an impaired cobalamin status in PCOS patients, and further suggests that serum cobalamin is a futile marker for judging cobalamin status in metformin-treated patients.

  7. Short-term memory across eye blinks.

    Science.gov (United States)

    Irwin, David E

    2014-01-01

    The effect of eye blinks on short-term memory was examined in two experiments. On each trial, participants viewed an initial display of coloured, oriented lines, then after a retention interval they viewed a test display that was either identical or different by one feature. Participants kept their eyes open throughout the retention interval on some blocks of trials, whereas on others they made a single eye blink. Accuracy was measured as a function of the number of items in the display to determine the capacity of short-term memory on blink and no-blink trials. In separate blocks of trials participants were instructed to remember colour only, orientation only, or both colour and orientation. Eye blinks reduced short-term memory capacity by approximately 0.6-0.8 items for both feature and conjunction stimuli. A third, control, experiment showed that a button press during the retention interval had no effect on short-term memory capacity, indicating that the effect of an eye blink was not due to general motoric dual-task interference. Eye blinks might instead reduce short-term memory capacity by interfering with attention-based rehearsal processes.

  8. Short-term memory and dual task performance

    Science.gov (United States)

    Regan, J. E.

    1982-01-01

    Two hypotheses concerning the way in which short-term memory interacts with another task in a dual task situation are considered. It is noted that when two tasks are combined, the activity of controlling and organizing performance on both tasks simultaneously may compete with either task for a resource; this resource may be space in a central mechanism or general processing capacity or it may be some task-specific resource. If a special relationship exists between short-term memory and control, especially if there is an identity relationship between short-term and a central controlling mechanism, then short-term memory performance should show a decrement in a dual task situation. Even if short-term memory does not have any particular identity with a controlling mechanism, but both tasks draw on some common resource or resources, then a tradeoff between the two tasks in allocating resources is possible and could be reflected in performance. The persistent concurrence cost in memory performance in these experiments suggests that short-term memory may have a unique status in the information processing system.

  9. Metformin for endometrial hyperplasia: a Cochrane protocol.

    Science.gov (United States)

    Clement, Naomi S; Oliver, Thomas R W; Shiwani, Hunain; Saner, Juliane R F; Mulvaney, Caroline A; Atiomo, William

    2016-08-16

    Endometrial hyperplasia is a precancerous lesion of the endometrium, commonly presenting with uterine bleeding. If managed expectantly, it frequently progresses to endometrial carcinoma, rates of which are increasing dramatically worldwide. However, the established treatment for endometrial hyperplasia (progestogens) involves multiple side effects and leaves the risk of recurrence. Metformin is the most commonly used oral hypoglycaemic agent in type 2 diabetes mellitus. It has also been linked to the reversal of endometrial hyperplasia and may therefore contribute to decreasing the prevalence of endometrial carcinoma without the fertility and side effect consequences of current therapies. However, the efficacy and safety of metformin being used for this therapeutic target is unclear and, therefore, this systematic review will aim to determine this. We will search the following trials and databases with no language restrictions: Cochrane Gynaecology and Fertility Specialised Register; Cochrane Central Register of Controlled Trials (CENTRAL); MEDLINE; EMBASE; EBSCO Cumulative Index to Nursing and Allied Health Literature; PubMed; Google Scholar; ClinicalTrials.gov; the WHO International Trials Registry Platform portal; OpenGrey and the Latin American and Caribbean Health Sciences Literature (LILACS). We will include randomised controlled trials (RCTs) of use of metformin compared with a placebo or no treatment, conventional medical treatment (eg, progestogens) or any other active intervention. Two review authors will independently assess the trial eligibility, risk of bias and extract appropriate data points. Trial authors will be contacted for additional data. The primary review outcome is the regression of endometrial hyperplasia histology towards normal histology. Secondary outcomes include hysterectomy rate; abnormal uterine bleeding; quality of life scores and adverse reactions to treatments. Dissemination of the completed review will be through the Cochrane

  10. Short-term nanostructural effects of high radiofrequency treatment on the skin tissues of rabbits.

    Science.gov (United States)

    Choi, Samjin; Cheong, Youjin; Shin, Jae-Ho; Lee, Hui-Jae; Lee, Gi-Ja; Choi, Seok Keun; Jin, Kyung-Hyun; Park, Hun-Kuk

    2012-09-01

    The aim of this study is to quantitatively investigate the short-term effects of RF tissue-tightening treatment in in vivo rabbit dermal collagen fibrils. These effects were measured at different energy levels and at varying pass procedures on the nanostructural response level using histology and AFM analysis. Each rabbit was divided into one of seven experimental groups, which included the following: control group, and six RF group according to RF energy (20 W and 40 W) and three RF pass procedures. The progressive changes in the diameter and D-periodicity of rabbit dermal collagen fibrils were investigated in detail over a 7-day post-treatment period. The dermal tissues treated with the RF tissue-tightening device showed more prominent inflammatory responses with inflammatory cell ingrowth compared to the control. This effect showed more prominent with the passage of day after treatment. Although an increase in the diameter and D-periodicity of dermal collagen fibrils was identified immediately after the RF treatment, a decrease in the morphology of dermal collagen fibrils continued until post-operative day 7. Furthermore, RF treatment led to the loss of distinct borders. Increases in RF energy with the same pass procedure, as well as an increase in the number of RF passes, increased the occurrence of irreversible collagen fibril injury. A multiple-pass treatment at low energy rather than a single-pass treatment at high energy showed a large amount of collagen fibrils contraction at the nanostructural level.

  11. Serum and follicular anti-Mullerian hormone levels in women with polycystic ovary syndrome (PCOS under metformin

    Directory of Open Access Journals (Sweden)

    Falbo Angela

    2010-07-01

    Full Text Available Abstract Background No data regarding metformin effects on follicular fluid anti-Müllerian hormone (AMH levels were to date available in literature. The aim of the present study was to evaluate in patients with polycystic ovary syndrome (PCOS whether metformin administration affects serum and follicular AMH levels, and whether this is related to ovarian response to the treatment. Methods Twenty young patients with PCOS who had received metformin were enrolled. Ten patients were anovulatory (Met-anov group, whereas the other 10 were ovulatory (Met-ov group but had failed to conceive. Further untreated PCOS (PCOS controls, n. 10 and healthy controls (non-PCOS controls, n. 10 who were scheduled for laparoscopic surgery were enrolled. In each subjects, clinical and biochemical evaluations were performed. AMH concentrations in blood and antral follicular fluid were assayed. Results In both Met-anov and Met-ov groups, and without difference between them, serum androgens and AMH, and indices of insulin resistance were significantly (p p Conclusions Metformin administration in patients with PCOS exerts a differential action on the ovarian AMH levels on the basis of ovulatory response. Changes in AMH levels in antral follicular fluid during metformin treatment could be involved in the local mechanisms mediating the ovulatory restoration.

  12. Short-term LNG-markets

    International Nuclear Information System (INIS)

    Eldegard, Tom; Lund, Arne-Christian; Miltersen, Kristian; Rud, Linda

    2005-01-01

    The global Liquefied Natural Gas (LNG) industry has experienced substantial growth in the past decades. In the traditional trade patterns of LNG the product has typically been handled within a dedicated chain of plants and vessels fully committed by long term contracts or common ownership, providing risk sharing of large investments in a non-liquid market. Increasing gas prices and substantial cost reductions in all parts of the LNG chain have made LNG projects viable even if only part of the capacity is secured by long-term contracts, opening for more flexible trade of the remainder. Increasing gas demand, especially in power generation, combined with cost reductions in the cost of LNG terminals, open new markets for LNG. For the LNG supplier, the flexibility of shifting volumes between regions represents an additional value. International trade in LNG has been increasing, now accounting for more than one fifth of the world's cross-border gas trade. Despite traditional vertical chain bonds, increased flexibility has contributed in fact to an increasing LNG spot trade, representing 8% of global trade in 2002. The focus of this paper is on the development of global short-term LNG markets, and their role with respect to efficiency and security of supply in European gas markets. Arbitrage opportunities arising from price differences between regional markets (such as North America versus Europe) are important impetuses for flexible short-term trade. However, the short-term LNG trade may suffer from problems related to market access, e.g. limited access to terminals and regulatory issues, as well as rigidities connected to vertical binding within the LNG chain. Important issues related to the role of short-term LNG-trade in the European gas market are: Competition, flexibility in meeting peak demand, security of supply and consequences of differences in pricing policies (oil-linked prices in Europe and spot market prices in North America). (Author)

  13. Metformin-like antidiabetic, cardio-protective and non-glycemic effects of naringenin: Molecular and pharmacological insights.

    Science.gov (United States)

    Nyane, Ntsoaki Annah; Tlaila, Thabiso Bethwel; Malefane, Tanki Gabriel; Ndwandwe, Dudu Edith; Owira, Peter Mark Oroma

    2017-05-15

    Metformin is a widely used drug for the treatment of type 2 diabetes (T2D). Its blood glucose-lowering effects are initially due to inhibition of hepatic glucose production and increased peripheral glucose utilization. Metformin has also been shown to have several beneficial effects on cardiovascular risk factors and it is the only oral antihyperglycaemic agent thus far associated with decreased macrovascular complications in patients with diabetes. Adenosine Monophosphate Activated-Protein Kinase (AMPK) is a major cellular regulator of lipid and glucose metabolism. Recent evidence shows that pharmacological activation of AMPK improves blood glucose homeostasis, lipid profiles, blood pressure and insulin-resistance making it a novel therapeutic target in the treatment of T2D. Naringenin a flavonoid found in high concentrations as its glycone naringin in citrus fruits, has been reported to have antioxidant, antiatherogenic, anti- dyslipidemic and anti-diabetic effects. It has been shown that naringenin exerts its anti-diabetic effects by inhibition of gluconeogenesis through upregulations of AMPK hence metformin-like effects. Naringin has further been shown to have non-glycemic affects like metformin that mitigate inflammation and cell proliferation. This review evaluates the potential of naringenin as anti-diabetic, anti-dyslipidemic anti-inflammatory and antineoplastic agent similar to metformin and proposes its further development for therapeutic use in clinical practice. Copyright © 2017 Elsevier B.V. All rights reserved.

  14. A Randomized, Double-Blind, Placebo-Controlled Trial of Adjunctive Metformin Therapy in Overweight/Obese Youth with Type 1 Diabetes.

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    Benjamin Udoka Nwosu

    Full Text Available Insulin resistance has been proposed as one of the causes of poor glycemic control in overweight/obese youth with type 1 diabetes (T1D. However, the role of adjunctive metformin, an insulin sensitizer, on glycemic control in these patients is unclear.To compare the effect of metformin vs. placebo on hemoglobin A1c (HbA1c, total daily dose (TDD of insulin, and other parameters in overweight/obese youth with T1D.Adjunctive metformin therapy will improve glycemic control in overweight/obese youth with T1D.A 9-mo randomized, double-blind, placebo controlled trial of metformin and placebo in 28 subjects (13m/15f of ages 10-20years (y, with HbA1c >8% (64 mmol/mol, BMI >85%, and T1D > 12 months was conducted at a university outpatient facility. The metformin group consisted of 15 subjects (8 m/ 7f, of age 15.0 ± 2.5 y; while the control group was made up of 13 subjects (5m/ 8f, of age 14.5 ± 3.1y. All participants employed a self-directed treat-to-target insulin regimen based on a titration algorithm of (-2-0-(+2 units to adjust their long-acting insulin dose every 3rd day from -3 mo through +9 mo to maintain fasting plasma glucose (FPG between 90-120 mg/dL (5.0-6.7 mmol/L. Pubertal maturation was determined by Tanner stage.Over the course of the 9 months of observation, the between-treatment differences in HbA1c of 0.4% (9.85% [8.82 to 10.88] for placebo versus 9.46% [8.47 to 10.46] for metformin was not significant (p = 0.903. There were non-significant reduction in fasting plasma glucose (189.4 mg/dL [133.2 to 245.6] for placebo versus 170.5 mg/dL [114.3 to 226.7] for metformin, (p = 0.927; total daily dose (TDD of short-acting insulin per kg body weight/day(p = 0.936; and the TDD of long-acting insulin per kg body weight per day (1.15 units/kg/day [0.89 to 1.41] for placebo versus 0.90 units/kg/day [0.64 to 1.16] for metformin (p = 0.221. There was no difference in the occurrence of hypoglycemia between the groups.This 9-month RCT of adjunctive

  15. Metformin Induces Apoptosis and Cell Cycle Arrest Mediated by Oxidative Stress, AMPK and FOXO3a in MCF-7 Breast Cancer Cells

    Science.gov (United States)

    Queiroz, Eveline A. I. F.; Puukila, Stephanie; Eichler, Rosangela; Sampaio, Sandra C.; Forsyth, Heidi L.; Lees, Simon J.; Barbosa, Aneli M.; Dekker, Robert F. H.; Fortes, Zuleica B.; Khaper, Neelam

    2014-01-01

    Recent studies have demonstrated that the anti-diabetic drug, metformin, can exhibit direct antitumoral effects, or can indirectly decrease tumor proliferation by improving insulin sensitivity. Despite these recent advances, the underlying molecular mechanisms involved in decreasing tumor formation are not well understood. In this study, we examined the antiproliferative role and mechanism of action of metformin in MCF-7 cancer cells treated with 10 mM of metformin for 24, 48, and 72 hours. Using BrdU and the MTT assay, it was found that metformin demonstrated an antiproliferative effect in MCF-7 cells that occurred in a time- and concentration- dependent manner. Flow cytometry was used to analyze markers of cell cycle, apoptosis, necrosis and oxidative stress. Exposure to metformin induced cell cycle arrest in G0-G1 phase and increased cell apoptosis and necrosis, which were associated with increased oxidative stress. Gene and protein expression were determined in MCF-7 cells by real time RT-PCR and western blotting, respectively. In MCF-7 cells metformin decreased the activation of IRβ, Akt and ERK1/2, increased p-AMPK, FOXO3a, p27, Bax and cleaved caspase-3, and decreased phosphorylation of p70S6K and Bcl-2 protein expression. Co-treatment with metformin and H2O2 increased oxidative stress which was associated with reduced cell number. In the presence of metformin, treating with SOD and catalase improved cell viability. Treatment with metformin resulted in an increase in p-p38 MAPK, catalase, MnSOD and Cu/Zn SOD protein expression. These results show that metformin has an antiproliferative effect associated with cell cycle arrest and apoptosis, which is mediated by oxidative stress, as well as AMPK and FOXO3a activation. Our study further reinforces the potential benefit of metformin in cancer treatment and provides novel mechanistic insight into its antiproliferative role. PMID:24858012

  16. Understanding the Representative Gut Microbiota Dysbiosis in Metformin-Treated Type 2 Diabetes Patients Using Genome-Scale Metabolic Modeling

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    Dorines Rosario

    2018-06-01

    Full Text Available Dysbiosis in the gut microbiome composition may be promoted by therapeutic drugs such as metformin, the world’s most prescribed antidiabetic drug. Under metformin treatment, disturbances of the intestinal microbes lead to increased abundance of Escherichia spp., Akkermansia muciniphila, Subdoligranulum variabile and decreased abundance of Intestinibacter bartlettii. This alteration may potentially lead to adverse effects on the host metabolism, with the depletion of butyrate producer genus. However, an increased production of butyrate and propionate was verified in metformin-treated Type 2 diabetes (T2D patients. The mechanisms underlying these nutritional alterations and their relation with gut microbiota dysbiosis remain unclear. Here, we used Genome-scale Metabolic Models of the representative gut bacteria Escherichia spp., I. bartlettii, A. muciniphila, and S. variabile to elucidate their bacterial metabolism and its effect on intestinal nutrient pool, including macronutrients (e.g., amino acids and short chain fatty acids, minerals and chemical elements (e.g., iron and oxygen. We applied flux balance analysis (FBA coupled with synthetic lethality analysis interactions to identify combinations of reactions and extracellular nutrients whose absence prevents growth. Our analyses suggest that Escherichia sp. is the bacteria least vulnerable to nutrient availability. We have also examined bacterial contribution to extracellular nutrients including short chain fatty acids, amino acids, and gasses. For instance, Escherichia sp. and S. variabile may contribute to the production of important short chain fatty acids (e.g., acetate and butyrate, respectively involved in the host physiology under aerobic and anaerobic conditions. We have also identified pathway susceptibility to nutrient availability and reaction changes among the four bacteria using both FBA and flux variability analysis. For instance, lipopolysaccharide synthesis, nucleotide sugar

  17. Maternal and fetal insulin levels at birth in women with polycystic ovary syndrome: data from a randomized controlled study on metformin.

    Science.gov (United States)

    Helseth, Ragnhild; Vanky, Eszter; Stridsklev, Solhild; Vogt, Christina; Carlsen, Sven M

    2014-05-01

    Metformin is suggested to reduce pregnancy complications in women with polycystic ovary syndrome (PCOS). Metformin crosses the placenta and therapeutic concentrations are measured in the fetal circulation. Whether metformin treatment in pregnant PCOS women affects maternal and fetal insulin concentrations at birth is not clarified. To investigate the possible effect of metformin on insulin concentrations in umbilical cord blood and the possible association between maternal and fetal insulin concentrations. Post-hoc analysis of a subgroup of PCOS women participating in a double-blind randomized controlled trial. University hospital setting. Women with PCOS (n=118), aged 19-39 years. Maternal and umbilical cord insulin concentrations immediately after birth. At delivery women randomized to metformin had lower insulin concentrations than those randomized to placebo (259±209 vs 361±261 pmol/l; P=0.020). No difference was found in insulin concentrations in umbilical venous (P=0.95) and arterial (P=0.39) blood between the metformin and placebo groups. The arteriovenous difference was also equal between the groups (P=0.38). Insulin concentrations were higher in the umbilical vein than in the umbilical artery independent of randomization (70±51 vs 45±48 pmol/l; Pmetformin treatment during pregnancy resulted in lower maternal insulin concentrations at delivery. Metformin treatment did not affect fetal insulin concentrations. Higher insulin concentrations in the umbilical vein indicate that the placenta somehow secretes insulin to the fetus. The possibility of placental insulin secretion to the fetus deserves further investigations.

  18. The short-term impacts of Earned Income Tax Credit disbursement on health.

    Science.gov (United States)

    Rehkopf, David H; Strully, Kate W; Dow, William H

    2014-12-01

    There are conflicting findings regarding long- and short-term effects of income on health. Whereas higher average income is associated with better health, there is evidence that health behaviours worsen in the short-term following income receipt.Prior studies revealing such negative short-term effects of income receipt focus on specific subpopulations and examine a limited set of health outcomes. The United States Earned Income Tax Credit (EITC) is an income supplement tied to work, and is the largest poverty reduction programme in the USA. We utilize the fact that EITC recipients typically receive large cash transfers in the months of February,March and April, in order to examine associated changes in health outcomes that can fluctuate on a monthly basis. We examine associations with 30 outcomes in the categories of diet, food security, health behaviours, cardiovascular biomarkers, metabolic biomarkers and infection and immunity among 6925 individuals from the U.S. National Health and Nutrition Survey. Our research design approximates a natural experiment,since whether individuals were sampled during treatment or non-treatment months is independent of social, demographic and health characteristics that do not vary with time. There are both beneficial and detrimental short-term impacts of income receipt.Although there are detrimental impacts on metabolic factors among women, most other impacts are beneficial, including those for food security, smoking and trying to lose weight. The short-term impacts of EITC income receipt are not universally health promoting, but on balance there are more health benefits than detriments.

  19. Effect of Short- and Long-Term Play Therapy Services on Teacher-Child Relationship Stress

    Science.gov (United States)

    Ray, Dee C.; Henson, Robin K.; Schottelkorb, April A.; Brown, April Garofano; Muro, Joel

    2008-01-01

    The purpose of the present study was to explore the effect of both short- and long term Child-Centered Play Therapy on teacher-student relationship stress. Teachers identified 58 students exhibiting emotional and behavioral difficulties who were randomly assigned to one of two treatment groups. Students in the short-term intensive play therapy…

  20. Drug treatment of type 2 diabetes mellitus in patients for whom metformin is contraindicated [Corrigendum

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    Irons BK

    2017-10-01

    Full Text Available Irons BK, Minze MG. Drug treatment of type 2 diabetes mellitus in patients for whom metformin is contraindicated. Diabetes Metab Syndr Obes. 2014;7:15–24.There is an error in the text on page 19:“Alpha-glucosidase inhibitors are infrequently used in the treatment of T2DM.3 These agents competitively inhibit the absorption of alpha-glucosidase along the brush border of the small intestine, which slows gut absorption of carbohydrates and ultimately reduces post-prandial blood glucose.34–36” should read as “Alpha-glucosidase inhibitors are infrequently used in the treatment of T2DM.3 These agents competitively inhibit the degradation of complex carbohydrates along the brush border of the small intestine, which slows gut absorption of metabolized carbohydrates and ultimately reduces post-prandial blood glucose.34–36”Read the original article

  1. Combining insulin with metformin or an insulin secretagogue in non-obese patients with type 2 diabetes

    DEFF Research Database (Denmark)

    Lund, Søren S; Tarnow, Lise; Frandsen, Merete

    2009-01-01

    . Patients had had type 2 diabetes for approximately 10 years. At the end of treatment, HbA(1c) concentration was reduced by a similar amount in the two treatment groups (insulin plus metformin: mean (standard deviation) HbA(1c) 8.15% (1.32) v 6.72% (0.66); insulin plus repaglinide: 8.07% (1.49) v 6.90% (0......OBJECTIVES: To study the effect of insulin treatment in combination with metformin or an insulin secretagogue, repaglinide, on glycaemic regulation in non-obese patients with type 2 diabetes. DESIGN: Randomised, double blind, double dummy, parallel trial. SETTING: Secondary care in Denmark between......% confidence interval -4.07 to -0.95). CONCLUSIONS: In non-obese patients with type 2 diabetes and poor glycaemic regulation on oral hypoglycaemic agents, overall glycaemic regulation with insulin in combination with metformin was equivalent to that with insulin plus repaglinide. Weight gain seemed less...

  2. Nutrients in Energy and One-Carbon Metabolism: Learning from Metformin Users

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    Fedra Luciano-Mateo

    2017-02-01

    Full Text Available Metabolic vulnerability is associated with age-related diseases and concomitant co-morbidities, which include obesity, diabetes, atherosclerosis and cancer. Most of the health problems we face today come from excessive intake of nutrients and drugs mimicking dietary effects and dietary restriction are the most successful manipulations targeting age-related pathways. Phenotypic heterogeneity and individual response to metabolic stressors are closely related food intake. Understanding the complexity of the relationship between dietary provision and metabolic consequences in the long term might provide clinical strategies to improve healthspan. New aspects of metformin activity provide a link to many of the overlapping factors, especially the way in which organismal bioenergetics remodel one-carbon metabolism. Metformin not only inhibits mitochondrial complex 1, modulating the metabolic response to nutrient intake, but also alters one-carbon metabolic pathways. Here, we discuss findings on the mechanism(s of action of metformin with the potential for therapeutic interpretations.

  3. Short-term incentive schemes for hospital managers

    Directory of Open Access Journals (Sweden)

    Lucas Malambe

    2013-10-01

    Full Text Available Orientation: Short-term incentives, considered to be an extrinsic motivation, are commonly used to motivate performance. This study explored hospital managers’ perceptions of short term incentives in maximising performance and retention. Research purpose: The study explored the experiences, views and perceptions of private hospital managers in South Africa regarding the use of short-term incentives to maximise performance and retention, as well as the applicability of the findings to public hospitals. Motivation for the study: Whilst there is an established link between performance reward schemes and organisational performance, there is little understanding of the effects of short term incentives on the performance and retention of hospital managers within the South African context. Research design, approach, and method: The study used a qualitative research design: interviews were conducted with a purposive sample of 19 hospital managers, and a thematic content analysis was performed. Main findings: Short-term incentives may not be the primary motivator for hospital managers, but they do play a critical role in sustaining motivation. Participants indicated that these schemes could also be applicable to public hospitals. Practical/managerial implications: Hospital managers are inclined to be more motivated by intrinsic than extrinsic factors. However, hospital managers (as middle managers also seem to be motivated by short-term incentives. A combination of intrinsic and extrinsic motivators should thus be used to maximise performance and retention. Contribution/value-add: Whilst the study sought to explore hospital managers’ perceptions of short-term incentives, it also found that an adequate balance between internal and external motivators is key to implementing an effective short-term incentive scheme.

  4. Why do short term workers have high mortality?

    DEFF Research Database (Denmark)

    Kolstad, Henrik; Olsen, Jørn

    1999-01-01

    or violence, the rate ratios for short term employment were 2.30 (95% Cl 1.74-3.06) and 1.86 (95% Cl 1.35-2.56), respectively. An unhealthy lifestyle may also be a determinant of short term employment. While it is possible in principle to adjust for lifestyle factors if proper data are collected, the health......Increased mortality is often reported among workers in short term employment. This may indicate either a health-related selection process or the presence of different lifestyle or social conditions among short term workers. The authors studied these two aspects of short term employment among 16...

  5. Metformin-Induced Changes of the Coding Transcriptome and Non-Coding RNAs in the Livers of Non-Alcoholic Fatty Liver Disease Mice.

    Science.gov (United States)

    Guo, Jun; Zhou, Yuan; Cheng, Yafen; Fang, Weiwei; Hu, Gang; Wei, Jie; Lin, Yajun; Man, Yong; Guo, Lixin; Sun, Mingxiao; Cui, Qinghua; Li, Jian

    2018-01-01

    Recent studies have suggested that changes in non-coding mRNA play a key role in the progression of non-alcoholic fatty liver disease (NAFLD). Metformin is now recommended and effective for the treatment of NAFLD. We hope the current analyses of the non-coding mRNA transcriptome will provide a better presentation of the potential roles of mRNAs and long non-coding RNAs (lncRNAs) that underlie NAFLD and metformin intervention. The present study mainly analysed changes in the coding transcriptome and non-coding RNAs after the application of a five-week metformin intervention. Liver samples from three groups of mice were harvested for transcriptome profiling, which covered mRNA, lncRNA, microRNA (miRNA) and circular RNA (circRNA), using a microarray technique. A systematic alleviation of high-fat diet (HFD)-induced transcriptome alterations by metformin was observed. The metformin treatment largely reversed the correlations with diabetes-related pathways. Our analysis also suggested interaction networks between differentially expressed lncRNAs and known hepatic disease genes and interactions between circRNA and their disease-related miRNA partners. Eight HFD-responsive lncRNAs and three metformin-responsive lncRNAs were noted due to their widespread associations with disease genes. Moreover, seven miRNAs that interacted with multiple differentially expressed circRNAs were highlighted because they were likely to be associated with metabolic or liver diseases. The present study identified novel changes in the coding transcriptome and non-coding RNAs in the livers of NAFLD mice after metformin treatment that might shed light on the underlying mechanism by which metformin impedes the progression of NAFLD. © 2018 The Author(s). Published by S. Karger AG, Basel.

  6. Metformin improves pregnancy and live-birth rates in women with polycystic ovary syndrome (PCOS): a multicenter, double-blind, placebo-controlled randomized trial.

    Science.gov (United States)

    Morin-Papunen, Laure; Rantala, Anni S; Unkila-Kallio, Leila; Tiitinen, Aila; Hippeläinen, Maritta; Perheentupa, Antti; Tinkanen, Helena; Bloigu, Risto; Puukka, Katri; Ruokonen, Aimo; Tapanainen, Juha S

    2012-05-01

    The role of metformin in the treatment of infertility in women with polycystic ovary syndrome (PCOS) is still controversial. OBJECTIVE AND OUTCOMES: We investigated whether metformin decreases the early miscarriage rate and improves the pregnancy rates (PR) and live-birth rates (LBR) in PCOS. This was a multicenter, randomized (1:1), double-blind, placebo-controlled study. Three hundred twenty women with PCOS and anovulatory infertility were randomized to metformin (n = 160, Diformin; obese women, 1000 mg two times daily; nonobese subjects, 500 mg + 1000 mg daily) or identical doses of placebo (n = 160). After 3 months' treatment, another appropriate infertility treatment was combined if necessary. If pregnancy occurred, metformin/placebo was continued up to the 12th week. Miscarriage rates were low and similar in the two groups (metformin 15.2% vs. placebo 17.9%, P = 0.8). Intent-to-treat analysis showed that metformin significantly improved PR and LBR (vs. placebo) in the whole study population (PR: 53.6 vs. 40.4%, P = 0.006; LBR: 41.9 vs. 28.8%, P = 0.014) and PR in obese women (49.0 vs. 31.4%, P = 0.04), and there was a similar trend in nonobese (PR: 58.6 vs. 47.6%, P = 0.09; LBR: 46.7 vs. 34.5%, P = 0.09) and in obese women with regard to LBR (35.7 vs. 21.9%, P = 0.07). Cox regression analysis showed that metformin plus standard infertility treatment increased the chance of pregnancy 1.6 times (hazard rate 1.6, 95% confidence interval 1.13-2.27). Obese women especially seem to benefit from 3 months' pretreatment with metformin and its combination thereafter with routine ovulation induction in anovulatory infertility.

  7. Identification of metformin poor responders, requiring supplemental insulin, during randomization of metformin versus insulin for the control of gestational diabetes mellitus.

    Science.gov (United States)

    Ashoush, Sherif; El-Said, Mourrad; Fathi, Hisham; Abdelnaby, Mohamed

    2016-06-01

    To evaluate glycemic control among women with gestational diabetes mellitus (GDM) under insulin versus metformin (with or without insulin supplementation), and to identify metformin poor responders requiring supplemental insulin. In Ain Shams University Hospital, mothers with 26-32-week GDM pregnancies, failing diet control, were randomized to receive metformin (n = 47) or insulin (n = 48). The primary outcome was glycemic control. Secondary outcomes included maternal weight, parameters predicting successful metformin monotherapy, neonatal hypoglycemia, and birthweight. Women using metformin (23.4% needing supplemental insulin) gained less weight (P metformin group was related to initial body mass index, HbA1c, oral glucose tolerance test (GTT), and first week mean glucose level. The 1-h glucose level during initial GTT (Hr1-GTT) and the mean fasting glucose level during the first week of therapy (Wk1-mFG) were the two independent parameters associated with requiring supplemental insulin. Women with Hr1-GTT >212 mg/dL and Wk1-mFG >95 mg/dL had a risk ratio of 58.6 (95%CI: 3.68-933.35, P = 0.004) and 11.5 (95%CI: 2.77-47.34,= 0.0008), respectively for needing supplemental insulin during the course of the study compared with women without. Metformin is an effective and safe alternative to insulin in GDM. Women using metformin (± supplemental insulin) had similar glycemic control, less weight gain, and similar rates of side-effects as those on insulin monotherapy. Insulin supplementation to metformin therapy was more likely with elevated Hr1-GTT and Wk1-mFG. © 2016 Japan Society of Obstetrics and Gynecology.

  8. Comparison clinical and metabolic effects of metformin and pioglitazone in polycystic ovary syndrome

    Directory of Open Access Journals (Sweden)

    Karoon Shahebrahimi

    2016-01-01

    Full Text Available Introduction: Polycystic ovary syndrome (PCOS is one of the most common endocrine disorders in women. PCOS comprises a broad spectrum of anomalies, including hyperandrogenism, chronic anovulation, obesity, and infertility. Insulin resistance and its compensatory hyperinsulinemia play a key role in the pathogenicity of PCOS. This study compares the effects of 2 types of insulin sensitizer drugs, metformin and pioglitazone, on clinical, metabolic, and endocrine characteristics of women with PCOS. Methods: In this randomized clinical trial, 56 women with PCOS (ages 20–49 years were treated orally with either metformin (500 mg 3 times daily or pioglitazone (30 mg daily for 3 months. Clinical (body weight, blood pressure [BP], and body mass index and laboratory indices (fasting blood sugar [FBS], serum triglyceride [TG], cholesterol, low-density lipoprotein, high-density lipoprotein, insulin, testosterone, and dehydroepiandrosterone [DHEA] were measured before and after therapy. Data were analyzed by Chi-square and McNemar's tests. Results: Significant decreases were seen after treatment with metformin in extent of hair loss (P = 0.008, wrist circle (P = 0.011, weight (P = 0.047, diastolic BP (P = 0.023, and DHEA (P = 0.035. A significant decrease in TG was seen with pioglitazone treatment (P = 0.047. In both groups, significant decreases in acne, menstrual disturbance, FBS, and serum insulin were seen. Conclusion: There is a significant amelioration of endocrine and metabolic indices with pioglitazone in PCOS patients. Although we were not able to recommend one treatment regime over the other, pioglitazone offers a useful, alternate treatment in women with PCOS who are not able to tolerate metformin.

  9. Effects of Type 2 Diabetes Mellitus in Patients on Treatment With Glibenclamide and Metformin on Carvedilol Enantiomers Metabolism.

    Science.gov (United States)

    Nardotto, Glauco H B; Coelho, Eduardo B; Paiva, Carlos E; Lanchote, Vera L

    2017-06-01

    Carvedilol is available in clinical practice as a racemate in which (S)-(-)-carvedilol is a β- and α 1 -adrenergic antagonist and (R)-(+)-carvedilol is only an α 1 -adrenergic antagonist. Carvedilol is mainly metabolized by glucuronidation, by CYP2D6 to hydroxyphenylcarvedilol (OHC), and by CYP2C9 to O-desmethylcarvedilol (DMC). This study evaluated the pharmacokinetics of carvedilol enantiomers and their metabolites OHC and DMC in healthy volunteers (n = 13) and in type 2 diabetes mellitus patients with good glycemic control (n = 13). The healthy subjects were enrolled to receive either a 25-mg oral single dose of carvedilol alone (no DDI) or carvedilol simultaneously with 5 mg glibenclamide and 500 mg metformin (DDI), whereas type 2 diabetes mellitus patients who were on long-term treatment with glibenclamide (5 mg/8 h) and metformin (500 mg/8 h) were enrolled to receive only a single oral dose of 25 mg carvedilol. The plasma concentrations of the (R)-(+)-carvedilol, (R)-(+)-DMC, and (R)-(+)-OHC were higher than those of (S)-(-)-carvedilol, (S)-(-)-DMC, and (S)-(-)-OHC in all investigated groups. The pharmacokinetics of the carvedilol enantiomers did not differ between the groups. However, the AUC values of the DMC enantiomers were lower in the type 2 diabetes mellitus patients than in the healthy volunteers (DDI and no DDI) [(R)-(+), 6.9, 10.4, 11.9 ng·h/mL; and (S)-(-), 2.4, 4.3, 4.0 ng·h/mL, respectively]. In contrast, the AUC values of the OHC enantiomers were higher in the type 2 diabetes mellitus patients [(R)-(+), 13.9, 6.6, 4.9 ng·h/mL; and (S)-(-), 7.2, 1.5, 1.5 ng·h/mL], which explains the fact that the carvedilol pharmacokinetics was unchanged. © 2017, The American College of Clinical Pharmacology.

  10. Short and long term effectiveness of a subject's specific novel brain and vestibular rehabilitation treatment modality in combat veterans suffering from PTSD

    Directory of Open Access Journals (Sweden)

    Frederick Robert Carrick

    2015-06-01

    Full Text Available AbstractIntroduction: Treatment for post-traumatic stress disorder (PTSD in combat veterans that have a long-term positive clinical effect has the potential to modify the treatment of PTSD. This outcome may result in changed and saved lives of our service personnel and their families. In a previous before-after-intervention study we demonstrated high statistical and substantively significant short-term changes in the Clinician Administered DSM-IV PTSD Scale (CAPS scores after a two week trial of a subject's particular novel brain and vestibular rehabilitation (VR program. The long-term maintenance of PTSD severity reduction was the subject of this study.Material and Methods:We studied the short and long term effectiveness of a subject's particular novel brain and VR treatment of PTSD in subjects who had suffered combat-related traumatic brain injuries in terms of PTSD symptom reduction. The trial was registered as ClinicalTrials.gov Identifier: NCT02003352. We analyzed the difference in the CAPS scores pre and post treatment (one week and three months using our subjects as their matched controls. Results:The generalized least squares (GLS technique demonstrated that with our 26 subjects in the 3 timed groups the R2 within groups was 0.000, R2 between groups was 0.000 and overall the R2 was 0.000. The GLS regression was strongly statistically significant z = 21.29, p < 0.001, 95% CI [58.7, 70.63]. The linear predictive margins over time demonstrated strong statistical and substantive significance of decreasing PTSD severity scores for all timed CAPS tests.Discussion:Our investigation has the promise of the development of superior outcomes of treatments in this area that will benefit a global society. The length of the treatment intervention involved (two weeks is less that other currently available treatments and has profound implications for cost, duration of disability and outcomes in the treatment of PTSD in combat veterans.

  11. The evaluation of the effect of metformin on breast fibrocystic disease.

    Science.gov (United States)

    Talaei, A; Moradi, A; Rafiei, F

    2017-01-01

    Fibrocystic changes (FCC) is the most common benign breast disease. The main pathophysiologic mechanism of FCC, excessive cell proliferation in response to monthly estrogen and progesterone changes. Regarding to antiproliferative of metformin, the aim of this study is the evaluation of the effect of metformin on FCC in women who were referred to gynecology clinics of ArakMETHODS:This study is a double blind placebo control randomized clinical trial. At the first among women who were referred to gynecology of Arak, 186 women with FCC between 18-40 years were selected. The women were randomly classified into three groups. The first group took metformin and the second group as placebo group took vitamin E and the third group did not take any drug during six months. All groups were compared in clinical symptoms based on visual analogue scale (VAS) and the sonographic data also were recorded and compared. Data analysis was performed by unilateral variance, student t and Chi-square. The three groups were not different in aspect of mean of the cysts number, cyst size, tenderness and discharge from breast before the intervention, but after the intervention, there was a significant decrease in metformin group (p value < 0.001) based on variance analysis test. There was not a meaningful difference of pain and the location of cysts between the groups after the intervention. The present study showed that metformin is effective in treatment of FCC and decreasing of clinical symptoms and imaging items.

  12. Metformin therapy in a hyperandrogenic anovulatory mutant murine model with polycystic ovarian syndrome characteristics improves oocyte maturity during superovulation

    Directory of Open Access Journals (Sweden)

    Sabatini Mary E

    2011-05-01

    Full Text Available Abstract Background Metformin, an oral biguanide traditionally used for the treatment of type 2 diabetes, is widely used for the management of polycystic ovary syndrome (PCOS-related anovulation. Because of the significant prevalence of insulin resistance and glucose intolerance in PCOS patients, and their putative role in ovulatory dysfunction, the use of metformin was touted as a means to improve ovulatory function and reproductive outcomes in PCOS patients. To date, there has been inconsistent evidence to demonstrate a favorable effect of metformin on oocyte quality and competence in women with PCOS. Given the heterogeneous nature of this disorder, we hypothesized that metformin may be beneficial in mice with aberrant metabolic characteristics similar to a significant number of PCOS patients. The aim of this study was to gain insight into the in vitro and in vivo effects of metformin on oocyte development and ovulatory function. Methods We utilized metformin treatment in the transgenic ob/ob and db/db mutant murine models which demonstrate metabolic and reproductive characteristics similar to women with PCOS. Results: Metformin did not improve in vitro oocyte maturation nor did it have an appreciable effect on in vitro granulosa cell luteinization (progesterone production in any genotype studied. Although both mutant strains have evidence of hyperandrogenemia, anovulation, and hyperinsulinemia, only db/db mice treated with metformin had a greater number of mature oocytes and total overall oocytes compared to control. There was no observed impact on body mass, or serum glucose and androgens in any genotype. Conclusions Our data provide evidence to suggest that metformin may optimize ovulatory performance in mice with a specific reproductive and metabolic phenotype shared by women with PCOS. The only obvious difference between the mutant murine models is that the db/db mice have elevated leptin levels raising the questions of whether their

  13. Prenatal metformin exposure in a maternal high fat diet mouse model alters the transcriptome and modifies the metabolic responses of the offspring.

    Science.gov (United States)

    Salomäki, Henriikka; Heinäniemi, Merja; Vähätalo, Laura H; Ailanen, Liisa; Eerola, Kim; Ruohonen, Suvi T; Pesonen, Ullamari; Koulu, Markku

    2014-01-01

    Despite the wide use of metformin in metabolically challenged pregnancies, the long-term effects on the metabolism of the offspring are not known. We studied the long-term effects of prenatal metformin exposure during metabolically challenged pregnancy in mice. Female mice were on a high fat diet (HFD) prior to and during the gestation. Metformin was administered during gestation from E0.5 to E17.5. Male and female offspring were weaned to a regular diet (RD) and subjected to HFD at adulthood (10-11 weeks). Body weight and several metabolic parameters (e.g. body composition and glucose tolerance) were measured during the study. Microarray and subsequent pathway analyses on the liver and subcutaneous adipose tissue of the male offspring were performed at postnatal day 4 in a separate experiment. Prenatal metformin exposure changed the offspring's response to HFD. Metformin exposed offspring gained less body weight and adipose tissue during the HFD phase. Additionally, prenatal metformin exposure prevented HFD-induced impairment in glucose tolerance. Microarray and annotation analyses revealed metformin-induced changes in several metabolic pathways from which electron transport chain (ETC) was prominently affected both in the neonatal liver and adipose tissue. This study shows the beneficial effects of prenatal metformin exposure on the offspring's glucose tolerance and fat mass accumulation during HFD. The transcriptome data obtained at neonatal age indicates major effects on the genes involved in mitochondrial ATP production and adipocyte differentiation suggesting the mechanistic routes to improved metabolic phenotype at adulthood.

  14. Gender differences in success at quitting smoking: Short- and long-term outcomes.

    Science.gov (United States)

    Marqueta, Adriana; Nerín, Isabel; Gargallo, Pilar; Beamonte, Asunción

    2016-06-14

    Smoking cessation treatments are effective in men and women. However, possible sex-related differences in the outcome of these treatments remain a controversial topic. This study evaluated whether there were differences between men and women in the success of smoking cessation treatment, including gender-tailored components, in the short and long term (> 1 year). A telephone survey was carried out between September 2008 and June 2009 in smokers attended in a Smoking Cessation Clinic. All patients who have successfully completed treatment (3 months) were surveyed by telephone to determine their long-term abstinence. Those who remained abstinent were requested to attend the Smoking Cessation Clinic for biochemical validation (expired CO ≤10 ppm). The probability of remaining abstinent in the long-term was calculated using a Kaplan-Meier survival analysis. The treatment success rate at 3-months was 41.3% (538/1302) with no differences by sex 89% (479/538) among those located in the telephonic follow-up study and 47.6% (256/479) were abstinent without differences by sex (p = .519); abstinence was validated with CO less than 10 ppm in 191 of the 256 (53.9% men and 46.1% women). In the survival analysis, the probability of men and women remaining abstinent in the long-term was not significant. There are no differences by sex in the outcome of smoking cessation treatment that included gender-tailored components in the short and long term (> 1 year).

  15. Metformin Antagonizes Cancer Cell Proliferation by Suppressing Mitochondrial-Dependent Biosynthesis.

    Directory of Open Access Journals (Sweden)

    Takla Griss

    2015-12-01

    Full Text Available Metformin is a biguanide widely prescribed to treat Type II diabetes that has gained interest as an antineoplastic agent. Recent work suggests that metformin directly antagonizes cancer cell growth through its actions on complex I of the mitochondrial electron transport chain (ETC. However, the mechanisms by which metformin arrests cancer cell proliferation remain poorly defined. Here we demonstrate that the metabolic checkpoint kinases AMP-activated protein kinase (AMPK and LKB1 are not required for the antiproliferative effects of metformin. Rather, metformin inhibits cancer cell proliferation by suppressing mitochondrial-dependent biosynthetic activity. We show that in vitro metformin decreases the flow of glucose- and glutamine-derived metabolic intermediates into the Tricarboxylic Acid (TCA cycle, leading to reduced citrate production and de novo lipid biosynthesis. Tumor cells lacking functional mitochondria maintain lipid biosynthesis in the presence of metformin via glutamine-dependent reductive carboxylation, and display reduced sensitivity to metformin-induced proliferative arrest. Our data indicate that metformin inhibits cancer cell proliferation by suppressing the production of mitochondrial-dependent metabolic intermediates required for cell growth, and that metabolic adaptations that bypass mitochondrial-dependent biosynthesis may provide a mechanism of tumor cell resistance to biguanide activity.

  16. Long-term tolerability of inhaled human insulin (Exubera) in patients with poorly controlled type 2 diabetes

    DEFF Research Database (Denmark)

    Barnett, A H; Lange, P; Dreyer, M

    2007-01-01

    OBJECTIVE: Inhaled human insulin (Exubera; EXU) has shown encouraging tolerability in short-term trials. We evaluated the safety profile of EXU after long-term exposure. DESIGN: In two, open-label, 2-year studies patients poorly controlled on a sulphonylurea were randomised to adjunctive EXU...... or metformin (study 1) and patients poorly controlled on metformin were randomised to adjunctive EXU or the sulphonylurea, glibenclamide (study 2). PATIENTS: The studies included 446 (study 1) and 476 (study 2) patients with type 2 diabetes, no clinically significant respiratory disease and glycosylated....... There was no discernable effect of long-term EXU therapy on pulmonary gas exchange. Insulin antibody binding reached a plateau at 6 months and did not correlate with HbA(1c) or lung function changes. Glycaemic control was maintained over 2 years. CONCLUSIONS: Exubera was well tolerated during long-term use. Pulmonary...

  17. Efficacy of vitamin B12 combined with metformin in treating type 2 diabetes and its effect on homocysteine

    Directory of Open Access Journals (Sweden)

    Na Geng

    2016-03-01

    Full Text Available Objective: To observe and analyze Vitamin B12 combined with metformin treat for the type 2 diabetes, which affect the homocysteine. Methods: 92 cases of type 2 diabetes were selected in our hospital for treatment and study from October 2014 to April 2014. All patients were randomly divided into control group (46 cases and observation group (46 cases. Treatment of patients in the control group: patients were treated by metformin; observation group patients: Take vitamin B12 to patients treated with metformin. Finally, patient outcomes, as well as vitamin B12 and homocysteine in patients before and after treatment were analyzed. Results: Before treatment, all patients vitamin B12 content difference comparisons were no significant differences (P>0.05. Patients were treated in January, June and 1 year after the vitamin B12 content of the observation group were significantly higher in patients with vitamin B12 levels of data compared to each other there was a significant difference (P0.05. Patients were treated in January, June and 1 year after the homocysteine content of the observation group were not significantly reduced, the control group of patients with homocysteine increased significantly (P<0.000 1. Conclusions: Vitamin B12 combined with metformin in type 2 diabetes treatment, can significantly increase a patient's body to control homocysteine, while the treatment effect is obvious, clinical recommendations widely implemented.

  18. Short-term mechanisms influencing volumetric brain dynamics

    Directory of Open Access Journals (Sweden)

    Nikki Dieleman

    2017-01-01

    Full Text Available With the use of magnetic resonance imaging (MRI and brain analysis tools, it has become possible to measure brain volume changes up to around 0.5%. Besides long-term brain changes caused by atrophy in aging or neurodegenerative disease, short-term mechanisms that influence brain volume may exist. When we focus on short-term changes of the brain, changes may be either physiological or pathological. As such determining the cause of volumetric dynamics of the brain is essential. Additionally for an accurate interpretation of longitudinal brain volume measures by means of neurodegeneration, knowledge about the short-term changes is needed. Therefore, in this review, we discuss the possible mechanisms influencing brain volumes on a short-term basis and set-out a framework of MRI techniques to be used for volumetric changes as well as the used analysis tools. 3D T1-weighted images are the images of choice when it comes to MRI of brain volume. These images are excellent to determine brain volume and can be used together with an analysis tool to determine the degree of volume change. Mechanisms that decrease global brain volume are: fluid restriction, evening MRI measurements, corticosteroids, antipsychotics and short-term effects of pathological processes like Alzheimer's disease, hypertension and Diabetes mellitus type II. Mechanisms increasing the brain volume include fluid intake, morning MRI measurements, surgical revascularization and probably medications like anti-inflammatory drugs and anti-hypertensive medication. Exercise was found to have no effect on brain volume on a short-term basis, which may imply that dehydration caused by exercise differs from dehydration by fluid restriction. In the upcoming years, attention should be directed towards studies investigating physiological short-term changes within the light of long-term pathological changes. Ultimately this may lead to a better understanding of the physiological short-term effects of

  19. Influence of duration and dose of metformin on cobalamin deficiency in type 2 diabetes patients using metformin

    NARCIS (Netherlands)

    Beulens, Joline W J; Hart, Huberta E.; Kuijs, Ron; Kooijman-Buiting, Antoinette M J; Rutten, Guy E H M

    2015-01-01

    Metformin use is associated with cobalamin (vitamin B12) deficiency. However, the influence of both duration and dose of metformin is unclear. Studies using holotranscobalamin, a marker for cellular cobalamin deficiency, are scarce. We therefore investigated the prevalence of cobalamin deficiency in

  20. Metformin, the aspirin of the 21st century: its role in gestational diabetes mellitus, prevention of preeclampsia and cancer, and the promotion of longevity.

    Science.gov (United States)

    Romero, Roberto; Erez, Offer; Hüttemann, Maik; Maymon, Eli; Panaitescu, Bogdan; Conde-Agudelo, Agustin; Pacora, Percy; Yoon, Bo Hyun; Grossman, Lawrence I

    2017-09-01

    Metformin is everywhere. Originally introduced in clinical practice as an antidiabetic agent, its role as a therapeutic agent is expanding to include treatment of prediabetes mellitus, gestational diabetes mellitus, and polycystic ovarian disease; more recently, experimental studies and observations in randomized clinical trials suggest that metformin could have a place in the treatment or prevention of preeclampsia. This article provides a brief overview of the history of metformin in the treatment of diabetes mellitus and reviews the results of metaanalyses of metformin in gestational diabetes mellitus as well as the treatment of obese, non-diabetic, pregnant women to prevent macrosomia. We highlight the results of a randomized clinical trial in which metformin administration in early pregnancy did not reduce the frequency of large-for-gestational-age infants (the primary endpoint) but did decrease the frequency of preeclampsia (a secondary endpoint). The mechanisms by which metformin may prevent preeclampsia include a reduction in the production of antiangiogenic factors (soluble vascular endothelial growth factor receptor-1 and soluble endoglin) and the improvement of endothelial dysfunction, probably through an effect on the mitochondria. Another potential mechanism whereby metformin may play a role in the prevention of preeclampsia is its ability to modify cellular homeostasis and energy disposition, mediated by rapamycin, a mechanistic target. Metformin has a molecular weight of 129 Daltons and therefore readily crosses the placenta. There is considerable evidence to suggest that this agent is safe during pregnancy. New literature on the role of metformin as a chemotherapeutic adjuvant in the prevention of cancer and in prolonging life and protecting against aging is reviewed briefly. Herein, we discuss the mechanisms of action and potential benefits of metformin. Published by Elsevier Inc.

  1. Metformin versus placebo in combination with insulin analogues in patients with type 2 diabetes mellitus-the randomised, blinded Copenhagen Insulin and Metformin Therapy (CIMT) trial

    DEFF Research Database (Denmark)

    Lundby-Christensen, Louise; Tarnow, Lise; Boesgaard, Trine W

    2016-01-01

    OBJECTIVE: To assess the effect of metformin versus placebo both in combination with insulin analogue treatment on changes in carotid intima-media thickness (IMT) in patients with type 2 diabetes. DESIGN AND SETTING: Investigator-initiated, randomised, placebo-controlled trial with a 2×3 factorial...... design conducted at eight hospitals in Denmark. PARTICIPANTS AND INTERVENTIONS: 412 participants with type 2 diabetes (glycated haemoglobin (HbA1c) ≥7.5% (≥58 mmol/mol); body mass index >25 kg/m2) were in addition to open-labelled insulin treatment randomly assigned 1:1 to 18 months blinded metformin (1...... weight gain, and smaller insulin dose compared with placebo plus insulin. However, the trial only reached 46% of the planned sample size and lack of power may therefore have affected our results. TRIAL REGISTRATION NUMBER: NCT00657943; Results....

  2. Verbal Short-Term Memory Span in Speech-Disordered Children: Implications for Articulatory Coding in Short-Term Memory.

    Science.gov (United States)

    Raine, Adrian; And Others

    1991-01-01

    Children with speech disorders had lower short-term memory capacity and smaller word length effect than control children. Children with speech disorders also had reduced speech-motor activity during rehearsal. Results suggest that speech rate may be a causal determinant of verbal short-term memory capacity. (BC)

  3. Uterine progesterone signaling is a target for metformin therapy in PCOS-like rats.

    Science.gov (United States)

    Hu, Min; Zhang, Yuehui; Feng, Jiaxing; Xu, Xue; Zhang, Jiao; Zhao, Wei; Guo, Xiaozhu; Li, Juan; Vestin, Edvin; Cui, Peng; Li, Xin; Wu, Xiao-Ke; Brännström, Mats; Shao, Linus R; Billig, Håkan

    2018-05-01

    Impaired progesterone (P4) signaling is linked to endometrial dysfunction and infertility in women with polycystic ovary syndrome (PCOS). Here, we report for the first time that elevated expression of progesterone receptor (PGR) isoforms A and B parallels increased estrogen receptor (ER) expression in PCOS-like rat uteri. The aberrant PGR-targeted gene expression in PCOS-like rats before and after implantation overlaps with dysregulated expression of Fkbp52 and Ncoa2 , two genes that contribute to the development of uterine P4 resistance. In vivo and in vitro studies of the effects of metformin on the regulation of the uterine P4 signaling pathway under PCOS conditions showed that metformin directly inhibits the expression of PGR and ER along with the regulation of several genes that are targeted dependently or independently of PGR-mediated uterine implantation. Functionally, metformin treatment corrected the abnormal expression of cell-specific PGR and ER and some PGR-target genes in PCOS-like rats with implantation. Additionally, we documented how metformin contributes to the regulation of the PGR-associated MAPK/ERK/p38 signaling pathway in the PCOS-like rat uterus. Our data provide novel insights into how metformin therapy regulates uterine P4 signaling molecules under PCOS conditions. © 2018 Society for Endocrinology.

  4. Real-time energy resources scheduling considering short-term and very short-term wind forecast

    Energy Technology Data Exchange (ETDEWEB)

    Silva, Marco; Sousa, Tiago; Morais, Hugo; Vale, Zita [Polytechnic of Porto (Portugal). GECAD - Knowledge Engineering and Decision Support Research Center

    2012-07-01

    This paper proposes an energy resources management methodology based on three distinct time horizons: day-ahead scheduling, hour-ahead scheduling, and real-time scheduling. In each scheduling process the update of generation and consumption operation and of the storage and electric vehicles storage status are used. Besides the new operation conditions, the most accurate forecast values of wind generation and of consumption using results of short-term and very short-term methods are used. A case study considering a distribution network with intensive use of distributed generation and electric vehicles is presented. (orig.)

  5. Metformin as a prophylactic treatment of gestational diabetes in pregnant patients with pregestational insulin resistance: A randomized study.

    Science.gov (United States)

    Valdés, Enrique; Sepúlveda-Martínez, Alvaro; Candia, Paula; Abusada, Nancy; Orellana, Rodrigo; Manukian, Bárbara; Cuellar, Eduardo

    2018-01-01

    We aimed to assess the use of metformin (MTF) in the prevention of gestational diabetes mellitus (GDM) in patients with pregestational insulin resistance (PIR). A double blind, multicenter, randomized trial was carried out in patients with a history of PIR and pregestational MTF treatment. Groups were allocated either to MTF 1700 mg/day or placebo. Patients were recruited between 12 +0 and 15 +6  gestational weeks, and treatment was extended until week 36. A multiple logistic regression analysis was applied to determine the relation between the use of metformin and the development of GDM. One hundred and forty one patients were randomized (68 patients in the MTF group and 73 in the placebo group). A total of 30 patients withdrew from the study during follow-up. Administration of MTF was not associated with a decrease in the incidence of GDM as compared to placebo (37.5% vs 25.4%, respectively; P = 0.2). Moreover, MTF administration was associated with a significant increase in drug intolerance as compared to placebo (14.3% vs 1.8%, respectively; P = 0.02). The use of MTF is not effective in prevention of GDM in populations with PIR. The use of MTF shows a significantly higher frequency of drug intolerance than placebo. © 2017 Japan Society of Obstetrics and Gynecology.

  6. [Insulin-sensitizing agents: metformin and thiazolidinedione derivatives].

    Science.gov (United States)

    Satoh, Jo

    2003-07-01

    Both metformin and thiazolidinedione derivatives(TZDs) improve insulin resistance, a major pathogenesis of type 2 diabetes, and decrease blood glucose levels without stimulating insulin secretion. Metformin inhibits glucose output from the liver, while TZDs increase glucose utilization in the peripheral tissues. In addition, there has been indicated that these agents ameliorate metabolic syndrome beyond glucose-level lowering. Molecular targets of these agents have recently been revealed; AMP-activated protein kinase (AMPK) for metformin and adiponectin, while PPAR gamma for TZDs which induce gene expression of adipocyte glycerol kinase and adiponectin. Insulin-sensitizing agents are clinically useful for obese diabetic patients with insulin resistance. However, periodical examinations are necessary to avoid serious adverse effects such as lactic acidosis, although rare, by metformin and liver injury by TZDs.

  7. Metformin: A Review of Characteristics, Properties, Analytical Methods and Impact in the Green Chemistry.

    Science.gov (United States)

    da Trindade, Mariana Teixeira; Kogawa, Ana Carolina; Salgado, Hérida Regina Nunes

    2018-01-02

    Diabetes mellitus (DM) is considered a public health problem. The initial treatment consists of improving the lifestyle and making changes in the diet. When these changes are not enough, the use of medication becomes necessary. The metformin aims to reduce the hepatic production of glucose and is the preferred treatment for type 2. The objective is to survey the characteristics and properties of metformin, as well as hold a discussion on the existing analytical methods to green chemistry and their impacts for both the operator and the environment. For the survey, data searches were conducted by scientific papers in the literature as well as in official compendium. The characteristics and properties are shown, also, methods using liquid chromatography techniques, titration, absorption spectrophotometry in the ultraviolet and the infrared region. Most of the methods presented are not green chemistry oriented. It is necessary the awareness of everyone involved in the optimization of the methods applied through the implementation of green chemistry to determine the metformin.

  8. Polycystic ovary syndrome and metformin in pregnancy

    DEFF Research Database (Denmark)

    Lilja, Anna E; Mathiesen, Elisabeth R

    2006-01-01

    UNLABELLED: The diagnostic criteria of polycystic ovary syndrome incorporate hyperandrogenism, polycystic ovaries, anovulation and irregular menstrual bleeding and the syndrome is a recognized reason behind infertility. The biguanide metformin has encouraging effects on several metabolic aspects...... of the syndrome, including insulin sensitivity, plasma glucose concentration and lipid profile. Moreover, metformin improves the ovarian function in women diagnosed with polycystic ovary syndrome. Hence, metformin is considered an agent for ovulation induction among these patients. However, even higher ovulation...

  9. Evaluation of fixed dose combination of glimepiride and metformin in patients with type 2 diabetes. Results of Russian observational study

    Directory of Open Access Journals (Sweden)

    Natalya Vladislavovna Zaytseva

    2015-04-01

    Full Text Available Aim. To investigate the efficacy and safety of combined glimepiride and metformin therapy in patients with type 2 diabetes mellitus (T2DM. Materials and methods. A multi-centre, open-label, prospective, observational study was conducted. A total of 1200 patients with T2DM inadequately controlled with metformin, glimepiride or combination of metformin + glimepiride were enrolled. Change in serum glycated haemoglobin (HbA1c, fasting plasma glucose (FPG, and postprandial blood glucose (PPG levels; weight; waist circumference and hypoglycemic episodes were evaluated. Results. Baseline HbA1c levels (8.24% ? 0.42% were significantly reduced after 12 weeks of treatment (7.48% ? 0.48% and at the end of the study. (6.88% ? 0.56%. Target HbA1c levels (?7% were achieved in 65.1% of patients at the final visit at 24 weeks. FPG and PPG levels decreased by 1.45 ? 1.14 mmol/l and 2.17 ? 1.27 mmol/l respectively (p < 0.001. No severe hypoglycemic events were reported. Body mass index reduced by 0.85 ? 1.28 kg/m2 (p < 0.001. Conclusion. . Combined glimepiride and metformin therapy significantly improved long-term glycemic control in patients with T2DM during the period of 24 weeks. without additional risk of hypoglycemic events or weight gain.

  10. Evaluation of fixed dose combination of glimepiride and metformin in patients with type 2 diabetes. Results of Russian observational study

    Directory of Open Access Journals (Sweden)

    Natalya Vladislavovna Zaytseva

    2015-04-01

    Full Text Available Aim.To investigate the efficacy and safety of combined glimepiride and metformin therapy in patients with type 2 diabetes mellitus (T2DM.Materials and methods.A multi-centre, open-label, prospective, observational study was conducted. A total of 1200 patients with T2DM inadequately controlled with metformin, glimepiride or combination of metformin + glimepiride were enrolled. Change in serum glycated haemoglobin (HbA1c, fasting plasma glucose (FPG, and postprandial blood glucose (PPG levels; weight; waist circumference and hypoglycemic episodes were evaluated.Results.Baseline HbA1c levels (8.24% ± 0.42% were significantly reduced after 12 weeks of treatment (7.48% ± 0.48% and at the end of the study(6.88% ± 0.56%. Target HbA1c levels (≤7% were achieved in 65.1% of patients at the final visit at 24 weeks. FPG and PPG levels decreased by 1.45 ± 1.14 mmol/l and 2.17 ± 1.27 mmol/l respectively (p < 0.001. No severe hypoglycemic events were reported. Body mass index reduced by 0.85 ± 1.28 kg/m2 (p < 0.001.Conclusion. Combined glimepiride and metformin therapy significantly improved long-term glycemic control in patients with T2DM during the period of 24 weeks without additional risk of hypoglycemic events or weight gain.

  11. The Mind and Brain of Short-Term Memory

    OpenAIRE

    Jonides, John; Lewis, Richard L.; Nee, Derek Evan; Lustig, Cindy A.; Berman, Marc G.; Moore, Katherine Sledge

    2008-01-01

    The past 10 years have brought near-revolutionary changes in psychological theories about short-term memory, with similarly great advances in the neurosciences. Here, we critically examine the major psychological theories (the “mind”) of short-term memory and how they relate to evidence about underlying brain mechanisms. We focus on three features that must be addressed by any satisfactory theory of short-term memory. First, we examine the evidence for the architecture of short-term memory, w...

  12. [Treatment with metformin in type 2 diabetes mellitus - new routines when renal function is reduced and in connection with administration of iodine contrast media].

    Science.gov (United States)

    Sterner, Gunnar; Frid, Anders

    2018-04-03

    Metformin is eliminated through glomerular filtration and tubular secretion in the kidneys. New guidelines recommend use of metformin down to a GFR of 30 mL/min under the condition that the dose is adjusted. As the risk of inducing lactic acidosis is very low in connection with administration of iodine contrast media, new recommendations in Sweden say that metformin must be stopped only when GFR is below 45 mL/min. Determination of metformin levels in serum is useful to guide therapeutic dose when GFR is low but also to confirm that lactic acidosis is caused by metformin.

  13. Very-long-term and short-term chromatic adaptation: are their influences cumulative?

    Science.gov (United States)

    Belmore, Suzanne C; Shevell, Steven K

    2011-02-09

    Very-long-term (VLT) chromatic adaptation results from exposure to an altered chromatic environment for days or weeks. Color shifts from VLT adaptation are observed hours or days after leaving the altered environment. Short-term chromatic adaptation, on the other hand, results from exposure for a few minutes or less, with color shifts measured within seconds or a few minutes after the adapting light is extinguished; recovery to the pre-adapted state is complete in less than an hour. Here, both types of adaptation were combined. All adaptation was to reddish-appearing long-wavelength light. Shifts in unique yellow were measured following adaptation. Previous studies demonstrate shifts in unique yellow due to VLT chromatic adaptation, but shifts from short-term chromatic adaptation to comparable adapting light can be far greater than from VLT adaptation. The question considered here is whether the color shifts from VLT adaptation are cumulative with large shifts from short-term adaptation or, alternatively, does simultaneous short-term adaptation eliminate color shifts caused by VLT adaptation. The results show the color shifts from VLT and short-term adaptation together are cumulative, which indicates that both short-term and very-long-term chromatic adaptation affect color perception during natural viewing. Copyright © 2010 Elsevier Ltd. All rights reserved.

  14. Effects of vildagliptin relative to sulfonylureas in Muslim patients with type 2 diabetes fasting during Ramadan: influence of age and treatment with/without metformin in the VIRTUE study

    Directory of Open Access Journals (Sweden)

    Hassoun AAK

    2016-07-01

    Full Text Available Ahmed AK Hassoun,1 Md Faruque Pathan,2 Rita C Medlej,3,4 Monira Alarouj,5 Inass Shaltout,6 Manoj S Chawla,7 Ditte Knap,8 Julius A Vaz9 1Dubai Diabetes Centre, Dubai, UAE; 2Department of Endocrinology, BIRDEM Hospital, Dhaka, Bangladesh; 3Department of Endocrinology, Hotel Dieu de France Hospital, 4Chronic Care Centre, Saint Joseph University, Beirut, Lebanon; 5Dasman Diabetes Institute, Dasman, Kuwait; 6Faculty of Medicine, Cairo University, Cairo, Egypt; 7Lina Diabetes Care Centre, Mumbai, India; 8Novartis Pharma AG, Basel, Switzerland; 9Novartis Healthcare Private Limited, Hyderabad, India Background: VIRTUE was a prospective, observational study assessing the effectiveness and safety of vildagliptin vs sulfonylureas (SUs (both as monotherapy and in combination with metformin in patients with type 2 diabetes mellitus who fasted during Ramadan. A post hoc analysis was carried out to assess the effect of treatment with/without metformin and age (<65 years or ≥65 years. Patients and methods: Patients were recruited from the Middle East and Asia. The primary end point was proportion of patients with one or more hypoglycemic event (HE during Ramadan. Secondary end points included change from baseline in glycated hemoglobin (HbA1c, body weight, and safety. Results: Overall, 684 patients received vildagliptin and 631 received SUs. Most patients received dual therapy with metformin (n=1,148 and were aged <65 years (n=1,189. A few patients experienced one or more HE with vildagliptin vs SU monotherapy (6.5% vs 14.5% and with vildagliptin + metformin vs SUs + metformin (5.3% vs 20.6%; the latter achieved statistical significance (P<0.001 in both age subgroups (<65 years: 5.5% vs 18.4%, P<0.001; ≥65 years: 2.8% vs 30.9%, P<0.001. Vildagliptin was associated with numerically greater HbA1c and body weight reductions vs SUs, regardless of the therapy type or age. A higher proportion of SU- vs vildagliptin-treated patients experienced adverse events

  15. Case series: Two cases of eyeball tattoos with short-term complications.

    Science.gov (United States)

    Duarte, Gonzalo; Cheja, Rashel; Pachón, Diana; Ramírez, Carolina; Arellanes, Lourdes

    2017-04-01

    To report two cases of eyeball tattoos with short-term post procedural complications. Case 1 is a 26-year-old Mexican man that developed orbital cellulitis and posterior scleritis 2 h after an eyeball tattoo. Patient responded satisfactorily to systemic antibiotic and corticosteroid treatment. Case 2 is a 17-year-old Mexican man that developed two sub-episcleral nodules in the ink injection sites immediately after the procedure. Eyeball tattoos are performed by non-ophthalmic trained personnel. There are a substantial number of short-term risks associated with this procedure. Long-term effects on the eyes and vision are still unknown, but in a worst case scenario could include loss of vision or permanent damage to the eyes.

  16. Beneficial effects of metformin on energy metabolism and visceral fat volume through a possible mechanism of fatty acid oxidation in human subjects and rats.

    Directory of Open Access Journals (Sweden)

    Ichiro Tokubuchi

    Full Text Available Metformin is known to have a beneficial effect on body weight and body composition, although the precise mechanism has not been elucidated yet. The aim of this study is to investigate the effects of metformin on energy metabolism and anthropometric factors in both human subjects and rats.In human studies, metformin (1500mg/day was administered to 23 healthy subjects and 18 patients with type 2 diabetes for 2 weeks. Metabolic parameters and energy metabolism were measured during a meal tolerance test in the morning before and after the treatment of metformin. In animal studies, 13 weeks old SD rats were fed 25-26 g of standard chow only during 12-hours dark phase with either treated by metformin (2.5mg/ml in drinking water or not for 2 weeks, and metabolic parameters, anthropometric factors and energy metabolism together with expressions related to fat oxidation and adaptive thermogenesis were measured either in fasting or post-prandial state at 15 weeks old.Post-prandial plasma lactate concentration was significantly increased after the metformin treatment in both healthy subjects and diabetic patients. Although energy expenditure (EE did not change, baseline respiratory quotient (RQ was significantly decreased and post-prandial RQ was significantly increased vice versa following the metformin treatment in both groups. By the administration of metformin to SD rats for 2 weeks, plasma levels of lactate and pyruvate were significantly increased in both fasting and post-prandial states. RQ during a fasting state was significantly decreased in metformin-treated rats compared to controls with no effect on EE. Metformin treatment brought about a significant reduction of visceral fat mass compared to controls accompanied by an up-regulation of fat oxidation-related enzyme in the liver, UCP-1 in the brown adipose tissue and UCP-3 in the skeletal muscle.From the results obtained, beneficial effects of metformin on visceral fat reduction has been

  17. Bioequivalence and food effect assessment for vildagliptin/metformin fixed-dose combination tablets relative to free combination of vildagliptin and metformin in Japanese healthy subjects.

    Science.gov (United States)

    Mita, Sachiko; Chitnis, Shripad D; Kulmatycki, Kenneth; Salunke, Atish; He, Yan-Ling; Zhou, Wei; Suzuki, Hikoe

    2016-04-01

    To assess the bioequivalence of vildagliptin/metformin fixeddose combination (FDC) tablets (50/250 mg and 50/500 mg) to free combinations of vildagliptin and metformin and the effect of food on the pharmacokinetics (PK) of vildagliptin and metformin following administration of 50/500 mg FDC tablets. Two openlabel, randomized, single-center, singledose, 2-period crossover studies were conducted in Japanese healthy male volunteers. Participants were administered vildagliptin/ metformin FDC tablets (study I: 50/250 mg, study II: 50/500 mg) or their free combinations under fasted condition. Food effect (standard Japanese breakfast: fat, 20 - 30% with ~ 600 kcal in total) was assessed during an additional period in study II (50/500 mg). PK parameters (AUC, C(max), t(max), t(1/2)) were calculated for vildagliptin and metformin. In both studies, vildagliptin/metformin FDC tablets were bioequivalent to their respective free combinations. Administration of FDC tablets after meals had no effect on vildagliptin PK parameters. The rate of absorption of metformin decreased when administered under fed condition, as reflected by a prolonged t(max) (3 hours in fasted state vs. 4 hours in fed state) and decrease in C(max) by 26%, however, the extent of absorption (AUC(last)) was similar to that in the fasted state. Vildagliptin/metformin FDC tablets were bioequivalent to their free combinations. Food decreased the C(max) of metformin by 26%, while AUC(last) was unchanged, consistent with previous reports. No food effect was observed on the C(max) or AUC(last) of vildagliptin. Thus, food had no clinically relevant effects on the PK of metformin or vildagliptin.

  18. Effect of metformin on plasma metabolite profile in the Copenhagen Insulin and Metformin Therapy (CIMT) trial

    DEFF Research Database (Denmark)

    Safai, N; Suvitaival, T; A, Ali

    2018-01-01

    of the Copenhagen Insulin and Metformin Therapy (CMIT) trial, a multicentre study from May 2008 to December 2012, was carried out. We used a non-target method to analyse 87 plasma metabolites in participants with Type 2 diabetes (n = 370) who were randomized in a 1 : 1 ratio to 18 months of metformin or placebo...

  19. Metformin utilisation in Australian community and aged care settings.

    Science.gov (United States)

    Huang, Weiyi; Peterson, Gregory M; Zaidi, Syed Tabish R; Castelino, Ronald L

    2015-05-01

    The objective of this study was to: (i) evaluate the potentially inappropriate prescribing (PIP; defined as the use of metformin in the presence of contraindications and/or use in excessive dosage based on the renal function) of metformin in people receiving medication reviews in Australia and (ii) identify the predictors for PIP of metformin. Retrospective study of patients taking metformin through a large medication review database, containing records between January 2010 and June 2012. Data, including demographics, medical conditions, medications and relevant pathology results, were extracted for analysis. Multivariate logistic regression analysis was used to detect risk factors for PIP of metformin. Medication reviews pertaining to 6386 patients who received Home Medicines Reviews (HMRs, n=5327) or Residential Medication Management Reviews (RMMRs, n=1059) were included in this study. Overall, there were 12.9% (n=685) of patients in the HMR group and 17.4% (n=184) of patients in the RMMR group who had PIP of metformin. Multivariate logistic regression showed age, gender and type of medication review service as the significant (pmetformin. Metformin was often used in patients with contraindications, or in higher than recommended dosages in patients with renal impairment. Given the recent debate in the literature about the role of metformin in the presence of contraindications, a detailed prospective study in patients with contraindications and its association with lactic acidosis is warranted to establish the way in which metformin is to be used in these patients. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  20. Effect of metformin on maternal and fetal outcomes in obese pregnant women (EMPOWaR): a randomised, double-blind, placebo-controlled trial.

    Science.gov (United States)

    Chiswick, Carolyn; Reynolds, Rebecca M; Denison, Fiona; Drake, Amanda J; Forbes, Shareen; Newby, David E; Walker, Brian R; Quenby, Siobhan; Wray, Susan; Weeks, Andrew; Lashen, Hany; Rodriguez, Aryelly; Murray, Gordon; Whyte, Sonia; Norman, Jane E

    2015-10-01

    Maternal obesity is associated with increased birthweight, and obesity and premature mortality in adult offspring. The mechanism by which maternal obesity leads to these outcomes is not well understood, but maternal hyperglycaemia and insulin resistance are both implicated. We aimed to establish whether the insulin sensitising drug metformin improves maternal and fetal outcomes in obese pregnant women without diabetes. We did this randomised, double-blind, placebo-controlled trial in antenatal clinics at 15 National Health Service hospitals in the UK. Pregnant women (aged ≥16 years) between 12 and 16 weeks' gestation who had a BMI of 30 kg/m(2) or more and normal glucose tolerance were randomly assigned (1:1), via a web-based computer-generated block randomisation procedure (block size of two to four), to receive oral metformin 500 mg (increasing to a maximum of 2500 mg) or matched placebo daily from between 12 and 16 weeks' gestation until delivery of the baby. Randomisation was stratified by study site and BMI band (30-39 vs ≥40 kg/m(2)). Participants, caregivers, and study personnel were masked to treatment assignment. The primary outcome was Z score corresponding to the gestational age, parity, and sex-standardised birthweight percentile of liveborn babies delivered at 24 weeks or more of gestation. We did analysis by modified intention to treat. This trial is registered, ISRCTN number 51279843. Between Feb 3, 2011, and Jan 16, 2014, inclusive, we randomly assigned 449 women to either placebo (n=223) or metformin (n=226), of whom 434 (97%) were included in the final modified intention-to-treat analysis. Mean birthweight at delivery was 3463 g (SD 660) in the placebo group and 3462 g (548) in the metformin group. The estimated effect size of metformin on the primary outcome was non-significant (adjusted mean difference -0·029, 95% CI -0·217 to 0·158; p=0·7597). The difference in the number of women reporting the combined adverse outcome of miscarriage