Effect of systemic insulin treatment on diabetic wound healing.

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Vatankhah, Nasibeh; Jahangiri, Younes; Landry, Gregory J; Moneta, Gregory L; Azarbal, Amir F

2017-04-01

This study investigates if different diabetic treatment regimens affect diabetic foot ulcer healing. From January 2013 to December 2014, 107 diabetic foot ulcers in 85 patients were followed until wound healing, amputation or development of a nonhealing ulcer at the last follow-up visit. Demographic data, diabetic treatment regimens, presence of peripheral vascular disease, wound characteristics, and outcome were collected. Nonhealing wound was defined as major or minor amputation or those who did not have complete healing until the last observation. Median age was 60.0 years (range: 31.1-90.1 years) and 58 cases (68.2%) were males. Twenty-four cases reached a complete healing (healing rate: 22.4%). The median follow-up period in subjects with classified as having chronic wounds was 6.0 months (range: 0.7-21.8 months). Insulin treatment was a part of diabetes management in 52 (61.2%) cases. Insulin therapy significantly increased the wound healing rate (30.3% [20/66 ulcers] vs. 9.8% [4/41 ulcers]) (p = 0.013). In multivariate random-effect logistic regression model, adjusting for age, gender, smoking status, type of diabetes, hypertension, chronic kidney disease, peripheral arterial disease, oral hypoglycemic use, wound infection, involved side, presence of Charcot's deformity, gangrene, osteomyelitis on x-ray, and serum hemoglobin A1C levels, insulin treatment was associated with a higher chance of complete healing (beta ± SE: 15.2 ± 6.1, p = 0.013). Systemic insulin treatment can improve wound healing in diabetic ulcers after adjusting for multiple confounding covariates. © 2017 by the Wound Healing Society.

Relative effectiveness of insulin pump treatment over multiple daily injections and structured education during flexible intensive insulin treatment for type 1 diabetes: cluster randomised trial (REPOSE).

Science.gov (United States)

2017-03-30

Objective  To compare the effectiveness of insulin pumps with multiple daily injections for adults with type 1 diabetes, with both groups receiving equivalent training in flexible insulin treatment. Design  Pragmatic, multicentre, open label, parallel group, cluster randomised controlled trial (Relative Effectiveness of Pumps Over MDI and Structured Education (REPOSE) trial). Setting  Eight secondary care centres in England and Scotland. Participants  Adults with type 1 diabetes who were willing to undertake intensive insulin treatment, with no preference for pumps or multiple daily injections. Participants were allocated a place on established group training courses that taught flexible intensive insulin treatment ("dose adjustment for normal eating," DAFNE). The course groups (the clusters) were then randomly allocated in pairs to either pump or multiple daily injections. Interventions  Participants attended training in flexible insulin treatment (using insulin analogues) structured around the use of pump or injections, followed for two years. Main outcome measures  The primary outcomes were a change in glycated haemoglobin (HbA1c) values (%) at two years in participants with baseline HbA1c value of ≥7.5% (58 mmol/mol), and the proportion of participants achieving an HbA1c value of intention to treat analysis, of which 235 (119 pump and 116 injection) had baseline HbA1c values of ≥7.5%. Glycaemic control and rates of severe hypoglycaemia improved in both groups. The mean change in HbA1c at two years was -0.85% with pump treatment and -0.42% with multiple daily injections. Adjusting for course, centre, age, sex, and accounting for missing values, the difference was -0.24% (-2.7 mmol/mol) in favour of pump users (95% confidence interval -0.53 to 0.05, P=0.10). Most psychosocial measures showed no difference, but pump users showed greater improvement in treatment satisfaction and some quality of life domains (dietary freedom and daily hassle) at 12 and 24

Review of biphasic insulin aspart in the treatment of type 1 and 2 diabetes

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Nazia Raja-Khan

2008-01-01

Full Text Available Nazia Raja-Khan, Sarah S Warehime, Robert A GabbayDivision of Endocrinology, Diabetes, and Metabolism, Penn State Institute for Diabetes and Obesity, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USABackground: Insulin is an effective treatment for achieving glycemic control and preventing complications in patients with diabetes. In order to make insulin therapy more acceptable to patients, newer formulations of insulin have been developed, such as biphasic insulins. Biphasic insulins conveniently provide both prandial and basal insulin in a single injection. One of the most well-studied biphasic insulins is biphasic insulin aspart 70/30.Objective: Our goal was to review the current literature on the safety and efficacy of biphasic insulin aspart in type 1 and type 2 diabetes.Methods: A MEDLINE search was conducted using the terms “biphasic insulin aspart” to identify clinical studies and reviews.Results: Biphasic insulin aspart more effectively reduces post-prandial glucose compared to other biphasic insulins and basal insulins. Compared to biphasic insulin aspart, fasting glucose levels are lower with NPH, similar with glargine, and similar or lower with biphasic human insulin. Treat-to-target trials have shown that a goal HbA1c below 6.5 or 7% can be achieved with biphasic insulin aspart. The risk of hypoglycemia is similar to or less than that seen with other biphasic insulins or NPH insulin.Conclusion: Biphasic insulin aspart 70/30 is a safe and effective treatment option for patients with diabetes.Keywords: biphasic insulin aspart, insulin, diabetes

Treatment of Severe Hypertriglyceridemia with Continuous Insulin Infusion

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Yesica Rodríguez Santana

2011-01-01

Full Text Available Severe hypertriglyceridemia (SH represents a therapeutic emergency because of the possibility of developing cardiovascular events and hyperlipemic acute pancreatitis (PA. Most patients with SH suffer primary or genetic abnormality in lipid metabolism in combination with a precipitating factor such as uncontrolled diabetes mellitus, alcoholism, and drug intake. The standard treatment of hypertriglyceridemia (HTG with omega 3 fatty acids and fibrates, along with dietary changes, has no effect on an emergency situation. There are no clinical guidelines to SH, but therapy with insulin, heparin, a combination of both, plasmapheresis, or octreotide have been tested succesfully. We report the case of a 10-year-old girl with clinical acute pancreatitis and diabetic ketoacidosis debut, along with incidental finding of an SH, who had a good outcome after treatment with insulin intravenous infusion.

Insulin Initiation in Insulin-Naïve Korean Type 2 Diabetic Patients Inadequately Controlled on Oral Antidiabetic Drugs in Real-World Practice: The Modality of Insulin Treatment Evaluation Study

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Sang Soo Kim

2015-12-01

Full Text Available BackgroundThe Modality of Insulin Treatment Evaluation (MOTIV study was performed to provide real-world data concerning insulin initiation in Korean type 2 diabetes mellitus (T2DM patients with inadequate glycemic control with oral hypoglycemic agents (OHAs.MethodsThis multicenter, non-interventional, prospective, observational study enrolled T2DM patients with inadequate glycemic control (glycosylated hemoglobin [HbA1c] ≥7.0% who had been on OHAs for ≥3 months and were already decided to introduce basal insulin by their physician prior to the start of the study. All treatment decisions were at the physician's discretion to reflect real-world practice.ResultsA total of 9,196 patients were enrolled, and 8,636 patients were included in the analysis (mean duration of diabetes, 8.9 years; mean HbA1c, 9.2%. Basal insulin plus one OHA was the most frequently (51.0% used regimen. After 6 months of basal insulin treatment, HbA1c decreased to 7.4% and 44.5% of patients reached HbA1c <7%. Body weight increased from 65.2 kg to 65.5 kg, which was not significant. Meanwhile, there was significant increase in the mean daily insulin dose from 16.9 IU at baseline to 24.5 IU at month 6 (P<0.001. Overall, 17.6% of patients experienced at least one hypoglycemic event.ConclusionIn a real-world setting, the initiation of basal insulin is an effective and well-tolerated treatment option in Korean patients with T2DM who are failing to meet targets with OHA therapy.

Benchmarking Insulin Treatment Persistence Among Patients with Type 2 Diabetes Across Different U.S. Payer Segments.

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Wei, Wenhui; Jiang, Jenny; Lou, Youbei; Ganguli, Sohini; Matusik, Mark S

2017-03-01

Treatment persistence with basal insulins is crucial to achieving sustained glycemic control, which is associated with a reduced risk of microvascular disease and other complications of type 2 diabetes (T2D). However, studies suggest that persistence with basal insulin treatment is often poor. To measure and benchmark real-world basal insulin treatment persistence among patients with T2D across different payer segments in the United States. This was a retrospective observational study of data from a national pharmacy database (Walgreen Co., Deerfield, IL). The analysis included patients with T2D aged ≥ 18 years who filled ≥ 1 prescription for basal insulins between January 2013 and June 2013 (the index prescription) and who had also filled prescriptions for ≥ 1 oral antidiabetes drug in the database. Patients with claims for premixed insulin were excluded. Treatment persistence was defined as remaining on the study medication(s) during the 1-year follow-up period. Patients were stratified according to treatment history (existing basal insulin users vs. new insulin users), payer segments (commercially insured, Medicare, Medicaid, or cash-pay), type of basal insulin (insulin glargine, insulin detemir, or neutral protamine Hagedorn insulin [NPH]), and device for insulin administration (pen or vial/syringe). A total of 274,102 patients were included in this analysis, 82% of whom were existing insulin users. In terms of payer segments, 45.3% of patients were commercially insured, 47.8% had Medicare, 5.9% had Medicaid, and 1.1% were cash-pay. At the 1-year follow-up, basal insulin treatment persistence rate was 66.8% overall, 61.7% for new users, and 67.9% for existing users. In general, for both existing and new basal insulin users, higher persistence rate and duration were associated with Medicare versus cash-pay patients, use of insulin pens versus vial/syringe, and use of insulin glargine versus NPH. This large-scale study provides a benchmark of basal insulin

Plasma testosterone and androstenedione in insulin dependent patients at time of diagnosis and during the first year of insulin treatment

DEFF Research Database (Denmark)

Gluud, C; Madsbad, S; Krarup, T

1982-01-01

Ten male patients and 6 female patients with newly diagnosed insulin dependent diabetes mellitus and significant ketosis were studied before and during the first year of insulin treatment. At onset plasma concentrations of testosterone and androstenedione were significantly (P less than 0...

Pertussis toxin treatment attenuates some effects of insulin in BC3H-1 murine myocytes

International Nuclear Information System (INIS)

Luttrell, L.M.; Hewlett, E.L.; Romero, G.; Rogol, A.D.

1988-01-01

The effects of pertussis toxin (PT) treatment on insulin-stimulated myristoyl-diacylglycerol (DAG) generation, hexose transport, and thymidine incorporation were studied in differentiated BC3H-1 mycocytes. Insulin treatment caused a biphasic increase in myristoyl-DAG production which was abolished in myocytes treated with PT. There was no effect of PT treatment on basal (nonstimulated) myristoyl-DAG production. Insulin-stimulated hydrolysis of a membrane phosphatidylinositol glycan was blocked by PT treatment. ADP-ribosylation of BC3H-1 plasma membranes with [ 32 P]NAD revealed a 40-kDa protein as the major PT substrate in vivo and in vitro. The time course and dose dependence of the effects of PT on diacylglycerol generation correlated with the in vivo ADP-ribosylation of the 40-kDa substrate. Pertussis toxin treatment resulted in a 71% attenuation of insulin-stimulated hexose uptake without effect on either basal or phorbol ester-stimulated uptake. The stimulatory effects of insulin and fetal calf serum on [ 3 H]thymidine incorporation into quiescent myocytes were attenuated by 61 and 59%, respectively, when PT was added coincidently with the growth factors. Nonstimulated and EGF-stimulated [ 3 H]thymidine incorporation was unaffected by PT treatment. These data suggest that a PT-sensitive G protein is involved in the cellular signaling mechanisms of insulin

One week treatment with the IL-1 receptor antagonist anakinra leads to a sustained improvement in insulin sensitivity in insulin resistant patients with type 1 diabetes mellitus.

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van Asseldonk, Edwin J P; van Poppel, Pleun C M; Ballak, Dov B; Stienstra, Rinke; Netea, Mihai G; Tack, Cees J

2015-10-01

Inflammation associated with obesity is involved in the development of insulin resistance. We hypothesized that anti-inflammatory treatment with the Interleukin-1 receptor antagonist anakinra would improve insulin sensitivity. In an open label proof-of-concept study, we included overweight patients diagnosed with type 1 diabetes with an HbA1c level over 7.5%. Selecting insulin resistant patients with longstanding type 1 diabetes allowed us to study the effects of anakinra on insulin sensitivity. Patients were treated with 100mg anakinra daily for one week. Insulin sensitivity, insulin need and blood glucose profiles were measured before, after one week and after four weeks of follow-up. Fourteen patients completed the study. One week of anakinra treatment led to an improvement of insulin sensitivity, an effect that was sustained for four weeks. Similarly, glucose profiles, HbA1c levels and insulin needs improved. In conclusion, one week of treatment with anakinra improves insulin sensitivity in patients with type 1 diabetes. Copyright © 2015 Elsevier Inc. All rights reserved.

Continuous intraperitoneal insulin infusion in the treatment of type 1 diabetes mellitus: Glycaemia and beyond

OpenAIRE

van Dijk, Peter R.

2015-01-01

Continuous intraperitoneal insulin infusion (CIPII) with an implantable pump is a last-resort treatment option for selected patients with type 1 diabetes mellitus (T1DM). As compared to the most commonly used forms of insulin administration -injections and an externally placed pump- which deliver insulin in the subcutaneous (SC) tissue, CIPII delivers the insulin in the intraperitoneal space. CIPII using an implantable pump is an unique treatment which has been available for more than 30 year...

[Satisfaction of patients with type 2 diabetes mellitus after starting treatment with insulin].

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Mancera-Romero, J; Carramiñana-Barrera, F; Muñoz-González, L; Guillén-Álvarez, P; Murillo-García, D; Sánchez-Pérez, M R

2016-01-01

The objective of this study is to evaluate if overcoming the barrier of starting treatment with insulin can lead to better clinical control and a higher level of patient satisfaction with their treatment. This is an observational, multicentre study of patients diagnosed with DM2 who attended primary care centres with poor glycaemic control (A1c≥8%) under treatment with oral antidiabetic drugs (OADs), and who were given motivational treatment to overcome their fear of injections, and started treatment with insulin. The level of satisfaction with the treatment was evaluated using the Diabetes Treatment Satisfaction Questionnaire (DTSQ). The questionnaire was used before initiating the treatment with insulin and in the follow-up visit (3-4 months from the beginning of treatment with basal insulin). A total of 573 patients with a mean age of 64±10 years were recruited. The overall mean score from the DTSQs satisfaction questionnaire was 18.3±6.3, and the change of treatment led to an improvement in patient satisfaction compared to the previous treatment (DTSQc mean score 8.8±5.9). A1c dropped from an initial value of 8.7% (SD 0.8) to 7.5% (SD 0.7) (P<.001). The frequency of hyperglycaemic episodes perceived by the patients was significantly lower after they overcame their fear of injections (35.6% compared to 11.5%; P<.001), but no statistically significant differences were found in the frequency of hypoglycaemic episodes (32% compared to 35%; P=.059). In patients with DM2 poorly controlled with OADs, overcoming a fear of injections and starting treatment with insulin was associated with an overall improvement in satisfaction with the new treatment, and decreased the perception of hyperglycaemic episodes. Glycaemic control and the metabolic profile of the patients also improved to a statistically significant degree with the change of treatment. Copyright © 2015 Sociedad Española de Médicos de Atención Primaria (SEMERGEN). Publicado por Elsevier España, S

Acupuncture treatment for insulin sensitivity of women with polycystic ovary syndrome and insulin resistance: a study protocol for a randomized controlled trial.

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Li, Juan; Ng, Ernest Hung Yu; Stener-Victorin, Elisabet; Hu, Zhenxing; Shao, Xiaoguang; Wang, Haiyan; Li, Meifang; Lai, Maohua; Xie, Changcai; Su, Nianjun; Yu, Chuyi; Liu, Jia; Wu, Taixiang; Ma, Hongxia

2017-03-09

Our prospective pilot study of acupuncture affecting insulin sensitivity on polycystic ovary syndrome (PCOS) combined with insulin resistance (IR) showed that acupuncture had a significant effect on improving the insulin sensitivity of PCOS. But there is still no randomized controlled trial to determine the effect of acupuncture on the insulin sensitivity in women with PCOS and IR. In this article, we present the protocol of a randomized controlled trial to compare the effect of true acupuncture on the insulin sensitivity of these patients compared with metformin and sham acupuncture. Acupuncture may be an effective therapeutic alternative that is superior to metformin and sham acupuncture in improving the insulin sensitivity of PCOS combined with IR. This study is a multi-center, controlled, double-blind, and randomized clinical trial aiming to evaluate the effect of acupuncture on the insulin sensitivity in PCOS combined with IR. In total 342 patients diagnosed with PCOS and IR will be enrolled. Participants will be randomized to one of the three groups: (1) true acupuncture + metformin placebo; (2) sham acupuncture + metformin, and (3) sham acupuncture + metformin placebo. Participants and assessors will be blinded. The acupuncture intervention will be given 3 days per week for a total of 48 treatment sessions during 4 months. Metformin (0.5 g per pill) or placebo will be given, three times per day, and for 4 months. Primary outcome measures are changes in homeostasis model assessment of insulin resistance (HOMA-IR) and improvement rate of HOMA-IR by oral glucose tolerance test (OGTT) and insulin releasing test (Ins). Secondary outcome measures are homeostasis model assessment-β (HOMA-β), area under the curve for glucose and insulin, frequency of regular menstrual cycles and ovulation, body composition, metabolic profile, hormonal profile, questionnaires, side effect profile, and expectation and credibility of treatment. Outcome measures are

Cytochrome C is tyrosine 97 phosphorylated by neuroprotective insulin treatment.

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Thomas H Sanderson

Full Text Available Recent advancements in isolation techniques for cytochrome c (Cytc have allowed us to discover post-translational modifications of this protein. We previously identified two distinct tyrosine phosphorylated residues on Cytc in mammalian liver and heart that alter its electron transfer kinetics and the ability to induce apoptosis. Here we investigated the phosphorylation status of Cytc in ischemic brain and sought to determine if insulin-induced neuroprotection and inhibition of Cytc release was associated with phosphorylation of Cytc. Using an animal model of global brain ischemia, we found a ∼50% decrease in neuronal death in the CA1 hippocampal region with post-ischemic insulin administration. This insulin-mediated increase in neuronal survival was associated with inhibition of Cytc release at 24 hours of reperfusion. To investigate possible changes in the phosphorylation state of Cytc we first isolated the protein from ischemic pig brain and brain that was treated with insulin. Ischemic brains demonstrated no detectable tyrosine phosphorylation. In contrast Cytc isolated from brains treated with insulin showed robust phosphorylation of Cytc, and the phosphorylation site was unambiguously identified as Tyr97 by immobilized metal affinity chromatography/nano-liquid chromatography/electrospray ionization mass spectrometry. We next confirmed these results in rats by in vivo application of insulin in the absence or presence of global brain ischemia and determined that Cytc Tyr97-phosphorylation is strongly induced under both conditions but cannot be detected in untreated controls. These data suggest a mechanism whereby Cytc is targeted for phosphorylation by insulin signaling, which may prevent its release from the mitochondria and the induction of apoptosis.

Update on insulin treatment for dogs and cats: insulin dosing pens and more

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Thompson A

2015-04-01

Full Text Available Ann Thompson,1 Patty Lathan,2 Linda Fleeman3 1School of Veterinary Science, The University of Queensland, Gatton, QLD, Australia; 2College of Veterinary Medicine Mississippi State University, Starkville, MS, USA; 3Animal Diabetes Australia, Melbourne, VIC, Australia Abstract: Insulin therapy is still the primary therapy for all diabetic dogs and cats. Several insulin options are available for each species, including veterinary registered products and human insulin preparations. The insulin chosen depends on the individual patient's requirements. Intermediate-acting insulin is usually the first choice for dogs, and longer-acting insulin is the first choice for cats. Once the insulin type is chosen, the best method of insulin administration should be considered. Traditionally, insulin vials and syringes have been used, but insulin pen devices have recently entered the veterinary market. Pens have different handling requirements when compared with standard insulin vials including: storage out of the refrigerator for some insulin preparations once pen cartridges are in use; priming of the pen to ensure a full dose of insulin is administered; and holding the pen device in place for several seconds during the injection. Many different types of pen devices are available, with features such as half-unit dosing, large dials for visually impaired people, and memory that can display the last time and dose of insulin administered. Insulin pens come in both reusable and disposable options. Pens have several benefits over syringes, including improved dose accuracy, especially for low insulin doses. Keywords: diabetes, mellitus, canine, feline, NPH, glargine, porcine lente

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

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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.

Mathematical modelling approach to the treatment of insulin ...

African Journals Online (AJOL)

Medical scientists have various ways of handling cases of insulin-dependent diabetes diseases of which one of the most popularly used methods is carrying out experiments on the patient. However, each time a case is presented, the need for fresh experiment to determine the treatment procedure will arise. To therefore ...

Therapeutically interchangeable? A study of real-world outcomes associated with switching basal insulin analogues among US patients with type 2 diabetes mellitus using electronic medical records data.

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Levin, P; Wei, W; Miao, R; Ye, F; Xie, L; Baser, O; Gill, J

2015-03-01

To evaluate real-world clinical outcomes for switching basal insulin analogues [insulin glargine (GLA) and insulin detemir (DET)] among US patients with type 2 diabetes mellitus (T2DM). Using the GE Centricity Electronic Medical Records database, this retrospective study examined two cohorts: cohort 1, comprising patients previously on GLA and then either switching to DET (DET-S) or continuing with GLA (GLA-C); and cohort 2, comprising patients previously on DET and then either switching to GLA (GLA-S) or continuing with DET (DET-C). Within each cohort, treatment groups were propensity-score-matched on baseline characteristics. At 1-year follow-up, insulin treatment patterns, glycated haemoglobin (HbA1c) levels, hypoglycaemic events, weight and body mass index (BMI) were evaluated. The analysis included 13 942 patients: cohort 1: n = 10 657 (DET-S, n = 1797 matched to GLA-C, n = 8860) and cohort 2: n = 3285 (GLA-S, n = 858 matched to DET-C, n = 2427). Baseline characteristics were similar between the treatment groups in each cohort. At 1-year follow-up, in cohort 1, patients in the DET-S subgroup were significantly less persistent with treatment, more likely to use a rapid-acting insulin analogue, had higher HbA1c values, lower HbA1c reductions and lower proportions of patients achieving HbA1c Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

The effect of mutations on the structure of insulin fibrils studied by Fourier transform infrared (FTIR) spectroscopy and electron microscopy.

Science.gov (United States)

Garriques, Liza Nielsen; Frokjaer, Sven; Carpenter, John F; Brange, Jens

2002-12-01

Fibril formation (aggregation) of human and bovine insulin and six human insulin mutants in hydrochloric acid were investigated by visual inspection, Thioflavin T fluorescence spectroscopy, transmission electron microscopy (TEM), and Fourier transform infrared (FTIR) spectroscopy. The fibrillation tendencies of the wild-type insulins and the insulin mutants were (in order of decreasing fibrillation tendencies): Glu(B1) + Glu(B27) = bovine < human < des-(B1,B2)-insulin < Ser(B2) + Asp(B10) < Glu(A13) + Glu(B10) = Gln(B17) < Asp(B10). Transmission electron micrographs showed that the protofibrils of the mutants were similar to those of wild-type insulins and had a diameter of 5-10 nm and lengths varying from 50 nm to several microns. The fibrils of human insulin mutants exhibited varying degrees of lateral aggregation. The Asp(B10) mutant and human insulin had greater tendency to form laterally aggregated fibrils arranged in parallel bundles, whereas fibrils of the other mutants and bovine insulin were mainly arranged in helical filaments. FTIR spectroscopy showed that the native secondary structure of the wild-type insulins and the human insulin mutants in hydrochloric acid were identical, whereas the secondary structure of the fibrils formed by heating at 50 degrees C depended on the amino acid substitution. FTIR spectra of fibrils of the human insulin mutants exhibited different beta-sheet bands at 1,620-1,640 cm(-1), indicating that the beta-sheet interactions in the fibrils depended on variations in the primary structure of insulin. Copyright 2002 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 91:2473-2480, 2002

Treatment of spontaneously hypertensive rats with rosiglitazone and/or enalapril restores balance between vasodilator and vasoconstrictor actions of insulin with simultaneous improvement in hypertension and insulin resistance.

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Potenza, Maria A; Marasciulo, Flora L; Tarquinio, Mariela; Quon, Michael J; Montagnani, Monica

2006-12-01

Spontaneously hypertensive rats (SHRs) exhibit endothelial dysfunction and insulin resistance. Reciprocal relationships between endothelial dysfunction and insulin resistance may contribute to hypertension by causing imbalanced regulation of endothelial-derived vasodilators (e.g., nitric oxide) and vasoconstrictors (e.g., endothelin-1 [ET-1]). Treatment of SHRs with rosiglitazone (insulin sensitizer) and/or enalapril (ACE inhibitor) may simultaneously improve hypertension, insulin resistance, and endothelial dysfunction by rebalancing insulin-stimulated production of vasoactive mediators. When compared with WKY control rats, 12-week-old vehicle-treated SHRs were hypertensive, overweight, and insulin resistant, with elevated fasting levels of insulin and ET-1 and reduced serum adiponectin levels. In mesenteric vascular beds (MVBs) isolated from vehicle-treated SHRs and preconstricted with norepinephrine (NE) ex vivo, vasodilator responses to insulin were significantly impaired, whereas the ability of insulin to oppose vasoconstrictor actions of NE was absent (versus WKY controls). Three-week treatment of SHRs with rosiglitazone and/or enalapril significantly reduced blood pressure, insulin resistance, fasting insulin, and ET-1 levels and increased adiponectin levels to values comparable with those observed in vehicle-treated WKY controls. By restoring phosphatidylinositol 3-kinase-dependent effects, rosiglitazone and/or enalapril therapy of SHRs also significantly improved vasodilator responses to insulin in MVB preconstricted with NE ex vivo. Taken together, our data provide strong support for the existence of reciprocal relationships between endothelial dysfunction and insulin resistance that may be relevant for developing novel therapeutic strategies for the metabolic syndrome.

Combined treatment with melatonin and insulin improves glycemic control, white adipose tissue metabolism and reproductive axis of diabetic male rats.

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Oliveira, Ariclecio Cunha de; Andreotti, Sandra; Sertie, Rogério António Laurato; Campana, Amanda Baron; de Proença, André Ricardo Gomes; Vasconcelos, Renata Prado; Oliveira, Keciany Alves de; Coelho-de-Souza, Andrelina Noronha; Donato-Junior, José; Lima, Fábio Bessa

2018-04-15

Melatonin treatment has been reported to be capable of ameliorating metabolic diabetes-related abnormalities but also to cause hypogonadism in rats. We investigated whether the combined treatment with melatonin and insulin can improve insulin resistance and other metabolic disorders in rats with streptozotocin-induced diabetes during neonatal period and the repercussion of this treatment on the hypothalamic-pituitary-gonadal axis. At the fourth week of age, diabetic animals started an 8-wk treatment with only melatonin (0.2 mg/kg body weight) added to drinking water at night or associated with insulin (NHP, 1.5 U/100 g/day) or only insulin. Animals were then euthanized, and the subcutaneous (SC), epididymal (EP), and retroperitoneal (RP) fat pads were excised, weighed and processed for adipocyte isolation for morphometric analysis as well as for measuring glucose uptake, oxidation, and incorporation of glucose into lipids. Hypothalamus was collected for gene expression and blood samples were collected for biochemical assays. The treatment with melatonin plus insulin (MI) was capable of maintaining glycemic control. In epididymal (EP) and subcutaneous (SC) adipocytes, the melatonin plus insulin (MI) treatment group recovered the insulin responsiveness. In the hypothalamus, melatonin treatment alone promoted a significant reduction in kisspeptin-1, neurokinin B and androgen receptor mRNA levels, in relation to control group. Combined treatment with melatonin and insulin promoted a better glycemic control, improving insulin sensitivity in white adipose tissue (WAT). Indeed, melatonin treatment reduced hypothalamic genes related to reproductive function. Copyright © 2017. Published by Elsevier Inc.

Insulin detemir for the treatment of obese patients with type 2 diabetes

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Hollander PA

2012-01-01

Full Text Available Priscilla A Hollander1,21Baylor Endocrine Center, 2Baylor Medical Center, Dallas, Texas, USAAbstract: The risk for developing type 2 diabetes (T2DM is greater among obese individuals. Following onset of the disease, patients with T2DM become more likely to be afflicted with diabetic micro- and macrovascular complications. Decreasing body weight has been shown to lower glycosylated hemoglobin and improve other metabolic parameters in patients with T2DM. Medications used to lower blood glucose may increase body weight in patients with T2DM and this has been repeatedly shown to be the case for conventional, human insulin formulations. Insulin detemir is a neutral, soluble, long-acting insulin analog in which threonine-30 of the insulin B-chain is deleted, and the C-terminal lysine is acetylated with myristic acid, a C14 fatty acid chain. Insulin detemir binds to albumin, a property that enhances its pharmacokinetic/pharmacodynamic profile. Results from clinical trials have demonstrated that treatment with insulin detemir is associated with less weight gain than either insulin glargine or neutral protamine Hagedorn insulin. There are many potential reasons for the lower weight gain observed among patients treated with insulin detemir, including lower risk for hypoglycemia and therefore decreased defensive eating due to concern about this adverse event, along with other effects that may be related to the albumin binding of this insulin that may account for lower within-patient variability and consistent action. These might include faster transport across the blood–brain barrier, induction of satiety signaling in the brain, and preferential inhibition of hepatic glucose production versus peripheral glucose uptake. Experiments in diabetic rats have also indicated that insulin detemir increases adiponectin levels, which is associated with both weight loss and decreased eating.Keywords: basal insulin, body mass index, detemir, insulin analog, satiety

Association between insulin resistance and sustained virologic response in hepatitis C treatment, genotypes 1 versus 2 and 3: systematic literature review and meta-analysis.

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Laurito, Marcela Pezzoto; Parise, Edison Roberto

2013-01-01

Controversial results have been found in literature for the association between insulin resistance and sustained virologic response to standard chronic hepatitis C treatment. This study aims to provide a systematic literature review with meta-analysis, in order to evaluate if insulin resistance interferes with sustained virologic response in patients infected by the HCV genotype 1 versus HCV genotypes 2 and 3, undergoing treatment with interferon and ribavirin or pegylated interferon and ribavarin. Systematic search was performed on main electronic databases until May 2012. Primary outcome was sustained virologic response, defined as undetectable levels of HCV-RNA six months after the end of treatment. Meta-analytic measure was estimated using Dersimonian and Laird's method, using Stata software. Thirteen studies involving 2238 infected patients were included. There was a statistically significant association between insulin resistance and lower sustained virologic response rate, and this difference occurred in HCV genotype G1 (OR: 2.23; 95% CI: 1.59-3.13) and G2/G3 (OR: 4.45; 95% CI: 1.59-12.49). In addition, a difference was seen in the cut-offs used for defining insulin resistance by Homeostasis Model Assessment of Insulin Resistance. To minimize this limitation, sub-analysis that excluded the studies that did not use 2 as a cut-off value was performed and the results still demonstrated association between insulin resistance and sustained virologic response, for both genotypic groups. This meta-analysis provides evidence that elevated Homeostasis Model Assessment of Insulin Resistance is associated with a lower sustained virologic response rate in patients with hepatitis C treated with interferon and ribavirin or pegylated interferon and ribavarin, regardless of their genotype. Copyright © 2013 Elsevier Editora Ltda. All rights reserved.

Long-term treatment with losartan versus atenolol improves insulin sensitivity in hypertension: ICARUS, a LIFE substudy

DEFF Research Database (Denmark)

Olsen, Michael H; Fossum, Eigil; Høieggen, Aud

2005-01-01

Hypertension and insulin resistance might be associated through peripheral vascular hypertrophy/rarefaction which compromises skeletal muscle blood flow and decreases glucose uptake, inducing insulin resistance. We hypothesized that treatment with losartan as compared to atenolol would improve...... insulin sensitivity through regression of peripheral vascular hypertrophy/rarefaction....

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)

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.

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.

Treatment of severe insulin resistance in pregnancy with 500 units per milliliter of concentrated insulin.

Science.gov (United States)

Mendez-Figueroa, Hector; Maggio, Lindsay; Dahlke, Joshua D; Daley, Julie; Lopes, Vrishali V; Coustan, Donald R; Rouse, Dwight J

2013-07-01

To evaluate glycemic control and pregnancy outcomes among pregnant women with severe insulin resistance treated with 500 units/mL concentrated insulin. Retrospective analysis of gravid women with severe insulin resistance (need for greater than 100 units of insulin per injection or greater than 200 units/d) treated with either 500 units/mL concentrated insulin or conventional insulin therapy. We performed a two-part analysis: 1) between gravid women treated with and without 500 units/mL concentrated insulin; and 2) among gravid women treated with 500 units/mL concentrated insulin, comparing glycemic control before and after its initiation. Seventy-three pregnant women with severe insulin resistance were treated with 500 units/mL concentrated insulin and 78 with conventional insulin regimens. Patients treated with 500 units/mL concentrated insulin were older and more likely to have type 2 diabetes mellitus. Average body mass index was comparable between both groups (38.6 compared with 40.4, P=.11) as were obstetric and perinatal outcomes and glycemic control during the last week of gestation. Within the 500 units/mL concentrated insulin cohort, after initiation of this medication, fasting and postprandial blood glucose concentrations improved. However, the rates of blood glucose values less than 60 mg/dL and less than 50 mg/dL were higher in the 500 units/mL concentrated insulin group after initiation than before, 4.8% compared with 2.0% (Pinsulin in severely obese insulin-resistant pregnant women confers similar glycemic control compared with traditional insulin regimens but may increase the risk of hypoglycemia. II.

Insulin aspart in diabetic pregnancy

DEFF Research Database (Denmark)

Mathiesen, Elisabeth R

2008-01-01

in insulin requirements during pregnancy necessitate short-acting insulins for postprandial control of hyperglycemia. The fast-acting insulin analogue insulin aspart has been tested in a large, randomized trial of pregnant women with Type 1 diabetes and offers benefits in control of postprandial...... hyperglycemia with a tendency towards fewer episodes of severe hypoglycemia compared with human insulin. Treatment with insulin aspart was associated with a tendency toward fewer fetal losses and preterm deliveries than treatment with human insulin. Insulin aspart could not be detected in the fetal circulation...... and no increase in insulin antibodies was found. Thus, the use of insulin aspart in pregnancy is regarded safe....

Effect of thiazolidinedione treatment on resistin levels in insulin resistant sprague dawley rats

International Nuclear Information System (INIS)

Yousaf, I.; Hameed, W.; Rajput, T.A.

2015-01-01

Insulin resistance is manifested by decreased effect of fixed quantity of insulin on glucose metabolism leading to type 2 diabetes mellitus. Visceral obesity has been positively correlated with insulin resistance but its mechanism is not fully defined. Insulin resistance may be the consequence of adipocytokines including visfatin and resistin. This study was designed to see the effect of thiazolidinediones on levels of resistin in insulin resistant rats. Methods: Ninety Sprague Dawley rats were randomly divided into three groups. Group I served as control. Rats in Group II and III were made insulin resistant diabetics. Group III was treated with rosiglitazone after development of diabetes. Plasma glucose, serum triglycerides, HDL, TG:HDL ratio and serum resistin levels were analysed. Results: Body weight and plasma glucose were significantly increased (p<0.05) along with TG:HDL ratio (p<0.05) in group II and group III at the end of 4th week. Serum resistin levels also increased significantly (p<0.05) in group II and III at the end of 4th week. Treatment of group III with rosiglitazone led to improvement in insulin resistance with decrease in serum resistin levels (p<0.05). Conclusion: Increased serum resistin level indicates insulin resistance and impending hyperglycaemia. Thiazolidinediones augment sensitivity of insulin to restore normoglycaemia by decreasing serum resistin level. (author)

A NEXAFS and mass spectrometry study of cysteine, cystine and insulin irradiated with intermediate energy (0.8 keV) electrons

Energy Technology Data Exchange (ETDEWEB)

Simões, G., E-mail: simoes.grazieli@gmail.com [Instituto de Química, Universidade Federal do Rio de Janeiro, Cidade Universitária, 21941-909 Rio de Janeiro (Brazil); Rodrigues, F.N. [Instituto de Química, Universidade Federal do Rio de Janeiro, Cidade Universitária, 21941-909 Rio de Janeiro (Brazil); Instituto Federal de Educação, Ciência e Tecnologia do Rio de Janeiro, Maracanã, 20270-021 Rio de Janeiro (Brazil); Bernini, R.B. [Instituto de Química, Universidade Federal do Rio de Janeiro, Cidade Universitária, 21941-909 Rio de Janeiro (Brazil); Instituto Federal de Educação, Ciência e Tecnologia do Rio de Janeiro, Duque de Caxias, 25050-100 Rio de Janeiro (Brazil); Castro, C.S.C. [Instituto Nacional de Metrologia, Qualidade e Tecnologia – Inmetro, 25250-020 Rio de Janeiro (Brazil); Souza, G.G.B. de, E-mail: gerson@iq.ufrj.br [Instituto de Química, Universidade Federal do Rio de Janeiro, Cidade Universitária, 21941-909 Rio de Janeiro (Brazil)

2014-03-01

Highlights: • Structural modifications in sulfur containing biomolecules were investigated. • Significant modifications were observed in insulin irradiated NEXAFS spectra. • Degradation of insulin can be observed even at low temperature. • Alterations in insulin spectrum were characterized according to the state of sulfur. - Abstract: We have performed a NEXAFS (S 1s) and mass spectrometry study of solid samples of cysteine, cystine and insulin irradiated with 0.8 keV electrons. The measured mass spectra point out to processes of desulfurization, deamination, decarbonylation and decarboxylation in the irradiated biomolecules. Electron beam irradiation was also conducted at low temperatures in order to evaluate the possible contribution from thermal degradation processes. The NEXAFS spectra of irradiated cysteine and cystine did not show substantial changes when compared to the same spectra obtained using non-irradiated samples. The sulfur K-edge photoabsorption spectrum of irradiated insulin, however, showed clear modifications when compared to the spectrum of the non-irradiated protein, even when the irradiation was conducted at low temperature. Using an empirical combination of the photoabsorption spectra of cysteine and cystine (which are associated respectively with reduced and oxidized forms of sulfur) we have been able to reproduce the absorption spectrum of irradiated insulin.

Dual-hormone treatment with insulin and glucagon in patients with type 1 diabetes

DEFF Research Database (Denmark)

Reiband, H K; Schmidt, S; Ranjan, Ajenthen

2015-01-01

Intensive insulin treatment in type 1 diabetes reduces the incidence and slows the progression of microvascular and macrovascular complications; however, it is associated with an increased risk of hypoglycaemia and weight gain. In this review, we propose dual-hormone treatment with insulin...... and glucagon as a method for achieving near normalization of blood glucose levels without increasing hypoglycaemia frequency and weight gain. We briefly summarize glucagon pathophysiology in type 1 diabetes as well as the current applications of glucagon for the treatment of hypoglycaemia. Until now, the use...... of glucagon has been limited by the need for reconstitution immediately before use, because of instability of the available compounds; however, stabile compounds are soon to be launched and will render long-term intensive dual-hormone treatment in type 1 diabetes possible....

Streptozotocin Aggravated Osteopathology and Insulin Induced Osteogenesis Through Co-treatment with Fluoride.

Science.gov (United States)

Yang, Chen; Zhang, Mengmeng; Li, Yagang; Wang, Yan; Mao, Weixian; Gao, Yuan; Xu, Hui

2015-12-01

The role of insulin in the mechanism underlying the excessive fluoride that causes skeletal lesion was studied. The in vitro bone marrow stem cells (BMSC) collected from Kunming mice were exposed to varying concentrations of fluoride with or without insulin. The cell viability and early differentiation of BMSC co-treated with fluoride and insulin were measured by using cell counting kit-8 and Gomori modified calcium-cobalt method, respectively. We further investigated the in vivo effects of varying dose of fluoride on rats co-treated with streptozotocin (STZ). Wistar rats were divided into six groups which included normal control, 10 mg fluoride/kg day group, 20 mg fluoride/kg day group, STZ control, STZ+10 mg fluoride/kg day group, and STZ+20 mg fluoride/kg day group. The rats were administered with sodium fluoride (NaF) by gavage with water at doses 10 and 20 mg fluoride/kg day for 2 months. In a period of one month, half of rats in every group were treated with streptozotocin (STZ) once through intraperitoneal injection at 52 mg/kg body weight. The serum glucose, HbA1c, and insulin were determined. Bone mineral content and insulin release were assessed. The results showed insulin combined with fluoride stimulated BMSC cell viability in vitro. The bone mineral content reduced in rats treated with higher dose of fluoride and decreased immensely in rat co-treated with fluoride and STZ. Similarly, a combination treatment of a high dose of fluoride and STZ decreased insulin sensitivity and activity. To sum up, these data indicated fluoride influenced insulin release, activity, and sensitivity. Furthermore, the insulin state in vivo interfered in the osteogenesis in turn and implied there was a close relation between insulin and bone pathogenesis in the mechanism of fluoride toxicity.

Intranasal insulin treatment of an experimental model of moderate traumatic brain injury.

Science.gov (United States)

Brabazon, Fiona; Wilson, Colin M; Jaiswal, Shalini; Reed, John; Frey, William H; Byrnes, Kimberly R

2017-09-01

Traumatic brain injury (TBI) results in learning and memory dysfunction. Cognitive deficits result from cellular and metabolic dysfunction after injury, including decreased cerebral glucose uptake and inflammation. This study assessed the ability of intranasal insulin to increase cerebral glucose uptake after injury, reduce lesion volume, improve memory and learning function and reduce inflammation. Adult male rats received a controlled cortical impact (CCI) injury followed by intranasal insulin or saline treatment daily for 14 days. PET imaging of [18F]-FDG uptake was performed at baseline and at 48 h and 10 days post-injury and MRI on days three and nine post injury. Motor function was tested with the beam walking test. Memory function was assessed with Morris water maze. Intranasal insulin after CCI significantly improved several outcomes compared to saline. Insulin-treated animals performed better on beam walk and demonstrated significantly improved memory. A significant increase in [18F]-FDG uptake was observed in the hippocampus. Intranasal insulin also resulted in a significant decrease in hippocampus lesion volume and significantly less microglial immunolabeling in the hippocampus. These data show that intranasal insulin improves memory, increases cerebral glucose uptake and decreases neuroinflammation and hippocampal lesion volume, and may therefore be a viable therapy for TBI.

Successful treatment of young infants presenting neonatal diabetes mellitus with continuous subcutaneous insulin infusion before genetic diagnosis.

Science.gov (United States)

Rabbone, Ivana; Barbetti, Fabrizio; Marigliano, Marco; Bonfanti, Riccardo; Piccinno, Elvira; Ortolani, Federica; Ignaccolo, Giovanna; Maffeis, Claudio; Confetto, Santino; Cerutti, Franco; Zanfardino, Angela; Iafusco, Dario

2016-08-01

Neonatal diabetes mellitus (NDM) is defined as hyperglycemia and impaired insulin secretion with onset within 6 months of birth. While rare, NDM presents complex challenges regarding the management of glycemic control. The availability of continuous subcutaneous insulin infusion pumps (CSII) in combination with continuous glucose monitoring systems (CGM) provides an opportunity to monitor glucose levels more closely and deliver insulin more safely. We report four cases of young infants with NDM successfully treated with CSII and CGM. Moreover, in two cases with Kir 6.2 mutation, we describe the use of CSII in switching therapy from insulin to sulfonylurea treatment. Insulin pump requirement for the 4 neonatal diabetes cases was the same regardless of disease pathogenesis and c-peptide levels. No dilution of insulin was needed. The use of an integrated CGM system helped in a more precise control of BG levels with the possibility of several modifications of insulin basal rates. Moreover, as showed in the first two case-reports, when the treatment was switched from insulin to glibenclamide, according to identification of Kir 6.2 mutation and diagnosis of NPDM, the CSII therapy demonstrated to be helpful in allowing gradual insulin suspension and progressive introduction of sulfonylurea. During the neonatal period, the use of CSII therapy is safe, more physiological, accurate and easier for the insulin administration management. Furthermore, CSII therapy is safe during the switch of therapy from insulin to glibenclamide for infants with permanent neonatal diabetes mellitus.

Treatment of Type 1 and Type 2 Diabetes Mellitus with Insulin Detemir, a Long-Acting Insulin Analog

Directory of Open Access Journals (Sweden)

Jason R. Young

2010-01-01

Full Text Available Insulin detemir is a long-acting basal insulin approved for use in patients with type 1 (T1DM or type 2 diabetes (T2DM. Insulin detemir has demonstrated equivalent glycemic control and hypoglycemic risk when compared to insulin glargine, and insulin detemir has generally but not consistently demonstrated less weight gain than insulin glargine in T2DM. The benefits of basal insulin analogs relative to NPH insulin are well recognized, including less FBG variability, lower risk of hypoglycemia, and less weight gain specifically with insulin detemir. However, NPH insulin continues to be widely prescribed, which may be due in part to economic considerations. While NPH insulin generally costs less per prescription, insulin detemir has been shown to be cost effective compared to NPH insulin as well as insulin glargine. Therefore, insulin detemir is an effective option from both clinical and economic perspectives for patients with T1DM or T2DM who require basal insulin to achieve glycemic control.

Long-term prophylactic insulin treatment can prevent spontaneous diabetes and thyroiditis development in the diabetes-prone bio-breeding rat, while short-term treatment is ineffective

NARCIS (Netherlands)

Visser, J.; Klatter, F; Vis, L; Groen, Harry; Strubbe, J.H.; Rozing, Nico

Objective: Prophylactic insulin treatment has been demonstrated to reduce diabetes development in the diabetes-prone bio-breeding (DP-BB) rat. These prophylactic insulin treatments were given from 50 to 150 days of age. However, several data indicate that the diabetogenic process in DP-BB rats

Central nervous insulin resistance: a promising target in the treatment of metabolic and cognitive disorders?

Science.gov (United States)

Hallschmid, M; Schultes, B

2009-11-01

Research on functions and signalling pathways of insulin has traditionally focused on peripheral tissues such as muscle, fat and liver, while the brain was commonly believed to be insensitive to the effects of this hormone secreted by pancreatic beta cells. However, since the discovery some 30 years ago that insulin receptors are ubiquitously found in the central nervous system, an ever-growing research effort has conclusively shown that circulating insulin accesses the brain, which itself does not synthesise insulin, and exerts pivotal functions in central nervous networks. As an adiposity signal reflecting the amount of body fat, insulin provides direct negative feedback to hypothalamic nuclei that control whole-body energy and glucose homeostasis. Moreover, insulin affects distinct cognitive processes, e.g. by triggering the formation of psychological memory contents. Accordingly, metabolic and cognitive disorders such as obesity, type 2 diabetes mellitus and Alzheimer's disease are associated with resistance of central nervous structures to the effects of insulin, which may derive from genetic polymorphisms as well as from long-term exposure to excess amounts of circulating insulin due to peripheral insulin resistance. Thus, overcoming central nervous insulin resistance, e.g. by pharmacological interventions, appears to be an attractive strategy in the treatment and prevention of these disorders. Enhancement of central nervous insulin signalling by administration of intranasal insulin, insulin analogues and insulin sensitisers in basic research approaches has yielded encouraging results that bode well for the successful translation of these effects into future clinical practice.

Intensive insulin treatment improves forearm blood flow in critically ill patients: a randomized parallel design clinical trial.

Science.gov (United States)

Žuran, Ivan; Poredos, Pavel; Skale, Rafael; Voga, Gorazd; Gabrscek, Lucija; Pareznik, Roman

2009-01-01

Intensive insulin treatment of critically ill patients was seen as a promising method of treatment, though recent studies showed that reducing the blood glucose level below 6 mmol/l had a detrimental outcome. The mechanisms of the effects of insulin in the critically ill are not completely understood. The purpose of the study was to test the hypothesis that intensive insulin treatment may influence forearm blood flow independently of global hemodynamic indicators. The study encompassed 29 patients of both sexes who were admitted to the intensive care unit due to sepsis and required artificial ventilation as the result of acute respiratory failure. 14 patients were randomly selected for intensive insulin treatment (Group 1; blood glucose concentration 4.4-6.1 mmol/l), and 15 were selected for conventional insulin treatment (Group 2; blood glucose level 7.0 mmol/l-11.0 mmol/l). At the start of the study (t0, beginning up to 48 hours after admittance and the commencement of artificial ventilation), at 2 hours (t1), 24 hours (t2), and 72 hours (t3) flow in the forearm was measured for 60 minutes using the strain-gauge plethysmography method. Student's t-test of independent samples was used for comparisons between the two groups, and Mann-Whitney's U-test where appropriate. Linear regression analysis and the Pearson correlation coefficient were used to determine the levels of correlation. The difference in 60-minute forearm flow at the start of the study (t0) was not statistically significant between groups, while at t2 and t3 significantly higher values were recorded in Group 1 (t2; Group 1: 420.6 +/- 188.8 ml/100 ml tissue; Group 2: 266.1 +/- 122.2 ml/100 ml tissue (95% CI 30.9-278.0, P = 0.02); t3; Group 1: 369.9 +/- 150.3 ml/100 ml tissue; Group 2: 272.6 +/- 85.7 ml/100 ml tissue (95% CI 5.4-190.0, P = 0.04). At t1 a trend towards significantly higher values in Group 1 was noted (P = 0.05). The level of forearm flow was related to the amount of insulin infusion (r

Classifying insulin regimens

DEFF Research Database (Denmark)

Neu, A; Lange, K; Barrett, T

2015-01-01

Modern insulin regimens for the treatment of type 1 diabetes are highly individualized. The concept of an individually tailored medicine accounts for a broad variety of different insulin regimens applied. Despite clear recommendations for insulin management in children and adolescents with type 1...

One week treatment with the IL-1 receptor antagonist anakinra leads to a sustained improvement in insulin sensitivity in insulin resistant patients with type 1 diabetes mellitus

NARCIS (Netherlands)

Asseldonk, van E.J.P.; Poppel, van P.C.M.; Ballak, D.B.; Stienstra, Rinke; Netea, M.G.; Tack, C.J.

2015-01-01

Inflammation associated with obesity is involved in the development of insulin resistance. We hypothesized that anti-inflammatory treatment with the Interleukin-1 receptor antagonist anakinra would improve insulin sensitivity.In an open label proof-of-concept study, we included overweight

Is insulin the preferred treatment for HbA1c >9%?

Science.gov (United States)

Bloomgarden, Zachary

2017-09-01

The algorithms and guidelines of the American Association of Clinical Endocrinologists and the American Diabetes Association recommend that insulin administration be strongly considered for people with type 2 diabetes (T2D) with HbA1c levels exceeding 9.0% and 10%, respectively. Although the caveat is given in both sets of recommendations that this is particularly appropriate when patients are "symptomatic," referring to urinary frequency with increased thirst and appetite, weight loss, and ketosis, the clinical definition of such presentations may be ill-defined, and it is noteworthy that both documents consider insulin to offer particular benefit under such circumstances. However, with multiple options for glycemic treatment, it is of interest to reconsider this argument for insulin use. It should be recalled that in the UK Prospective Diabetes Study, diet alone was associated with a reduction in HbA1c from 9% to 7%. Drug-naïve people with T2D do often show surprisingly strong reductions in HbA1c with metformin-based dual-agent oral treatment approaches; a recent report showed that even with baseline HbA1c >11%, the combination of metformin with a sulfonylurea, pioglitazone, or sitagliptin was associated with reduction in HbA1c from 11.6% to 6.0%. A 32-week study of the combination of rosiglitazone with metformin in patients with mean baseline HbA1c 8.9% showed a mean HbA1c reduction of 2.3%, and an open-label cohort with baseline HbA1c 11.8% had a reduction in HbA1c to 7.8%. With metformin plus sitagliptin, a mean placebo-adjusted HbA1c reduction of 2.1% from a baseline of 8.8% was reported, with those patients with baseline HbA1c >9% having a 2.6% reduction in HbA1c, and an open-label cohort with baseline HbA1c 11.2% having a 2.9% reduction in HbA1c. Similar 2% HbA1c reductions from baseline levels of 9.1% were seen with metformin in initial combination with the sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin. Although such dual oral agent

Effects of exendin-4 on glucose tolerance, insulin secretion, and beta-cell proliferation depend on treatment dose, treatment duration and meal contents

International Nuclear Information System (INIS)

Arakawa, Masayuki; Ebato, Chie; Mita, Tomoya; Hirose, Takahisa; Kawamori, Ryuzo; Fujitani, Yoshio; Watada, Hirotaka

2009-01-01

Beta-cell proliferation is regulated by various metabolic demands including peripheral insulin resistance, obesity, and hyperglycemia. In addition to enhancement of glucose-induced insulin secretion, agonists for glucagon-like peptide-1 receptor (GLP-1R) stimulate proliferation and inhibit apoptosis of beta-cells, thereby probably preserve beta-cell mass. To evaluate the beta-cell preserving actions of GLP-1R agonists, we assessed the acute and chronic effects of exendin-4 on beta-cell proliferation, mass and glucose tolerance in C57BL/6J mice under various conditions. Short-term administration of high-dose exendin-4 transiently stimulated beta-cell proliferation. Comparative transcriptomic analysis showed upregulation of IGF-1 receptor and its downstream effectors in islets. Treatment of mice with exendin-4 daily for 4 weeks (long-term administration) and feeding high-fat diet resulted in significant inhibition of weight gain and improvement of glucose tolerance with reduced insulin secretion and beta-cell mass. These findings suggest that long-term GLP-1 treatment results in insulin sensitization of peripheral organs, rather than enhancement of beta-cell proliferation and function, particularly when animals are fed high-fat diet. Thus, the effects of exendin-4 on glucose tolerance, insulin secretion, and beta-cell proliferation largely depend on treatment dose, duration of treatment and meal contents. While GLP-1 enhances proliferation of beta-cells in some diabetic mice models, our results suggest that GLP-1 stimulates beta-cell growth only when expansion of beta-cell mass is required to meet metabolic demands.

Effects of exendin-4 on glucose tolerance, insulin secretion, and beta-cell proliferation depend on treatment dose, treatment duration and meal contents

Energy Technology Data Exchange (ETDEWEB)

Arakawa, Masayuki; Ebato, Chie; Mita, Tomoya [Department of Medicine, Metabolism and Endocrinology, Juntendo University School of Medicine, Tokyo (Japan); Hirose, Takahisa [Department of Medicine, Metabolism and Endocrinology, Juntendo University School of Medicine, Tokyo (Japan); Center for Therapeutic Innovations in Diabetes, Juntendo University School of Medicine, Tokyo (Japan); Kawamori, Ryuzo [Department of Medicine, Metabolism and Endocrinology, Juntendo University School of Medicine, Tokyo (Japan); Center for Therapeutic Innovations in Diabetes, Juntendo University School of Medicine, Tokyo (Japan); Center for Beta Cell Biology and Regeneration, Juntendo University School of Medicine, Tokyo (Japan); Sportology Center, Juntendo University School of Medicine, Tokyo (Japan); Fujitani, Yoshio, E-mail: fujitani@juntendo.ac.jp [Department of Medicine, Metabolism and Endocrinology, Juntendo University School of Medicine, Tokyo (Japan); Center for Therapeutic Innovations in Diabetes, Juntendo University School of Medicine, Tokyo (Japan); Watada, Hirotaka, E-mail: hwatada@juntendo.ac.jp [Department of Medicine, Metabolism and Endocrinology, Juntendo University School of Medicine, Tokyo (Japan); Sportology Center, Juntendo University School of Medicine, Tokyo (Japan)

2009-12-18

Beta-cell proliferation is regulated by various metabolic demands including peripheral insulin resistance, obesity, and hyperglycemia. In addition to enhancement of glucose-induced insulin secretion, agonists for glucagon-like peptide-1 receptor (GLP-1R) stimulate proliferation and inhibit apoptosis of beta-cells, thereby probably preserve beta-cell mass. To evaluate the beta-cell preserving actions of GLP-1R agonists, we assessed the acute and chronic effects of exendin-4 on beta-cell proliferation, mass and glucose tolerance in C57BL/6J mice under various conditions. Short-term administration of high-dose exendin-4 transiently stimulated beta-cell proliferation. Comparative transcriptomic analysis showed upregulation of IGF-1 receptor and its downstream effectors in islets. Treatment of mice with exendin-4 daily for 4 weeks (long-term administration) and feeding high-fat diet resulted in significant inhibition of weight gain and improvement of glucose tolerance with reduced insulin secretion and beta-cell mass. These findings suggest that long-term GLP-1 treatment results in insulin sensitization of peripheral organs, rather than enhancement of beta-cell proliferation and function, particularly when animals are fed high-fat diet. Thus, the effects of exendin-4 on glucose tolerance, insulin secretion, and beta-cell proliferation largely depend on treatment dose, duration of treatment and meal contents. While GLP-1 enhances proliferation of beta-cells in some diabetic mice models, our results suggest that GLP-1 stimulates beta-cell growth only when expansion of beta-cell mass is required to meet metabolic demands.

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)

Concentrated insulins: the new basal insulins

Directory of Open Access Journals (Sweden)

Lamos EM

2016-03-01

Full Text Available Elizabeth M Lamos,1 Lisa M Younk,2 Stephen N Davis3 1Division of Endocrinology, Diabetes and Nutrition, 2Department of Medicine, University of Maryland School of Medicine, 3Department of Medicine, University of Maryland Medical Center, Baltimore, MD, USA Introduction: Insulin therapy plays a critical role in the treatment of type 1 and type 2 diabetes mellitus. However, there is still a need to find basal insulins with 24-hour coverage and reduced risk of hypoglycemia. Additionally, with increasing obesity and insulin resistance, the ability to provide clinically necessary high doses of insulin at low volume is also needed. Areas covered: This review highlights the published reports of the pharmacokinetic (PK and glucodynamic properties of concentrated insulins: Humulin-R U500, insulin degludec U200, and insulin glargine U300, describes the clinical efficacy, risk of hypoglycemic, and metabolic changes observed, and finally, discusses observations about the complexity of introducing a new generation of concentrated insulins to the therapeutic market. Conclusion: Humulin-R U500 has a similar onset but longer duration of action compared with U100 regular insulin. Insulin glargine U300 has differential PK/pharmacodynamic effects when compared with insulin glargine U100. In noninferiority studies, glycemic control with degludec U200 and glargine U300 is similar to insulin glargine U100 and nocturnal hypoglycemia is reduced. Concentrated formulations appear to behave as separate molecular entities when compared with earlier U100 insulin analog compounds. In the review of available published data, newer concentrated basal insulins may offer an advantage in terms of reduced intraindividual variability as well as reducing the injection burden in individuals requiring high-dose and large volume insulin therapy. Understanding the PK and pharmacodynamic properties of this new generation of insulins is critical to safe dosing, dispensing, and administration

Change in body mass index and insulin resistance after 1-year treatment with gonadotropin-releasing hormone agonists in girls with central precocious puberty.

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Park, Jina; Kim, Jae Hyun

2017-03-01

Gonadotropin-releasing hormone agonist (GnRHa) is used as a therapeutic agent for central precocious puberty (CPP); however, increased obesity may subsequently occur. This study compared body mass index (BMI) and insulin resistance during the first year of GnRHa treatment for CPP. Patient group included 83 girls (aged 7.0-8.9 years) with developed breasts and a peak luteinizing hormone level of ≥5 IU/L after GnRH stimulation. Control group included 48 prepubertal girls. BMI and insulin resistance-related indices (homeostasis model assessment of insulin resistance [HOMA-IR] and quantitative insulin sensitivity check index [QUICKI]) were used to compare the groups before treatment, and among the patient group before and after GnRHa treatment. No statistical difference in BMI z -score was detected between the 2 groups before treatment. Fasting insulin and HOMA-IR were increased in the patient group; fasting glucose-to-insulin ratio and QUICKI were increased in the control group (all P resistance compared to the control group. During GnRHa treatment, normal-weight individuals showed increased BMI z -scores without increased insulin resistance; the overweight group demonstrated increased insulin resistance without significantly altered BMI z -scores. Long-term follow-up of BMI and insulin resistance changes in patients with CPP is required.

Hyperandrogenemia Induced by Letrozole Treatment of Pubertal Female Mice Results in Hyperinsulinemia Prior to Weight Gain and Insulin Resistance.

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Skarra, Danalea V; Hernández-Carretero, Angelina; Rivera, Alissa J; Anvar, Arya R; Thackray, Varykina G

2017-09-01

Women with polycystic ovary syndrome (PCOS) diagnosed with hyperandrogenism and ovulatory dysfunction have an increased risk of developing metabolic disorders, including type 2 diabetes and cardiovascular disease. We previously developed a model that uses letrozole to elevate endogenous testosterone levels in female mice. This model has hallmarks of PCOS, including hyperandrogenism, anovulation, and polycystic ovaries, as well as increased abdominal adiposity and glucose intolerance. In the current study, we further characterized the metabolic dysfunction that occurs after letrozole treatment to determine whether this model represents a PCOS-like metabolic phenotype. We focused on whether letrozole treatment results in altered pancreatic or liver function as well as insulin resistance. We also investigated whether hyperinsulinemia occurs secondary to weight gain and insulin resistance in this model or if it can occur independently. Our study demonstrated that letrozole-treated mice developed hyperinsulinemia after 1 week of treatment and without evidence of insulin resistance. After 2 weeks of letrozole treatment, mice became significantly heavier than placebo mice, demonstrating that weight gain was not required to develop hyperinsulinemia. After 5 weeks of letrozole treatment, mice exhibited blunted glucose-stimulated insulin secretion, insulin resistance, and impaired insulin-induced phosphorylation of AKT in skeletal muscle. Moreover, letrozole-treated mice exhibited dyslipidemia after 5 weeks of treatment but no evidence of hepatic disease. Our study demonstrated that the letrozole-induced PCOS mouse model exhibits multiple features of the metabolic dysregulation observed in obese, hyperandrogenic women with PCOS. This model will be useful for mechanistic studies investigating how hyperandrogenemia affects metabolism in females. Copyright © 2017 Endocrine Society.

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

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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

Insulin resistance and the mitochondrial link. Lessons from cultured human myotubes

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Gaster, Michael

2007-01-01

In order to better understand the impact of reduced mitochondrial function for the development of insulin resistance and cellular metabolism, human myotubes were established from lean, obese, and T2D subjects and exposed to mitochondrial inhibitors, either affecting the electron transport chain...... lipid uptake. The metabolic phenotype during respiratory uncoupling resembled the above picture, except for an increase in glucose and palmitate oxidation. Antimycin A and oligomycin treatment induced insulin resistance at the level of glucose and palmitate uptake in all three study groups while......, at the level of glycogen synthesis, insulin resistance was only seen in lean myotubes. Primary insulin resistance in diabetic myotubes was significantly worsened at the level of glucose and lipid uptake. The present study is the first convincing data linking functional mitochondrial impairment per se...

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

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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

[Mechanism of action of insulin sensitizer agents in the treatment of polycystic ovarian syndrome].

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Galindo García, Carlos G; Vega Arias, Maria de Jesús; Hernández Marín, Imelda; Ayala, Aquiles R

2007-03-01

Polycystic ovarian disease (PCOD) is the most important endocrine abnormality that affects women in reproductive age. It is characterized by chronic anovulation and hyperandrogenemia probably secondary to insulin resistance. Hence insulin sensitizers agents had been used in PCOD. Metformin is a biguanide used in the treatment of PCOD via decrease of hepatic gluconeogenesis and insulinemia; improvement peripheral glucose utilization, oxidative glucose metabolism, nonoxidative glucose metabolism and intracellular glucose transport. Such effects, when this drug is administered alone during 3 to 6 months, increase sex hormone binding globulin (SHBG), reduce free androgens index and hirsutism, decrease insulin resistance, and regulate menses in 60 to 70% of cases. Thiazolidinodiones are drugs that decrease insulin resistance in the liver with hepatic glucose production. Their mechanism of action is through the peroxisome proliferator-activated receptors gamma (PPAR-gamma), that help to decrease plasmatic concentrations of free fatty acids, pre and postprandial glucose, insulin, triglycerides, increased HDL cholesterol and decreased LDL, menses return to normality, with improvement of ovulation and decreased hirsutism. It seems that by modulation and attenuation of insulin resistance, hypoglucemic agents such as metfomin and thiazolidinodiones can be used effectively to treat anovulation, infertility and hyperandrogenemia.

Treatment with insulin (analogues) and breast cancer risk in diabetics; a systematic review and meta-analysis of in vitro, animal and human evidence

NARCIS (Netherlands)

Bronsveld, Heleen K; ter Braak, Bas; Karlstad, Øystein; Vestergaard, Peter; Starup-Linde, Jakob; Bazelier, Marloes T; De Bruin, Marie L; de Boer, Anthonius; Siezen, Christine L E; van de Water, Bob; van der Laan, Jan Willem; Schmidt, Marjanka K

2015-01-01

INTRODUCTION: Several studies have suggested that anti-diabetic insulin analogue treatment might increase cancer risk. The aim of this study was to review the postulated association between insulin and insulin analogue treatment and breast cancer development, and plausible mechanisms. METHOD: A

Change in body mass index and insulin resistance after 1-year treatment with gonadotropin-releasing hormone agonists in girls with central precocious puberty

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Jina Park

2017-03-01

Full Text Available PurposeGonadotropin-releasing hormone agonist (GnRHa is used as a therapeutic agent for central precocious puberty (CPP; however, increased obesity may subsequently occur. This study compared body mass index (BMI and insulin resistance during the first year of GnRHa treatment for CPP.MethodsPatient group included 83 girls (aged 7.0–8.9 years with developed breasts and a peak luteinizing hormone level of ≥5 IU/L after GnRH stimulation. Control group included 48 prepubertal girls. BMI and insulin resistance-related indices (homeostasis model assessment of insulin resistance [HOMA-IR] and quantitative insulin sensitivity check index [QUICKI] were used to compare the groups before treatment, and among the patient group before and after GnRHa treatment.ResultsNo statistical difference in BMI z-score was detected between the 2 groups before treatment. Fasting insulin and HOMA-IR were increased in the patient group; fasting glucose-to-insulin ratio and QUICKI were increased in the control group (all P<0.001. In normal-weight subjects in the patient group, BMI z-score was significantly increased during GnRHa treatment (−0.1±0.7 vs. 0.1±0.8, P<0.001, whereas HOMA-IR and QUICKI exhibited no differences. In overweight subjects in the patient group; BMI z-score and HOMA-IR were not significantly different, whereas QUICKI was significantly decreased during GnRHa treatment (0.35±0.03 vs. 0.33±0.02, P=0.044.ConclusionGirls with CPP exhibited increased insulin resistance compared to the control group. During GnRHa treatment, normal-weight individuals showed increased BMI z-scores without increased insulin resistance; the overweight group demonstrated increased insulin resistance without significantly altered BMI z-scores. Long-term follow-up of BMI and insulin resistance changes in patients with CPP is required.

Exogenous insulin antibody syndrome (EIAS): a clinical syndrome associated with insulin antibodies induced by exogenous insulin in diabetic patients.

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Hu, Xiaolei; Chen, Fengling

2018-01-01

Insulin has been used for diabetes therapy and has achieved significant therapeutic effect. In recent years, the use of purified and recombinant human insulin preparations has markedly reduced, but not completely suppressed, the incidence of insulin antibodies (IAs). IAs induced by exogenous insulin in diabetic patients is associated with clinical events, which is named exogenous insulin antibody syndrome (EIAS). The present review is based on our research and summarizes the characterization of IAs, the factors affecting IA development, the clinical significance of IAs and the treatments for EIAS. © 2018 The authors.

Explaining psychological insulin resistance in adults with non-insulin-treated type 2 diabetes

DEFF Research Database (Denmark)

Holmes-Truscott, Elizabeth; Skinner, Timothy Chas; Pouwer, F

2016-01-01

to the model. CONCLUSIONS: Psychological insulin resistance may reflect broader distress about diabetes and concerns about its treatment but not general beliefs about medicines, depression or anxiety. Reducing diabetes distress and current treatment concerns may improve attitudes towards insulin as a potential......AIMS: To investigate the contribution of general and diabetes-specific emotional wellbeing and beliefs about medicines in the prediction of insulin therapy appraisals in adults with non-insulin-treated type 2 diabetes. METHODS: The sample included Diabetes MILES-Australia cross-sectional survey...... diabetes medications (BMQ Specific); negative insulin therapy appraisals (ITAS); depression (PHQ-9); anxiety (GAD-7), and diabetes distress (DDS-17). Factors associated with ITAS Negative scores were examined using hierarchical multiple regressions. RESULTS: Twenty-two percent of the variance in ITAS...

The impact of pegvisomant treatment on substrate metabolism and insulin sensitivity in patients with acromegaly

DEFF Research Database (Denmark)

Lindberg-Larsen, Rune; Møller, Niels; Schmitz, Ole

2007-01-01

CONTEXT: Pegvisomant is a specific GH receptor antagonist that is able to normalize serum IGF-I concentrations in most patients with acromegaly. The impact of pegvisomant on insulin sensitivity and substrate metabolism is less well described. PATIENTS AND METHODS: We assessed basal and insulin......-stimulated (euglycemic clamp) substrate metabolism in seven patients with active acromegaly before and after 4-wk pegvisomant treatment (15 mg/d) in an open design. RESULTS: After pegvisomant, IGF-I decreased, whereas GH increased (IGF-I, 621 +/- 82 vs. 247 +/- 33 microg/liter, P = 0.02; GH, 5.3 +/- 1.5 vs. 10.8 +/- 3...... vs. 1563 +/- 101 kcal/24 h, P = 0.03), but the rate of lipid oxidation did not change significantly. CONCLUSIONS: 1) Pegvisomant treatment for 4 wk improves peripheral and hepatic insulin sensitivity in acromegaly. 2) This is associated with a decrease in resting energy expenditure, whereas free...

Experiments on the inclusion of insulin in lecithin microvesicles using 125I insulin and 131I lecithin as indicators

International Nuclear Information System (INIS)

Sarrach, D.; Lachmann, U.; Zipper, J.; Axt, J.; Akademie der Wissenschaften der DDR, Berlin. Inst. fuer Wirkstofforschung)

1980-01-01

Egg lecithin was labelled with 131 ICl and used together with 125 I insulin for studying the insulin inclusion in lecithin monolayer liposomes. The application of ultrasonics led to the formation of insulin-containing microvesicles which were characterized by electron microscopy and gel chromatography. With growing insulin concentration the yield of bound insulin increased to a value comparable to the included water volume. In the presence of lecithin insulin disintegration by ultrasonics was strongly reduced The bound insulin proved to be in good immunological state. (author)

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

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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.

Pregestational diabetes with extreme insulin resistance: use of U-500 insulin in pregnancy.

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Zuckerwise, Lisa C; Werner, Erika F; Pettker, Christian M; McMahon-Brown, Erin K; Thung, Stephen F; Han, Christina S

2012-08-01

Increased insulin requirements in pregnancy can hinder attainment of glycemic control in diabetic patients. U-500 insulin is a concentrated form of regular insulin that can be a valuable tool in the treatment of patients with severe insulin resistance. A 24-year-old woman with pregestational diabetes mellitus experienced increasing insulin requirements during pregnancy, peaking at 650 units daily. The frequent, large-volume injections of standard-concentration insulin were poorly tolerated by the patient and resulted in nonadherence. She subsequently achieved glycemic control on thrice-daily U-500 insulin. Pregnancy exacerbates insulin resistance in diabetic patients, and these patients may require high doses of insulin. U-500 insulin is an effective alternative for patients with severe insulin resistance and should be considered for pregnant women with difficulty achieving glycemic control.

What next after basal insulin? Treatment intensification with lixisenatide in Asian patients with type 2 diabetes mellitus.

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Chan, Wing B; Luk, Andrea; Chow, Wing S; Yeung, Vincent T F

2017-06-01

There is increasing evidence that the pathophysiology of type 2 diabetes mellitus (T2DM) in Asian patients differs from that in Western patients, with early phase insulin deficiencies, increased postprandial glucose excursions, and increased sensitivity to insulin. Asian patients may also experience higher rates of gastrointestinal adverse events associated with glucagon-like peptide-1 receptor agonists (GLP-1RAs), such as nausea and vomiting, compared with their Western counterparts. These factors should be taken into consideration when selecting therapy for basal insulin treatment intensification in Asian patients. However, the majority of studies to establish various agents for treatment intensification in T2DM have been conducted in predominantly Western populations, and the levels of evidence available in Chinese or Asian patients are limited. This review discusses the different mechanisms of action of short-acting, prandial, and long-acting GLP-1RAs in addressing hyperglycemia, and describes the rationale and available clinical data for basal insulin in combination with the short-acting prandial GLP-1RA lixisenatide, with a focus on treatment of Asian patients with T2DM. © 2016 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.

Insulin treatment promotes tyrosine phosphorylation of PKR and inhibits polyIC induced PKR threonine phosphorylation.

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Swetha, Medchalmi; Ramaiah, Kolluru V A

2015-11-01

Tyrosine phosphorylation of insulin receptor beta (IRβ) in insulin treated HepG2 cells is inversely correlated to ser(51) phosphorylation in the alpha-subunit of eukaryotic initiation factor 2 (eIF2α) that regulates protein synthesis. Insulin stimulates interaction between IRβ and PKR, double stranded RNA-dependent protein kinase, also known as EIF2AK2, and phosphorylation of tyrosine residues in PKR, as analyzed by immunoprecipitation and pull down assays using anti-IRβ and anti-phosphotyrosine antibodies, recombinant IRβ and immunopurified PKR. Further polyIC or synthetic double stranded RNA-induced threonine phosphorylation or activation of immunopurified and cellular PKR is suppressed in the presence of insulin treated purified IRβ and cell extracts. Acute, but not chronic, insulin treatment enhances tyrosine phosphorylation of IRβ, its interaction with PKR and tyrosine phosphorylation of PKR. In contrast, lipopolysaccharide that stimulates threonine phosphorylation of PKR and eIF2α phosphorylation and AG 1024, an inhibitor of the tyrosine kinase activity of IRβ, reduces PKR association with the receptor, IRβ in HepG2 cells. These findings therefore may suggest that tyrosine phosphorylated PKR plays a role in the regulation of insulin induced protein synthesis and in maintaining insulin sensitivity, whereas, suppression of polyIC-mediated threonine phosphorylation of PKR by insulin compromises its ability to fight against virus infection in host cells. Copyright © 2015 Elsevier Inc. All rights reserved.

Adherence to treatment for diabetes mellitus: validation of instruments for oral antidiabetics and insulin.

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Boas, Lilian Cristiane Gomes-Villas; Lima, Maria Luisa Soares Almeida Pedroso de; Pace, Ana Emilia

2014-01-01

to verify the face validity, criterion-related validity and the reliability of two distinct forms of presentation of the instrument Measurement of Adherence to Treatment, one being for ascertaining the adherence to the use of oral antidiabetics and the other for adherence to the use of insulin, as well as to assess differences in adherence between these two modes of drug therapy. a methodological study undertaken with 90 adults with Type 2 Diabetes Mellitus. The criterion-related validity was verified using the Receiver Operating Characteristic curves; and for the reliability, the researchers calculated the Cronbach alpha coefficient, the item-total correlation, and the Pearson correlation coefficient. the oral antidiabetics and the other showed sensitivity of 0.84, specificity of 0.35 and a Cronbach correlation coefficient of 0.84. For the adherence to the use of insulin, the values found were, respectively, 0.60, 0.21 and 0.68. A statistically significant difference was found between the final scores of the two forms of the instrument, indicating greater adherence to the use of insulin than to oral antidiabetics. it is concluded that the two forms of the Measurement of Adherence to Treatment instrument are reliable and should be used to evaluate adherence to drug treatment among people with diabetes mellitus.

Insulin Initiation in Type 2 Diabetes – Why, When and How?

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Popa Simona Georgiana

2016-03-01

Full Text Available Type 2 diabetes is a progressive disease and, despite recent progress in the treatment of diabetes, the glycemic control usually deteriorates gradually and insulin therapy is needed. When insulin therapy should be started and which are the appropriate insulin therapy strategies, still represent subjects of debates. Insulin represents a therapeutic option in type 2 diabetes due to the existence of early β-cell dysfunction and significant reduction of β-cell mass in natural history of type 2 diabetes. The current guidelines recommend insulin in double therapy in association with metformin or in combination with metformin and other noninsulin agent. Initiation of insulin therapy is recommended in patients with newly diagnosed type 2 diabetes and symptomatic and/or presenting important hyperglycemia or elevated HbA1c. Initiation of insulin therapy in type 2 diabetes should take into consideration the pathophysiology of type 2 diabetes, the effects and the potential risks of insulin therapy, the guidelines recommendations and the barriers to insulin use. Literatures of only English language were analyzed from NCBI database. Guidelines were accessed electronically from organisations, i.e. American Diabetes Associations, American Association of Clinical Endocrinologists and American College of Endocrinology, European Association for the Study of Diabetes, International Diabetes Federation.

Exogenous insulin antibody syndrome (EIAS: a clinical syndrome associated with insulin antibodies induced by exogenous insulin in diabetic patients

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Xiaolei Hu

2018-01-01

Full Text Available Insulin has been used for diabetes therapy and has achieved significant therapeutic effect. In recent years, the use of purified and recombinant human insulin preparations has markedly reduced, but not completely suppressed, the incidence of insulin antibodies (IAs. IAs induced by exogenous insulin in diabetic patients is associated with clinical events, which is named exogenous insulin antibody syndrome (EIAS. The present review is based on our research and summarizes the characterization of IAs, the factors affecting IA development, the clinical significance of IAs and the treatments for EIAS.

Akt/PKB activation and insulin signaling: a novel insulin signaling pathway in the treatment of type 2 diabetes

OpenAIRE

Mackenzie, Richard WA; Elliott, Bradley T

2014-01-01

Richard WA Mackenzie, Bradley T Elliott Department of Human and Health Sciences, Facility of Science and Technology, University of Westminster, London, UK Abstract: Type 2 diabetes is a metabolic disease categorized primarily by reduced insulin sensitivity, β-cell dysfunction, and elevated hepatic glucose production. Treatments reducing hyperglycemia and the secondary complications that result from these dysfunctions are being sought after. Two distinct pathways encourage glucose tr...

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...

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

Pancreas transplantation for treatment of generalized allergy to human insulin in type 1 diabetes.

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Malaise, J; Leonet, J; Goffin, E; Lefebvre, C; Tennstedt, D; Vandeleene, B; Buysschaert, M; Squifflet, J P

2005-01-01

We report the case of a 29-year-old man with a 14-year history of type 1 diabetes, normal renal function, and mild diabetic retinopathy. The patient progressively developed a generalized allergic reaction to two insulin excipients--protamine and metacresol--with systemic manifestations of tremor, tachycardia, vertigo, shortness of breath, and short episodes of unconsciousness causing him to be out of work. In June 2003, he received a vascularized cadaveric pancreas transplant using induction with polyclonal antibodies along with tacrolimus and sirolimus but without steroids. A hyperglycemic episode following corticosteroid therapy for rejection treatment required reintroduction of insulin therapy with prompt reappearance of allergic manifestations. Now, the patient is euglycemic without insulin or allergic manifestations and a glycated hemoglobin of 6.4%.

Novel Simple Insulin Delivery Device Reduces Barriers to Insulin Therapy in Type 2 Diabetes

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Hermanns, Norbert; Lilly, Leslie C.; Mader, Julia K.; Aberer, Felix; Ribitsch, Anja; Kojzar, Harald; Warner, Jay; Pieber, Thomas R.

2015-01-01

Background: The PaQ® insulin delivery system is a simple-to-use patch-on device that provides preset basal rates and bolus insulin on demand. In addition to feasibility of use, safety, and efficacy (reported elsewhere), this study analyzed the impact of PaQ on patient-reported outcomes, including barriers to insulin treatment, diabetes-related distress, and attitudes toward insulin therapy in patients with type 2 diabetes on a stable multiple daily injection (MDI) regimen. Methods: This single-center, open-label, single-arm study comprised three 2-week periods: baseline (MDI), transition from MDI to PaQ, and PaQ treatment. Validated questionnaires were administered during the baseline and PaQ treatment periods: Barriers to Insulin Treatment questionnaire (BIT), Insulin Treatment Appraisal Scale (ITAS), and Problem Areas in Diabetes scale (PAID). Results: Eighteen patients (age 59 ± 5 years, diabetes duration 15 ± 7 years, 21% female, HbA1c 7.7 ± 0.7%) completed the questionnaires. There was a strong, significant effect of PaQ use in mean BIT total scores (difference [D] = −5.4 ± 0.7.7, P = .01, effect size [d] = 0.70). Patients perceived less stigmatization by insulin injection (D = −2.2 ± 6.2, P = .18, d = 0.35), increased positive outcome (D = 1.9 ± 6.6, P = .17, d = 0.29), and less fear of injections (1.3 ± 4.8, P = .55, d = 0.28). Mean change in ITAS scores after PaQ device use showed a nonsignificant improvement of 1.71 ± 5.63 but moderate effect size (d = 0.30, P = .14). No increase in PAID scores was seen. Conclusions: The results and moderate to large effects sizes suggest that PaQ device use has beneficial and clinically relevant effects to overcoming barriers to and negative appraisal of insulin treatment, without increasing other diabetes-related distress. PMID:25670847

Hyperinsulinemic hypoglycemia associated with insulin antibodies caused by exogenous insulin analog

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Chih-Ting Su

2016-11-01

Full Text Available Insulin antibodies (IA associated with exogenous insulin administration seldom caused hypoglycemia and had different characteristics from insulin autoantibodies (IAA found in insulin autoimmune syndrome (IAS, which was first described by Dr Hirata in 1970. The characteristic of IAS is the presence of insulin-binding autoantibodies and related fasting or late postprandial hypoglycemia. Here, we report a patient with type 1 diabetes mellitus under insulin glargine and insulin aspart treatment who developed recurrent spontaneous post-absorptive hyperinsulinemic hypoglycemia with the cause probably being insulin antibodies induced by exogenous injected insulin. Examinations of serial sera disclosed a high titre of insulin antibodies (33%, normal <5%, high insulin concentration (111.9 IU/mL and undetectable C-peptide when hypoglycemia occurred. An oral glucose tolerance test revealed persistent high serum levels of total insulin and undetectable C-peptide. Image studies of the pancreas were unremarkable, which excluded the diagnosis of insulinoma. The patient does not take any of the medications containing sulfhydryl compounds, which had been reported to cause IAS. After administering oral prednisolone for 3 weeks, hypoglycemic episodes markedly improved, and he was discharged smoothly.

PEDF expression is inhibited by insulin treatment in adipose tissue via suppressing 11β-HSD1.

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Yinli Zhou

Full Text Available Early intensive insulin therapy improves insulin sensitivity in type 2 diabetic patients; while the underlying mechanism remains largely unknown. Pigment epithelium-derived factor (PEDF, an anti-angiogenic factor, is believed to be involved in the pathogenesis of insulin resistance. Here, we hypothesize that PEDF might be down regulated by insulin and then lead to the improved insulin resistance in type 2 diabetic patients during insulin therapy. We addressed this issue by investigating insulin regulation of PEDF expression in diabetic conditions. The results showed that serum PEDF was reduced by 15% in newly diagnosed type 2 diabetic patients after insulin therapy. In adipose tissue of diabetic Sprague-Dawley rats, PEDF expression was associated with TNF-α elevation and it could be decreased both in serum and in adipose tissue by insulin treatment. In adipocytes, PEDF was induced by TNF-α through activation of NF-κB. The response was inhibited by knockdown and enhanced by over expression of NF-κB p65. However, PEDF expression was indirectly, not directly, induced by NF-κB which promoted 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1 expression in adipocytes. 11β-HSD1 is likely to stimulate PEDF expression through production of active form of glucocorticoids as dexamethasone induced PEDF expression in adipose tissue. Insulin inhibited PEDF by down-regulating 11β-HSD1 expression. The results suggest that PEDF activity is induced by inflammation and decreased by insulin through targeting 11β-HSD1/glucocorticoid pathway in adipose tissue of diabetic patients.

Long-term testosterone treatment during pregnancy does not alter insulin or glucose profile in a sheep model of polycystic ovary syndrome.

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Recabarren, Monica; Carrasco, Albert; Sandoval, Daniel; Diaz, Felipe; Sir-Petermann, Teresa; Recabarren, Sergio E

2017-09-07

The administration of testosterone to pregnant sheep to resemble fetal programming of the polycystic ovary syndrome could alter other hormones/factors of maternal origin with known effects on fetal growth. Hence, we studied the weekly profile of insulin, progesterone and glucose during a treatment with testosterone propionate given biweekly from weeks 5 to 17 of pregnancy (term at 21 weeks) and checked the outcome of their fetuses at 17 weeks of gestation after C-section. Control dams were only exposed to the vehicle of the hormone. The testosterone administration did not cause any significant change in the maternal weekly profile of insulin, progesterone or glucose concentration, although the plasma levels of testosterone in the treated dams were inversely correlated to the levels of progesterone. Testosterone treatment also induced an inverse correlation between mean maternal insulin levels and fetal insulin levels; however, the fetal zoometric parameters, body weight, or insulin levels did not differ between exposed and not exposed fetuses. Therefore, treatment with testosterone during pregnancy does not cause significant impact on insulin levels in the mother, leading to less effect on the programming of fetal growth.

Intensive insulin therapy improves insulin sensitivity and mitochondrial function in severely burned children.

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Fram, Ricki Y; Cree, Melanie G; Wolfe, Robert R; Mlcak, Ronald P; Qian, Ting; Chinkes, David L; Herndon, David N

2010-06-01

To institute intensive insulin therapy protocol in an acute pediatric burn unit and study the mechanisms underlying its benefits. Prospective, randomized study. An acute pediatric burn unit in a tertiary teaching hospital. Children, 4-18 yrs old, with total body surface area burned > or =40% and who arrived within 1 wk after injury were enrolled in the study. Patients were randomized to one of two groups. Intensive insulin therapy maintained blood glucose levels between 80 and 110 mg/dL. Conventional insulin therapy maintained blood glucose patients were included in the data analysis consisting of resting energy expenditure, whole body and liver insulin sensitivity, and skeletal muscle mitochondrial function. Studies were performed at 7 days postburn (pretreatment) and at 21 days postburn (posttreatment). Resting energy expenditure significantly increased posttreatment (1476 +/- 124 to 1925 +/- 291 kcal/m(2) x day; p = .02) in conventional insulin therapy as compared with a decline in intensive insulin therapy. Glucose infusion rate was identical between groups before treatment (6.0 +/- 0.8 conventional insulin therapy vs. 6.8 +/- 0.9 mg/kg x min intensive insulin therapy; p = .5). Intensive insulin therapy displayed a significantly higher glucose clamp infusion rate posttreatment (9.1 +/- 1.3 intensive insulin therapy versus 4.8 +/- 0.6 mg/kg x min conventional insulin therapy, p = .005). Suppression of hepatic glucose release was significantly greater in the intensive insulin therapy after treatment compared with conventional insulin therapy (5.0 +/- 0.9 vs. 2.5 +/- 0.6 mg/kg x min; intensive insulin therapy vs. conventional insulin therapy; p = .03). States 3 and 4 mitochondrial oxidation of palmitate significantly improved in intensive insulin therapy (0.9 +/- 0.1 to 1.7 +/- 0.1 microm O(2)/CS/mg protein/min for state 3, p = .004; and 0.7 +/- 0.1 to 1.3 +/- 0.1 microm O(2)/CS/mg protein/min for state 4, p protocol improves insulin sensitivity and mitochondrial

Intranasal Insulin Restores Metabolic Parameters and Insulin Sensitivity in Rats with Metabolic Syndrome.

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Derkach, K V; Ivantsov, A O; Chistyakova, O V; Sukhov, I B; Buzanakov, D M; Kulikova, A A; Shpakov, A O

2017-06-01

We studied the effect of 10-week treatment with intranasal insulin (0.5 IU/day) on glucose tolerance, glucose utilization, lipid metabolism, functions of pancreatic β cells, and insulin system in the liver of rats with cafeteria diet-induced metabolic syndrome. The therapy reduced body weight and blood levels of insulin, triglycerides, and atherogenic cholesterol that are typically increased in metabolic syndrome, normalized glucose tolerance and its utilization, and increased activity of insulin signaling system in the liver, thus reducing insulin resistance. The therapy did not affect the number of pancreatic islets and β cells. The study demonstrates prospects of using intranasal insulin for correction of metabolic parameters and reduction of insulin resistance in metabolic syndrome.

Treatment with insulin (analogues) and breast cancer risk in diabetics; a systematic review and meta-analysis of in vitro, animal and human evidence

DEFF Research Database (Denmark)

Bronsveld, Heleen K; ter Braak, Bas; Karlstad, Øystein

2015-01-01

INTRODUCTION: Several studies have suggested that anti-diabetic insulin analogue treatment might increase cancer risk. The aim of this study was to review the postulated association between insulin and insulin analogue treatment and breast cancer development, and plausible mechanisms. METHOD......: A systematic literature search was performed on breast cell-line, animal and human studies using the key words 'insulin analogue' and 'breast neoplasia' in MEDLINE at PubMed, EMBASE, and ISI Web of Science databases. A quantitative and qualitative review was performed on the epidemiological data; due...

Acute effect of insulin on guinea pig airways and its amelioration by pre-treatment with salbutamol

International Nuclear Information System (INIS)

Sharif, M.; Khan, B. T.; Anwar, M. A.

2014-01-01

Objective: To study the magnitude of insulin-mediated airway hyper-reactivity and to explore the protective effects of salbutamol in inhibiting the insulin-induced airway hyper-responsiveness on tracheal smooth muscle of guinea pigs in vitro. Methods: The quasi-experimental study was conducted at the Pharmacology Department of Army Medical College, Rawalpindi, in collaboration with the Centre for Research in Experimental and Applied Medicine from December 2011 to July 2012. It used 18 healthy Dunkin Hartely guinea pigs of either gender. Effects of increasing concentrations of histamine (10-8-10-3M), insulin (10-8-10-3 M) and insulin pre-treated with salbutamol (10-6 M) were observed on isolated tracheal strip of guinea pig in vitro by constructing cumulative concentration response curves. The tracheal smooth muscle contractions were recorded with Transducer on Four Channel Oscillograph. Mean and standard error of mean were calculated. SPSS 16 was used for statistical analysis. Results: Histamine and insulin produced a concentration-dependent reversible contraction of isolated tracheal muscle of guinea pig. The mean of maximum amplitudes of contraction with histamine, insulin and insulin pre-treated with salbutamol were 92. 1.20 mm, 35+-1.13 mm and 14.55+-0.62 mm respectively. Salbutamol shifted the concentration response curve of insulin to the right and downwards. Conclusions: Salbutamol significantly reduced the insulin mediated airway hyper-reactivity in guinea pigs, suggesting that pre-treatment of inhaled insulin with salbutamol may have clinical implication in the amelioration of its potential respiratory adverse effects such as bronchoconstriction. (author)

Chronic insulin treatment of diabetes does not fully normalize alterations in the retinal transcriptome

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Kimball Scot R

2011-05-01

euglycemic diabetic rats. Gene expression changes not rescued or prevented by insulin treatment may be critical to the pathogenesis of diabetic retinopathy, as it occurs in diabetic patients receiving insulin replacement, and are prototypical of metabolic memory.

An observational 7-year study of continuous subcutaneous insulin infusion for the treatment of type 1 diabetes mellitus.

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Papargyri, Panagiota; Ojeda Rodríguez, Sylvie; Corrales Hernández, Juan José; Mories Álvarez, María Teresa; Recio Córdova, José María; Delgado Gómez, Manuel; Sánchez Marcos, Ana Isabel; Iglesias López, Rosa Ana; Herrero Ruiz, Ana; Beaulieu Oriol, Myriam; Miralles García, José Manuel

2014-03-01

This work reports the experience with use of continuous subcutaneous insulin infusion (CSII) in 112 type 1 diabetic patients followed up for 7 years and previously treated with multiple daily insulin injections (MDII). A retrospective, observational study in 112 patients with diabetes mellitus treated with CSII from 2005 to 2012, previously treated with MDII and receiving individualized diabetic education with a specific protocol. Variables analyzed included: prevalence of the different indications of pump treatment; mean annual HbA1c and fructosamine values before and after CSII treatment; and hypoglycemia frequency and symptoms. The most common reason for pump treatment was brittle diabetes (74.1%), followed by frequent or severe hypoglycemia or hypoglycemia unawareness (44.6%). Other indications were irregular food intake times for professional reasons (20.2%), dawn phenomenon (15.7%), pregnancy (12.3%), requirement of very low insulin doses (8.9%), and gestational diabetes (0.9%). HbA1c decreased by between 0.6% and 0.9%, and fructosamine by between 5.1% and 12.26%. Nine percent of patients experienced hypoglycemia weekly, 24% every two weeks, and 48% monthly. No hypoglycemia occurred in 19% of patients. Only 10% had neuroglycopenic symptoms. Hypoglycemia unawareness was found in 21%. Hypoglycemia was more common at treatment start, and its frequency rapidly decreased thereafter. CSII therapy provides a better glycemic control than MDII treatment. Specific patient training and fine adjustment of insulin infusion doses are required to prevent hypoglycemic episodes, which are the most common complications, mainly at the start of treatment. Copyright © 2013 SEEN. Published by Elsevier Espana. All rights reserved.

Transformation of Nonfunctioning Pancreatic Neuroendocrine Carcinoma Cells into Insulin Producing Cells after Treatment with Sunitinib

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Jung Hun Ohn

2013-06-01

Full Text Available We report a rare case of severe hypoglycemia after sunitinib treatment for pancreatic neuroendocrine carcinoma. We describe the initial clinical presentation, laboratory results, pathologic findings, and managment in a patient with a nonfunctioning pancreatic neuroendocrine carcinoma with liver metastases who developed life threatening hypoglycemia after 2 months of sunitinib therapy. A 46-year-old woman presented to the emergency department with loss of consciousness from hypoglycemia. Serum C-peptide and insulin levels at fasting state revealed that the hypoglycemia resulted from endogenous hyperinsulinemia. She had been diagnosed with nonfunctioning pancreatic neuroendocrine carcinoma based on a biopsy of metastatic cervical lymph node and was being treated with sunitinib, a small molecule tyrosine kinase inhibitor. Immunohistochemical stain of the metastatic liver mass demonstrated that the initially nonfunctioning neuroendocrine carcinoma cells had changed into insulin-producing cells after sunitinib therapy. Transarterial chemoembolization of the liver masses and systemic chemotherapy with streptozotocin/adriamycin relieved the hypoglycemia. A nonfunctioning pancreatic neuroendocrine carcinoma was transformed into an insulin-producing tumor after treatment with sunitinib, causing endogenous hyperinsulinemia and severe hypoglycemia.

Electron beam collimation with a photon MLC for standard electron treatments

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Mueller, S.; Fix, M. K.; Henzen, D.; Frei, D.; Frauchiger, D.; Loessl, K.; Stampanoni, M. F. M.; Manser, P.

2018-01-01

Standard electron treatments are currently still performed using standard or molded patient-specific cut-outs placed in the electron applicator. Replacing cut-outs and electron applicators with a photon multileaf collimator (pMLC) for electron beam collimation would make standard electron treatments more efficient and would facilitate advanced treatment techniques like modulated electron radiotherapy (MERT) and mixed beam radiotherapy (MBRT). In this work, a multiple source Monte Carlo beam model for pMLC shaped electron beams commissioned at a source-to-surface distance (SSD) of 70 cm is extended for SSDs of up to 100 cm and validated for several Varian treatment units with field sizes typically used for standard electron treatments. Measurements and dose calculations agree generally within 3% of the maximal dose or 2 mm distance to agreement. To evaluate the dosimetric consequences of using pMLC collimated electron beams for standard electron treatments, pMLC-based and cut-out-based treatment plans are created for a left and a right breast boost, a sternum, a testis and a parotid gland case. The treatment plans consist of a single electron field, either alone (1E) or in combination with two 3D conformal tangential photon fields (1E2X). For each case, a pMLC plan with similar treatment plan quality in terms of dose homogeneity to the target and absolute mean dose values to the organs at risk (OARs) compared to a cut-out plan is found. The absolute mean dose to an OAR is slightly increased for pMLC-based compared to cut-out-based 1E plans if the OAR is located laterally close to the target with respect to beam direction, or if a 6 MeV electron beam is used at an extended SSD. In conclusion, treatment plans using cut-out collimation can be replaced by plans of similar treatment plan quality using pMLC collimation with accurately calculated dose distributions.

Insulin Treatment Cannot Promote Lipogenesis in Rat Fetal Lung in Gestational Diabetes Mellitus Because of Failure to Redress the Imbalance Among SREBP-1, SCAP, and INSIG-1.

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Li, Jinyan; Qian, Guanhua; Zhong, Xiaocui; Yu, Tinghe

2018-03-01

Gestational diabetes mellitus (GDM) has a higher incidence of neonatal respiratory distress syndrome, and lipogenesis is required for the synthesis of pulmonary surfactants. The aim of this study was to determine the effect of insulin treatment in GDM on the production of lipids in the lungs of fetal rats. GDM was induced by streptozotocin, and insulin was used to manage diabetes. Type II alveolar epithelial cells (AEC II), bronchoalveolar lavage fluid (BALF), and lung tissues of the neonatal rats were sampled for analyses. Insulin treatment could not decrease plasma glucose to normal level at a later gestational stage. Lipids/phospholipids in AEC II, BALF, and lung tissues decreased in GDM, and insulin treatment could not increase the levels; quantitative PCR and western blotting demonstrated a lower level of sterol regulator element-binding protein 1 (SREBP-1), SREBP cleavage-activating protein (SCAP), and insulin-induced gene 1 (INSIG-1) in GDM, but insulin treatment upregulated only SREBP-1. Nuclear translocation of the SREBP-1 protein in AEC II was impaired in GDM, which could not be ameliorated by insulin treatment. These findings indicated that insulin treatment in GDM cannot promote lipogenesis in the fetal lung because of failure to redress the imbalance among SREBP-1, SCAP, and INSIG-1.

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.

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

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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

Insulin and Glucagon

DEFF Research Database (Denmark)

Holst, Jens Juul; Holland, William; Gromada, Jesper

2017-01-01

In August 2016, several leaders in glucagon biology gathered for the European Association for the Study of Diabetes Hagedorn Workshop in Oxford, England. A key point of discussion focused on the need for basal insulin to allow for the therapeutic benefit of glucagon blockade in the treatment...... of the discussion as a consensus was reached. Agents that antagonize glucagon may be of great benefit for the treatment of diabetes; however, sufficient levels of basal insulin are required for their therapeutic efficacy....

Effects of insulin-free plasma on the charcoal-separation method for radioimmunoassay of insulin

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Frayn, K N [Medical Research Council, Carshalton (UK). Toxicology Unit

1976-03-01

Radioimmunoassay of insulin in rat plasma using a popular method involving charcoal-separation of free and antibody-bound insulin was found to be unsatisfactory despite inclusion in standard tubes of insulin-free plasma prepared in either of two ways. Insulin-free plasma and untreated plasma had different effects on adsorption of free insulin to the charcoal. It was concluded that separation with charcoal is very sensitive to any prior treatment of the plasma. Particular care must be taken to ensure that hormone-free plasma is identical in all other respects to untreated plasma.

Insulin-induced CARM1 upregulation facilitates hepatocyte proliferation

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Yeom, Chul-gon; Kim, Dong-il; Park, Min-jung; Choi, Joo-hee [College of Veterinary Medicine, Chonnam National University, Gwangju 500-757 (Korea, Republic of); Jeong, Jieun; Wi, Anjin; Park, Whoashig [Jeollanamdo Forest Resources Research Institute, Naju 520-833 (Korea, Republic of); Han, Ho-jae [College of Veterinary Medicine, Seoul National University, Seoul 151-741 (Korea, Republic of); Park, Soo-hyun, E-mail: parksh@chonnam.ac.kr [College of Veterinary Medicine, Chonnam National University, Gwangju 500-757 (Korea, Republic of)

2015-06-05

Previously, we reported that CARM1 undergoes ubiquitination-dependent degradation in renal podocytes. It was also reported that CARM1 is necessary for fasting-induced hepatic gluconeogenesis. Based on these reports, we hypothesized that treatment with insulin, a hormone typically present under the ‘fed’ condition, would inhibit gluconeogenesis via CARM1 degradation. HepG2 cells, AML-12 cells, and rat primary hepatocytes were treated with insulin to confirm CARM1 downregulation. Surprisingly, insulin treatment increased CARM1 expression in all cell types examined. Furthermore, treatment with insulin increased histone 3 methylation at arginine 17 and 26 in HepG2 cells. To elucidate the role of insulin-induced CARM1 upregulation, the HA-CARM1 plasmid was transfected into HepG2 cells. CARM1 overexpression did not increase the expression of lipogenic proteins generally increased by insulin signaling. Moreover, CARM1 knockdown did not influence insulin sensitivity. Insulin is known to facilitate hepatic proliferation. Like insulin, CARM1 overexpression increased CDK2 and CDK4 expression. In addition, CARM1 knockdown reduced the number of insulin-induced G2/M phase cells. Moreover, GFP-CARM1 overexpression increased the number of G2/M phase cells. Based on these results, we concluded that insulin-induced CARM1 upregulation facilitates hepatocyte proliferation. These observations indicate that CARM1 plays an important role in liver pathophysiology. - Highlights: • Insulin treatment increases CARM1 expression in hepatocytes. • CARM1 overexpression does not increase the expression of lipogenic proteins. • CARM1 knockdown does not influence insulin sensitivity. • Insulin-induced CARM1 upregulation facilitates hepatocyte proliferation.

Insulin-induced CARM1 upregulation facilitates hepatocyte proliferation

International Nuclear Information System (INIS)

Yeom, Chul-gon; Kim, Dong-il; Park, Min-jung; Choi, Joo-hee; Jeong, Jieun; Wi, Anjin; Park, Whoashig; Han, Ho-jae; Park, Soo-hyun

2015-01-01

Previously, we reported that CARM1 undergoes ubiquitination-dependent degradation in renal podocytes. It was also reported that CARM1 is necessary for fasting-induced hepatic gluconeogenesis. Based on these reports, we hypothesized that treatment with insulin, a hormone typically present under the ‘fed’ condition, would inhibit gluconeogenesis via CARM1 degradation. HepG2 cells, AML-12 cells, and rat primary hepatocytes were treated with insulin to confirm CARM1 downregulation. Surprisingly, insulin treatment increased CARM1 expression in all cell types examined. Furthermore, treatment with insulin increased histone 3 methylation at arginine 17 and 26 in HepG2 cells. To elucidate the role of insulin-induced CARM1 upregulation, the HA-CARM1 plasmid was transfected into HepG2 cells. CARM1 overexpression did not increase the expression of lipogenic proteins generally increased by insulin signaling. Moreover, CARM1 knockdown did not influence insulin sensitivity. Insulin is known to facilitate hepatic proliferation. Like insulin, CARM1 overexpression increased CDK2 and CDK4 expression. In addition, CARM1 knockdown reduced the number of insulin-induced G2/M phase cells. Moreover, GFP-CARM1 overexpression increased the number of G2/M phase cells. Based on these results, we concluded that insulin-induced CARM1 upregulation facilitates hepatocyte proliferation. These observations indicate that CARM1 plays an important role in liver pathophysiology. - Highlights: • Insulin treatment increases CARM1 expression in hepatocytes. • CARM1 overexpression does not increase the expression of lipogenic proteins. • CARM1 knockdown does not influence insulin sensitivity. • Insulin-induced CARM1 upregulation facilitates hepatocyte proliferation

Limited Documentation and Treatment Quality of Glycemic Inpatient Care in Relation to Structural Deficits of Heterogeneous Insulin Charts at a Large University Hospital.

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Kopanz, Julia; Lichtenegger, Katharina M; Sendlhofer, Gerald; Semlitsch, Barbara; Cuder, Gerald; Pak, Andreas; Pieber, Thomas R; Tax, Christa; Brunner, Gernot; Plank, Johannes

2018-02-09

Insulin charts represent a key component in the inpatient glycemic management process. The aim was to evaluate the quality of structure, documentation, and treatment of diabetic inpatient care to design a new standardized insulin chart for a large university hospital setting. Historically grown blank insulin charts in use at 39 general wards were collected and evaluated for quality structure features. Documentation and treatment quality were evaluated in a consecutive snapshot audit of filled-in charts. The primary end point was the percentage of charts with any medication error. Overall, 20 different blank insulin charts with variable designs and significant structural deficits were identified. A medication error occurred in 55% of the 102 audited filled-in insulin charts, consisting of prescription and management errors in 48% and 16%, respectively. Charts of insulin-treated patients had more medication errors relative to patients treated with oral medication (P international standards, a new insulin chart was developed to overcome these quality hurdles.

Silica-Coated Liposomes for Insulin Delivery

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Neelam Dwivedi; M. A. Arunagirinathan; Somesh Sharma; Jayesh Bellare

2010-01-01

Liposomes coated with silica were explored as protein delivery vehicles for their enhanced stability and improved encapsulation efficiency. Insulin was encapsulated within the fluidic phosphatidylcholine lipid vesicles by thin film hydration at pH 2.5, and layer of silica was formed above lipid bilayer by acid catalysis. The presence of silica coating and encapsulated insulin was identified using confocal and electron microscopy. The native state of insulin present in the formulation was evid...

Targeting Insulin and Insulin-Like Growth Factor Pathways in Epithelial Ovarian Cancer

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Marie-Claude Beauchamp

2010-01-01

Full Text Available Ovarian cancer is the most lethal of all gynecological malignancies, due in part to the diagnosis at an advanced stage caused by the lack of specific signs and symptoms and the absence of reliable tests for screening and early detection. Most patients will respond initially to treatment but about 70% of them will suffer a recurrence. Therefore, new therapeutic modalities are urgently needed to overcome chemoresistance observed in ovarian cancer patients. Evidence accumulates suggesting that the insulin/insulin growth factor (IGF pathways could act as a good therapeutic target in several cancers, including ovarian cancer. In this paper, we will focus on the role of insulin/IGF in ovarian cancer tumorigenesis and treatment.

Implementation of telehealth support for patients with type 2 diabetes using insulin treatment: an exploratory study.

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Turner, Jane; Larsen, Mark; Tarassenko, Lionel; Neil, Andrew; Farmer, Andrew

2009-01-01

Initiating and adjusting insulin treatment for people with type 2 diabetes (T2D) requires frequent clinician contacts both face-to-face and by telephone. We explored the use of a telehealth system to offer additional support to these patients. Twenty-three patients with uncontrolled T2D were recruited from nine general practices to assess the feasibility and acceptability of telehealth monitoring and support for insulin initiation and adjustment. The intervention included a standard algorithm for self-titration of insulin dose, a Bluetooth enabled glucose meter linked to a mobile phone, an integrated diary to record insulin dose, feedback of charted blood glucose data and telehealth nurse review with telephone follow-up. Additional contact with patients was initiated when no readings were transmitted for >3 days or when persistent hyper- or hypoglycaemia was identified. Reponses of patients and clinicians to the system were assessed informally. The mean (SD) patient age was 58 years (12) with 78% male. The mean (SD) diabetes duration was 6.4 years (4.5), HbA1c at baseline was 9.5% (2.2), and the decrease in HbA1c at three months was 0.52% (0.91) with an insulin dose increase of 9 units (26). A mean (SD) of 160 (93) blood glucose readings was transmitted per patient in these three months. Practice nurses and general practitioners (GPs) viewed the technology as having the potential to improve patient care. Most patients were able to use the equipment with training and welcomed review of their blood glucose readings by a telehealth nurse. Although the concept of telehealth monitoring is unfamiliar to most patients and practice nurses, the technology improved the support available for T2D patients commencing insulin treatment.

In Vitro Palmitate Treatment of Myotubes from Postmenopausal Women Leads to Ceramide Accumulation, Inflammation and Affected Insulin Signaling

DEFF Research Database (Denmark)

Abildgaard, Julie; Henstridge, Darren C; Pedersen, Anette Tønnes

2014-01-01

Menopause is associated with an increased incidence of insulin resistance and metabolic diseases. In a chronic palmitate treatment model, we investigated the role of skeletal muscle fatty acid exposure in relation to the metabolic deterioration observed with menopause. Human skeletal muscle......, post-myotubes showed a blunted insulin stimulated phosphorylation of AS160 in response to chronic palmitate treatment compared with pre-myotubes (p = 0.02). The increased intramyocellular ceramide content in the post-myotubes was associated with a significantly higher mRNA expression of Serine...... Palmitoyltransferase1 (SPT1) after one day of palmitate treatment (p = 0.03) in post-myotubes compared with pre-myotubes. Our findings indicate that post-myotubes are more prone to develop lipid accumulation and defective insulin signaling following chronic saturated fatty acid exposure as compared to pre-myotubes....

Treatment of dwarfism with recombinant human insulin-like growth factor-1.

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Ranke, Michael B; Wölfle, Joachim; Schnabel, Dirk; Bettendorf, Markus

2009-10-01

The growth hormone-IGF (insulin-like growth factor) system plays a central role in hormonal growth regulation. Recombinant human (rh) growth hormone (GH) has been available since the late 1980s for replacement therapy in GH-deficient patients and for the stimulation of growth in patients with short stature of various causes. Growth promotion by GH occurs in part indirectly through the induction of IGF-1 synthesis. In primary disturbances of IGF-1 production, short stature can only be treated with recombinant human IGF-1 (rhIGF-1). rhIGF-1 was recently approved for this indication but can also be used to treat other conditions. Selective review of the literature on IGF-1 therapy, based on a PubMed search. In children with severe primary IGF-1 deficiency (a rare condition whose prevalence is less than 1:10,000), the prognosis for final height is very poor (ca. 130 cm), and IGF-1 therapy is the appropriate form of pathophysiologically based treatment. There is no alternative treatment at present. The subcutaneous administration of IGF-1 twice daily in doses of 80 to 120 microg/kg accelerates growth and increases final height by 12 to 15 cm, according to current data. There is, however, a risk of hypoglycemia, as IGF-1 has an insulin-like effect. As treatment with IGF-1 is complex, this new medication should only be prescribed, for the time being, by experienced pediatric endocrinologists and diabetologists.

[Continuous insulin therapy versus multiple insulin injections in the management of type 1 diabetes: a longitutinal study].

Science.gov (United States)

Ribeiro, Maria Estela Bellini; Del Roio Liberatore Junior, Raphael; Custodio, Rodrigo; Martinelli Junior, Carlos Eduardo

2016-01-01

To compare multiple doses of insulin and continuous insulin infusion therapy as treatment for type 1 diabetes melito. 40 patients with type 1 diabetes melito (21 female) with ages between 10 and 20 years (mean=14.2) and mean duration of diabetes of 7 years used multiple doses of insulin for at least 6 months and after that, continuous insulin infusion therapy for at least 6 months. Each one of the patients has used multiple doses of insulin and continuous insulin infusion therapy. For analysis of HbA1c, mean glycated hemoglobin levels (mHbA1c) were obtained during each treatment period (multiple doses of insulin and continuous insulin infusion therapy period). Although mHbA1c levels were lower during continuous insulin infusion therapy the difference was not statistically significant. During multiple doses of insulin, 14.2% had mHbA1c values below 7.5% vs. 35.71% while on continuous insulin infusion therapy; demonstrating better glycemic control with the use of continuous insulin infusion therapy. During multiple doses of insulin, 15-40 patients have severe hypoglycemic events versus 5-40 continuous insulin infusion therapy. No episodes of ketoacidosis events were recorded. This is the first study with this design comparing multiple doses of insulin and continuous insulin infusion therapy in Brazil showing no significant difference in HbA1c; hypoglycemic events were less frequent during continuous insulin infusion therapy than during multiple doses of insulin and the percentage of patients who achieved a HbA1c less than 7.5% was greater during continuous insulin infusion therapy than multiple doses of insulin therapy. Copyright © 2015 Sociedade de Pediatria de São Paulo. Publicado por Elsevier Editora Ltda. All rights reserved.

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

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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.

Role of PTEN in TNFα induced insulin resistance

International Nuclear Information System (INIS)

Bulger, David A.; Conley, Jermaine; Conner, Spencer H.; Majumdar, Gipsy; Solomon, Solomon S.

2015-01-01

Aims/hypothesis: PTEN may play a reversible role in TNFα induced insulin resistance, which has been linked to obesity-associated insulin resistance (IR). Methods: Western blots for PTEN and p-Akt were performed on H-411E liver cells incubated with insulin, TNFα, and in selected experiments VO-OHpic vanadium complex in the presence and absence of PTEN siRNA. Total PTEN was compared to β-actin loading control and p-Akt was compared to total Akt. Results: Western blot and Real Time RT-PCR experiments showed increased PTEN after TNFα treatment (p = 0.04); slightly decreased PTEN after insulin treatment; and slightly increased PTEN after insulin + TNFα treatment. PTEN siRNA markedly inhibited the TNFα-induced increase in PTEN (p < 0.01) without significantly changing the p-Akt levels. The vanadium complex, exhibiting insulin-like effects, also significantly prevented the TNFα-induced increase in PTEN. Combining insulin and VO-OHpic was additive, providing both proof of concept and insight into mechanism. Discussion: The PTEN increase due to TNFα treatment was reversible by both PTEN siRNA knockdown and VO-OHpic treatment. Thus, PTEN is identified as a potential new therapeutic target for reducing IR in Type 2 DM. - Highlights: • TNFα treatment induced a significant increase in PTEN in H-411E liver cells. • PTEN siRNA knockdown prevented this effect. • VO-OHpic (vanadium complex) treatment, like insulin, decreased PTEN protein levels. • Thus, PTEN is identified as a potential therapeutic target in DM Type 2

Role of PTEN in TNFα induced insulin resistance

Energy Technology Data Exchange (ETDEWEB)

Bulger, David A. [Departments of Medicine and Pharmacology, University of Tennessee Health Science Center, Memphis, TN 38163 (United States); Medicine and Research Services, Veterans Association Medical Center, Memphis, TN 38104 (United States); Wellcome Trust Medical Research Council Institute of Metabolic Science, Cambridge CB2 0QQ (United Kingdom); National Institute of Diabetes & Digestive & Kidney Disease, National Institutes of Health, Bethesda, MD 20892 (United States); Conley, Jermaine [Medicine and Research Services, Veterans Association Medical Center, Memphis, TN 38104 (United States); Conner, Spencer H.; Majumdar, Gipsy [Departments of Medicine and Pharmacology, University of Tennessee Health Science Center, Memphis, TN 38163 (United States); Medicine and Research Services, Veterans Association Medical Center, Memphis, TN 38104 (United States); Solomon, Solomon S., E-mail: ssolomon@uthsc.edu [Departments of Medicine and Pharmacology, University of Tennessee Health Science Center, Memphis, TN 38163 (United States); Medicine and Research Services, Veterans Association Medical Center, Memphis, TN 38104 (United States)

2015-06-05

Aims/hypothesis: PTEN may play a reversible role in TNFα induced insulin resistance, which has been linked to obesity-associated insulin resistance (IR). Methods: Western blots for PTEN and p-Akt were performed on H-411E liver cells incubated with insulin, TNFα, and in selected experiments VO-OHpic vanadium complex in the presence and absence of PTEN siRNA. Total PTEN was compared to β-actin loading control and p-Akt was compared to total Akt. Results: Western blot and Real Time RT-PCR experiments showed increased PTEN after TNFα treatment (p = 0.04); slightly decreased PTEN after insulin treatment; and slightly increased PTEN after insulin + TNFα treatment. PTEN siRNA markedly inhibited the TNFα-induced increase in PTEN (p < 0.01) without significantly changing the p-Akt levels. The vanadium complex, exhibiting insulin-like effects, also significantly prevented the TNFα-induced increase in PTEN. Combining insulin and VO-OHpic was additive, providing both proof of concept and insight into mechanism. Discussion: The PTEN increase due to TNFα treatment was reversible by both PTEN siRNA knockdown and VO-OHpic treatment. Thus, PTEN is identified as a potential new therapeutic target for reducing IR in Type 2 DM. - Highlights: • TNFα treatment induced a significant increase in PTEN in H-411E liver cells. • PTEN siRNA knockdown prevented this effect. • VO-OHpic (vanadium complex) treatment, like insulin, decreased PTEN protein levels. • Thus, PTEN is identified as a potential therapeutic target in DM Type 2.

Quinapril treatment increases insulin-stimulated endothelial function and adiponectin gene expression in patients with type 2 diabetes

DEFF Research Database (Denmark)

Hermann, Thomas S; Li, Weijie; Dominguez, Helena

2005-01-01

OBJECTIVE: Angiotensin-converting enzyme inhibitors reduce cardiovascular mortality and improve endothelial function in type 2 diabetic patients. We hypothesized that 2 months of quinapril treatment would improve insulin-stimulated endothelial function and glucose uptake in type 2 diabetic subjects...... and simultaneously increase the expression of genes that are pertinent for endothelial function and metabolism. METHODS: Twenty-four type 2 diabetic subjects were randomized to receive 2 months of quinapril 20 mg daily or no treatment in an open parallel study. Endothelium-dependent and -independent vasodilation...... occlusion plethysmography. Gene expression was measured by real-time PCR. RESULTS: Quinapril treatment increased insulin-stimulated endothelial function in the type 2 diabetic subjects (P = 0.005), whereas forearm glucose uptake was unchanged. Endothelial function was also increased by quinapril (P = 0...

Short- and long-term metabolic effects of recombinant human IGF-I treatment in patients with severe insulin resistance and diabetes mellitus

DEFF Research Database (Denmark)

Vestergaard, H; Rossen, M; Urhammer, S A

1997-01-01

In patients suffering from the genetic syndromes of severe insulin resistance it appears that diabetes develops when the adaptive hypersecretion of insulin fails and often these forms of diabetes will be insensitive to insulin treatment. The objective of the present study was to examine......-resistant diabetes mellitus and (b) during a long-term (10 weeks) period with rhIGF-I given once a day in a low dose (40 micrograms/kg body weight) in three of the four patients. Two siblings had known mutations in the tyrosine kinase domain of the insulin receptor and a deletion of exon 17 in part of their insulin......-50%), proinsulin (40-50%) and C-peptide (10-65%) and an improvement in glycaemic control as evaluated by decreased glycosylated haemoglobin and serum fructosamine. During the long-term study period blood glucose-lowering effects of rhIGF-I were seen after 2 weeks of treatment and fasting plasma glucose and serum...

Prevention of diabetes and cardiovascular disease in women with PCOS: treatment with insulin sensitizers.

Science.gov (United States)

Sharma, Susmeeta T; Nestler, John E

2006-06-01

Polycystic ovary syndrome (PCOS) is the most common cause of anovulatory infertility in United States, affecting 6-10% of females in the reproductive age group. Recent studies have shown that insulin resistance plays an important role in the pathogenesis of PCOS. Traditionally, management of PCOS consisted mainly of ovulation induction, treatment of acne and hirsutism, and prevention of endometrial cancer. However, with mounting evidence showing that PCOS is associated with dysmetabolic syndrome and an increased risk for developing diabetes and heart disease, this can no longer be our sole focus. Current data support a strong recommendation that women with PCOS should undergo comprehensive evaluation for diabetes and recognized cardiovascular risk factors and receive appropriate treatment as needed. Lifestyle modifications remain the first-line therapy for all obese women with PCOS. However, many obese women with PCOS find weight loss difficult to achieve and maintain, and this is not an option for lean women with PCOS. For these reasons, insulin-sensitizing drugs are proving to be a promising and unique therapeutic option for chronic treatment of PCOS.

Insulin resistance, insulin sensitization and inflammation in polycystic ovarian syndrome

Directory of Open Access Journals (Sweden)

Dhindsa G

2004-04-01

Full Text Available It is estimated that 5-10% of women of reproductive age have polycystic ovarian syndrome (PCOS. While insulin resistance is not part of the diagnostic criteria for PCOS, its importance in the pathogenesis of PCOS cannot be denied. PCOS is associated with insulin resistance independent of total or fat-free body mass. Post-receptor defects in the action of insulin have been described in PCOS which are similar to those found in obesity and type 2 diabetes. Treatment with insulin sensitizers, metformin and thiazolidinediones, improve both metabolic and hormonal patterns and also improve ovulation in PCOS. Recent studies have shown that PCOS women have higher circulating levels of inflammatory mediators like C-reactive protein, tumour necrosis factor- , tissue plasminogen activator and plasminogen activator inhibitor-1 (PAI-1 . It is possible that the beneficial effect of insulin sensitizers in PCOS may be partly due to a decrease in inflammation.

Comparison of the effects of intensive insulin treatment modalities on cardiovascular biomarkers in type 1 diabetes mellitus.

Science.gov (United States)

Cetinkalp, Sevki; Felekoglu, Canan; Karadeniz, Muammer; Boyacıoglu, Hayal; Delen, Yasemin; Yildirim, Eser; Yilmaz, Candeger

2015-01-01

To evaluate effects of intensive insulin treatment modalities on cardiovascular biomarkers in patients with type 1 diabetes mellitus (T1DM). A total of 25 patients with T1DM receiving intensive insulin therapy either in the form of continuous insulin pump (IP group; n=13) or as multiple daily injections (MDI group; n=12) and 13 controls (control group, n=13) were included. Data on demographics, anthropometrics, diabetes history, and laboratory findings including glycemic and lipid parameters, and cardiovascular biomarkers [C-reactive protein (mg/dL), homocysteine (μmol/L), fibrinogen (mg/dL), oxidized LDL (ng/dL), PAI-1 (ng/mL), MCP-1 (pg/mL) and VEGF (pg/mL)] were recorded in each group. Correlation of cardiovascular biomarkers to other parameters was also evaluated in T1DM patients. Apart from significantly higher mean (SD) values for HbA1c [6.1 (0.3) vs. 5.6 (0.5)% (43 (3) vs. 38 (5) mmol/mol), p1.5 (13.6) vs. 58.2 (10.8), p1) in the IP than in the MDI group, no significance difference was noted between insulin treatment modalities as well as between patient and control groups in terms of demographic, anthropometric and laboratory parameters. Negative correlation of MCP-1 to treatment duration (r=-0.615, p=0.025), and HDL-c to CRP (r=-0.685, p=0.010) and VEGF (r=-0.678, p=0.011) was noted in IP group, whereas positive correlation of PAI-1 to diabetes age (r=0.805, p=0.002) and treatment duration was noted in MDI group. Our findings in a cohort of T1DM patients with optimal glycemic control revealed that intensive insulin therapy was not associated with an increase in atherosclerotic markers in T1DM, regardless of whether continuous IP infusion or MDIs was administered. Copyright © 2015 Diabetes India. Published by Elsevier Ltd. All rights reserved.

Health-Related Quality of Life, Treatment Satisfaction, and Costs Associated With Intraperitoneal Versus Subcutaneous Insulin Administration in Type 1 Diabetes

NARCIS (Netherlands)

Logtenberg, Susan J.; Kleefstra, Nanne; Houweling, Sebastiaan T.; Groenier, Klaas H.; Gans, Reinold O.; Bilo, Henk J.

OBJECTIVE - To investigate the effects of continuous intraperitoneal insulin infusion (CIPII) compared with subcutaneous insulin on health-related quality of life (HRQOL) and treatment satisfaction, and to perform a cost analysis in type 1 diabetes. RESEARCH DESIGN AND METHODS - We used an

Testosterone treatment increases androgen receptor and aromatase gene expression in myotubes from patients with PCOS and controls, but does not induce insulin resistance.

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Eriksen, Mette Brandt; Glintborg, Dorte; Nielsen, Michael Friberg Bruun; Jakobsen, Marianne Antonius; Brusgaard, Klaus; Tan, Qihua; Gaster, Michael

2014-09-05

Polycystic ovary syndrome (PCOS) is associated with insulin resistance and increased risk of type 2 diabetes. Skeletal muscle is the major site of insulin mediated glucose disposal and the skeletal muscle tissue is capable to synthesize, convert and degrade androgens. Insulin sensitivity is conserved in cultured myotubes (in vitro) from patients with PCOS, but the effect of testosterone on this insulin sensitivity is unknown. We investigated the effect of 7days testosterone treatment (100nmol/l) on glucose transport and gene expression levels of hormone receptors and enzymes involved in the synthesis and conversion of testosterone (HSD17B1, HSD17B2, CYP19A1, SRD5A1-2, AR, ER-α, HSD17B6 and AKR1-3) in myotubes from ten patients with PCOS and ten matched controls. Testosterone treatment significantly increased aromatase and androgen receptor gene expression levels in patients and controls. Glucose transport in myotubes was comparable in patients with PCOS vs. controls and was unchanged by testosterone treatment (p=0.21 PCOS vs. controls). These results suggest that testosterone treatment of myotubes increases the aromatase and androgen receptor gene expression without affecting insulin sensitivity and if testosterone is implicated in muscular insulin resistance in PCOS, this is by and indirect mechanism. Copyright © 2014 Elsevier Inc. All rights reserved.

Insulin and 20-hydroxyecdysone action in Bombyx mori: Glycogen content and expression pattern of insulin and ecdysone receptors in fat body.

Science.gov (United States)

Keshan, Bela; Thounaojam, Bembem; Kh, Sanathoibi D

2017-01-15

Insulin and ecdysone signaling play a critical role on the growth and development of insects including Bombyx mori. Our previous study showed that Bombyx larvae reached critical weight for metamorphosis between day 3.5 and 4 of the fifth larval instar. The present study showed that the effect of insulin on the accumulation of glycogen in fat body of Bombyx larvae depends on the critical growth period. When larvae are in active growth period (before reaching critical weight), insulin caused increased accumulation of glycogen, while its treatment in larvae at terminal growth period (after critical period) resulted in an increased mobilization of glycogen. During terminal growth period, insulin and 20-hydroxyecdysone (20E) showed an antagonistic effect on the accumulation of fat body glycogen in fed, food deprived and decapitated larvae as well as in isolated abdomens. Insulin treatment decreased the glycogen content, whereas, 20E increased it. Food deprivation and decapitation caused an increase in the transcript levels of insulin receptor (InR) and this increase in InR expression might be attributed to a decrease in synthesis/secretion of insulin-like peptides, as insulin treatment in these larvae showed a down-regulation in InR expression. However, insulin showed an up-regulation in InR in isolated abdomens and it suggests that in food deprived and decapitated larvae, the exogenous insulin may interact with some head and/or thoracic factors in modulating the expression of InR. Moreover, in fed larvae, insulin-mediated increase in InR expression indicates that its regulation by insulin-like peptides also depends on the nutritional status of the larvae. The treatment of 20E in fed larvae showed an antagonistic effect on the transcript levels since a down-regulation in InR expression was observed. 20E treatment also led to a decreased expression of InR in food deprived and decapitated larvae as well as in isolated abdomens. Insulin and 20E also modulated the

The effect of tubing dwell time on insulin adsorption during intravenous insulin infusions.

Science.gov (United States)

Thompson, Cecilia D; Vital-Carona, Jessica; Faustino, E Vincent S

2012-10-01

Insulin adsorbs to plastic tubing, which decreases the concentration of an insulin solution delivered from an intravenous infusion set. Dwelling insulin within tubing before starting the infusion decreases adsorption but delays treatment initiation and wastes time in infusion preparation. The lack of data on dwell time effects results in wide variability in practice. We aim to determine the effect of dwell time on insulin concentration from intravenous infusion tubing. In this in vitro study, we used insulin solutions with concentrations of 0.1 unit/mL, 1 unit/mL, and 10 units/mL. Each solution dwelled in intravenous infusion sets for 0, 15, 30, or 60 min. After the dwell, we measured insulin concentrations from the solution bags and tubing. We repeated each insulin concentration-dwell time combination five times. Comparisons were performed using analyses of variance. For each of the three insulin concentrations, the mean insulin concentrations from the tubing were not significantly different between dwell times. Duration of dwell time did not affect insulin adsorption in polypropylene intravenous infusion sets. We recommend that following a 20-mL flush, insulin infusions can be started without any dwell time. Removal of dwell times may improve clinical practice by minimizing preparation time and will allow faster initiation of insulin infusion therapy.

Novel simple insulin delivery device reduces barriers to insulin therapy in type 2 diabetes: results from a pilot study.

Science.gov (United States)

Hermanns, Norbert; Lilly, Leslie C; Mader, Julia K; Aberer, Felix; Ribitsch, Anja; Kojzar, Harald; Warner, Jay; Pieber, Thomas R

2015-05-01

The PaQ® insulin delivery system is a simple-to-use patch-on device that provides preset basal rates and bolus insulin on demand. In addition to feasibility of use, safety, and efficacy (reported elsewhere), this study analyzed the impact of PaQ on patient-reported outcomes, including barriers to insulin treatment, diabetes-related distress, and attitudes toward insulin therapy in patients with type 2 diabetes on a stable multiple daily injection (MDI) regimen. This single-center, open-label, single-arm study comprised three 2-week periods: baseline (MDI), transition from MDI to PaQ, and PaQ treatment. Validated questionnaires were administered during the baseline and PaQ treatment periods: Barriers to Insulin Treatment questionnaire (BIT), Insulin Treatment Appraisal Scale (ITAS), and Problem Areas in Diabetes scale (PAID). Eighteen patients (age 59 ± 5 years, diabetes duration 15 ± 7 years, 21% female, HbA1c 7.7 ± 0.7%) completed the questionnaires. There was a strong, significant effect of PaQ use in mean BIT total scores (difference [D] = -5.4 ± 0.7.7, P = .01, effect size [d] = 0.70). Patients perceived less stigmatization by insulin injection (D = -2.2 ± 6.2, P = .18, d = 0.35), increased positive outcome (D = 1.9 ± 6.6, P = .17, d = 0.29), and less fear of injections (1.3 ± 4.8, P = .55, d = 0.28). Mean change in ITAS scores after PaQ device use showed a nonsignificant improvement of 1.71 ± 5.63 but moderate effect size (d = 0.30, P = .14). No increase in PAID scores was seen. The results and moderate to large effects sizes suggest that PaQ device use has beneficial and clinically relevant effects to overcoming barriers to and negative appraisal of insulin treatment, without increasing other diabetes-related distress. © 2015 Diabetes Technology Society.

Neonatal and obstetric outcomes in diet- and insulin-treated women with gestational diabetes mellitus : a retrospective study

NARCIS (Netherlands)

Koning, Sarah H.; Hoogenberg, Klaas; Scheuneman, Kirsten A.; Baas, Mick G.; Korteweg, Fleurisca J.; Sollie, Krystyna M.; Schering, Bertine J.; van Loon, Aren J.; Wolffenbuttel, Bruce H. R.; van den Berg, Paul P.; Lutgers, Helen L.

2016-01-01

Background: To evaluate the neonatal and obstetric outcomes of pregnancies complicated by gestational diabetes mellitus (GDM). Screening and treatment-diet-only versus additional insulin therapy-were based on the 2010 national Dutch guidelines. Methods: Retrospective study of the electronic medical

Electron beam treatment of industrial wastewater

International Nuclear Information System (INIS)

Han, Bumsoo; Kim, JinKyu; Kim, Yuri

2004-01-01

For industrial wastewater with low impurity levels such as contaminated ground water, cleaning water and etc., purification only with electron beam is possible, but it should be managed carefully with reducing required irradiation doses as low as possible. Also for industrial wastewater with high impurity levels such as dyeing wastewater, leachate and etc., purification only with electron beam requires high amount of doses and far beyond economies. Electron beam treatment combined with conventional purification methods such as coagulation, biological treatment, etc. is suitable for reduction of non-biodegradable impurities in wastewater and will extend the application area of electron beam. A pilot plant with electron beam for treating 1,000 m 3 /day of wastewater from dyeing industries has constructed and operated continuously since Oct 1998. Electron beam irradiation instead of chemical treatment shows much improvement in removing impurities and increases the efficiency of biological treatment. Actual plant is under consideration based upon the experimental results. (author)

Intranasal insulin therapy: the clinical realities

DEFF Research Database (Denmark)

Hilsted, J; Madsbad, Sten; Hvidberg, A

1995-01-01

To evaluate metabolic control and safety parameters (hypoglycaemia frequency and nasal mucosa physiology), 31 insulin-dependent diabetic patients were treated with intranasal insulin at mealtimes for 1 month and with subcutaneous fast-acting insulin at meals for another month in an open, crossover...... randomized trial. During both treatment periods the patients were treated with intermediate-acting insulin at bedtime. Six of the patients were withdrawn from the study during intranasal insulin therapy due to metabolic dysregulation. Serum insulin concentrations increased more rapidly and decreased more...... quickly during intranasal as compared with subcutaneous insulin administration. Metabolic control deteriorated, as assessed by haemoglobin A1c concentrations, slightly but significantly after intranasal as compared with subcutaneous insulin therapy. The bioavailability of intranasally applied insulin...

Diabetes, insulin and exercise

DEFF Research Database (Denmark)

Richter, Erik; Galbo, H

1986-01-01

The metabolic and hormonal adaptations to single exercise sessions and to exercise training in normal man and in patients with insulin-dependent as well as non-insulin-dependent diabetes mellitus are reviewed. In insulin-dependent (type I) diabetes good metabolic control is best obtained...... by a regular pattern of life which will lead to a fairly constant demand for insulin from day to day. Exercise is by nature a perturbation that makes treatment of diabetes difficult: Muscle contractions per se tend to decrease the plasma glucose concentration whereas the exercise-induced response of the so......-called counter-regulatory hormones tend to increase plasma glucose by increasing hepatic glucose production and adipose tissue lipolysis. If the pre-exercise plasma insulin level is high, hypoglycaemia may develop during exercise whereas hyperglycaemia and ketosis may develop if pre-exercise plasma insulin...

Switching to multiple daily injection therapy with glulisine improves glycaemic control, vascular damage and treatment satisfaction in basal insulin glargine-injected diabetic patients.

Science.gov (United States)

Yanagisawa, Katsuyuki; Ashihara, Junya; Obara, Shinji; Wada, Norio; Takeuchi, Masayoshi; Nishino, Yuri; Maeda, Sayaka; Ishibashi, Yuji; Yamagishi, Sho-ichi

2014-11-01

Basal and bolus insulin therapy is required for strict blood control in diabetic patients, which could lead to prevention of vascular complications in diabetes. However, the optimal combination regimen is not well established. Fifty-nine diabetic patients (49 type 1 and 10 type 2; 52.9 ± 13.3 years old) whose blood glucose levels were uncontrolled (HbA1c  > 6.2%) by combination treatment of basal insulin glargine with multiple daily pre-meal injections of bolus short-acting insulin [aspart (n = 19), lispro (n = 37) and regular human insulin (n = 3)] for at least 8 weeks were enrolled in this study. We examined whether glycaemic control and vascular injury were improved by replacement of short-acting insulin with glulisine. Patient satisfaction was assessed with Diabetes Treatment Satisfaction Questionnaire. Although bolus and basal insulin doses were almost unchanged before and after replacement therapy, switching to glulisine insulin for 24 weeks significantly decreased level of HbA1c , advanced glycation end products (AGEs), soluble receptor for AGEs (sRAGE), monocyte chemoattractant protein-1 (MCP-1) and urinary albumin excretion. In multiple stepwise regression analysis, change in MCP-1 values from baseline (ΔMCP-1) was a sole determinant of log urinary albumin excretion. ΔAGEs and ΔsRAGE were independently correlated with each other. The relationship between ΔMCP-1 and ΔsRAGE was marginally significant (p = 0.05). Replacement of short-acting insulin by glulisine significantly increased Diabetes Treatment Satisfaction Questionnaire scores. Our present study suggests that combination therapy of glargine with multiple daily pre-meal injections of glulisine might show superior efficacy in controlling blood glucose, preventing vascular damage and improving treatment satisfaction in diabetic patients. Copyright © 2014 John Wiley & Sons, Ltd.

Silica-Coated Liposomes for Insulin Delivery

Directory of Open Access Journals (Sweden)

Neelam Dwivedi

2010-01-01

Full Text Available Liposomes coated with silica were explored as protein delivery vehicles for their enhanced stability and improved encapsulation efficiency. Insulin was encapsulated within the fluidic phosphatidylcholine lipid vesicles by thin film hydration at pH 2.5, and layer of silica was formed above lipid bilayer by acid catalysis. The presence of silica coating and encapsulated insulin was identified using confocal and electron microscopy. The native state of insulin present in the formulation was evident from Confocal Micro-Raman spectroscopy. Silica coat enhances the stability of insulin-loaded delivery vehicles. In vivo study shows that these silica coated formulations were biologically active in reducing glucose levels.

Mechanisms of insulin resistance in obesity

Science.gov (United States)

Ye, Jianping

2014-01-01

Obesity increases the risk for type 2 diabetes through induction of insulin resistance. Treatment of type 2 diabetes has been limited by little translational knowledge of insulin resistance although there have been several well-documented hypotheses for insulin resistance. In those hypotheses, inflammation, mitochondrial dysfunction, hyperinsulinemia and lipotoxicity have been the major concepts and have received a lot of attention. Oxidative stress, endoplasmic reticulum (ER) stress, genetic background, aging, fatty liver, hypoxia and lipodystrophy are active subjects in the study of these concepts. However, none of those concepts or views has led to an effective therapy for type 2 diabetes. The reason is that there has been no consensus for a unifying mechanism of insulin resistance. In this review article, literature is critically analyzed and reinterpreted for a new energy-based concept of insulin resistance, in which insulin resistance is a result of energy surplus in cells. The energy surplus signal is mediated by ATP and sensed by adenosine monophosphate-activated protein kinase (AMPK) signaling pathway. Decreasing ATP level by suppression of production or stimulation of utilization is a promising approach in the treatment of insulin resistance. In support, many of existing insulin sensitizing medicines inhibit ATP production in mitochondria. The effective therapies such as weight loss, exercise, and caloric restriction all reduce ATP in insulin sensitive cells. This new concept provides a unifying cellular and molecular mechanism of insulin resistance in obesity, which may apply to insulin resistance in aging and lipodystrophy. PMID:23471659

A Review of the Clinical Efficacy and Safety of Insulin Degludec and Glargine 300 U/mL in the Treatment of Diabetes Mellitus.

Science.gov (United States)

Woo, Vincent C

2017-08-01

The treatment of type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) using insulin is not ideal at this time. Despite advances made with basal insulin analogues, many individuals achieve less than optimal glycemic control or are at risk for hypoglycemia. Currently available basal insulin analogues do not deliver steady, peakless, continuous insulin for >24 hours and are associated with adverse events, including hypoglycemia. The objective of this paper was to review the clinical efficacy and safety of upcoming long-acting insulin analogues such as insulin degludec and insulin glargine 300 U/mL (Gla-300). A comprehensive literature search of PubMed and Google Scholar was conducted from 1966 to 2015. The search included randomized controlled trials that specifically assessed the efficacy and safety of insulin degludec and Gla-300 in patients with T1DM and T2DM. The efficacy of insulin degludec and Gla-300 in achieving glycemic control has been reported in clinical trials in adults with T1DM and T2DM. Not only did a large number of patients succeed in meeting glycosylated hemoglobin targets, but they also experienced reductions in hypoglycemic events. These 2 therapies are associated with a reduced risk of nocturnal hypoglycemia and are generally well tolerated. The long-acting insulin analogues insulin degludec and Gla-300 are promising therapies in the treatment of T1DM and T2DM. Their improved insulin delivery for >24 hours offers glycemic control with a good safety profile. Copyright © 2017 Elsevier HS Journals, Inc. All rights reserved.

Evaluation of immunogenicity of LY2963016 insulin glargine compared with Lantus® insulin glargine in patients with type 1 or type 2 diabetes mellitus.

Science.gov (United States)

Ilag, L L; Deeg, M A; Costigan, T; Hollander, P; Blevins, T C; Edelman, S V; Konrad, R J; Ortmann, R A; Pollom, R K; Huster, W J; Zielonka, J S; Prince, M J

2016-02-01

To compare the immunogenicity profiles and the potential effects on clinical outcomes of LY2963016 insulin glargine (LY IGlar) and Lantus® insulin glargine (IGlar), products with identical primary amino acid sequences, in patients with type 1 or type 2 diabetes mellitus (T1DM or T2DM). To assess immunogenicity, anti-insulin glargine antibodies (measured as percent binding) were compared between treatments in 52-week (open-label) and 24-week (double-blind) randomized studies in total study populations of patients with T1DM (N = 535) and T2DM (N = 756), respectively, and two subgroups of patients with T2DM: insulin-naïve patients and those reporting prestudy IGlar treatment (prior IGlar). Relationships between insulin antibody levels and clinical outcomes were assessed using analysis of covariance and partial correlations. Insulin antibody levels were assessed using Wilcoxon rank sum. Treatment comparisons for treatment-emergent antibody response (TEAR) and incidence of detectable antibodies were analysed using Fisher's exact test. No significant treatment differences were observed for insulin antibody levels, incidence of detectable anti-insulin glargine antibodies, or incidence of TEAR [overall and endpoint, by last-observation-carried-forward (LOCF)] in patients with T1DM or patients with T2DM, including the insulin-naïve subgroup. A statistically significant difference was noted in the overall incidence of detectable antibodies but not at endpoint (LOCF) nor in TEAR for the prior IGlar subgroup of patients with T2DM. Insulin antibody levels were low (Insulin antibody levels or developing TEAR was not associated with clinical outcomes. LY IGlar and IGlar have similar immunogenicity profiles; anti-insulin glargine antibody levels were low for both treatments, with no observed effect on efficacy and safety outcomes. © 2015 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

Comparison of Insulin Detemir and Insulin Glargine for Hospitalized Patients on a Basal-Bolus Protocol

Directory of Open Access Journals (Sweden)

Sondra Davis

2017-04-01

Full Text Available BACKGROUND: The primary purpose of this study is to determine whether insulin detemir is equivalent to insulin glargine in controlling hyperglycemia for the adult hospitalized patient on a basal-bolus treatment regimen. METHODS: A retrospective study was conducted at two acute care hospitals within the same health system. Patients from both facilities who were initiated on a basal-bolus subcutaneous insulin regimen were included in the study. The basal-bolus regimen consisted of three components: basal, bolus, and corrective insulin with only the data from the first seven days analyzed. Once the basal-bolus protocol was initiated, all previous glycemic agents were discontinued. The target glycemic goal of the study was 100–180 mg/dL. RESULTS: In both groups, 50% of the patients had achieved the target glycemic control goal (100–180 mg/dL by day 2 (p = 0.3. However, on the seventh or last day of basal-bolus treatment, whichever came first, 36.36% of patients receiving insulin detemir (n = 88 achieved the blood glucose reading goal compared to 52.00% in patients receiving insulin glargine (n = 100 (p = 0.03. This corresponded to an adjusted odds ratio of 2.12 (1.08 to 4.15, p = 0.03. The adjusting variables were provider type, whether the patient was hospitalized within 30 days prior and diagnosis of stroke. The mean blood glucose readings for the insulin glargine and the insulin detemir groups while on basal-bolus therapy were 200 mg/dL and 215 mg/dL, respectively (p = 0.05. The total number of blood glucose readings less than 70 mg/dL and less than 45 mg/dL was very low and there were no differences in number of episodes with hypoglycemia between the two groups. CONCLUSION: There was not a statistical difference between the two groups at 2 days, however there was on the seventh day or the last day of basal-bolus treatment. There were nonsignificant hypoglycemia events between basal insulin groups and the results for the last or seventh day

The impact of pegylated interferon and ribavirin combination treatment on lipid metabolism and insulin resistance in chronic hepatitis C patients.

Science.gov (United States)

Jung, Hee Jae; Kim, Young Seok; Kim, Sang Gyune; Lee, Yun Nah; Jeong, Soung Won; Jang, Jae Young; Lee, Sae Hwan; Kim, Hong Soo; Kim, Boo Sung

2014-03-01

Lipid profile and insulin resistance (IR) are associated with hepatitis C virus (HCV) and may predict the chronic hepatitis C (CHC) treatment response. The aim of this study was to determine the association between CHC treatment response and lipid profile and IR change during treatment. In total, 203 CHC patients were reviewed retrospectively between January 2005 and December 2011 at Soon Chun Hyang University Hospital. The lipid profile, homeostasis model for assessment (HOMA) of IR (HOMA-IR), and HOMA of β cells (HOMA-β) were evaluated before interferon plus ribavirin therapy (BTx), at the end of treatment (DTx), and 24 weeks after the end of treatment (ATx). A sustained virologic response (SVR) was achieved by 81% of all patients (49/60), 60% (n=36) of whom possessed genotype 1, with the remainder being non-genotype-1 (40%, n=24). Apart from age, which was significantly higher in the non-SVR group (SVR, 48.0 ± 11.2 years, mean ± SD; non-SVR, 56.6 ± 9.9 years; PC) had significantly changed at DTx and ATx compared to BTx. In addition, HOMA-IR and HOMA-β were significantly changed at DTx in the SVR group. Among those with a high baseline insulin resistance (HOMA-IR >2.5), HOMA-IR was significantly changed at DTx in the SVR group. LDL-C appears to be associated with HCV treatment in SVR patients. Furthermore, eradication of HCV may improve whole-body IR and insulin hypersecretion, as well as high baseline insulin resistance (HOMA-IR >2.5).

Effect of Anthelmintic Treatment on Insulin Resistance: A Cluster-Randomized, Placebo-Controlled Trial in Indonesia

NARCIS (Netherlands)

Tahapary, D.L.; Ruiter, K. de; Martin, I.; Brienen, E.A.T.; Lieshout, L. van; Cobbaert, C.M.; Soewondo, P.; Djuardi, Y.; Wiria, A.E.; Houwing-Duistermaat, J.J.; Sartono, E.; Smit, J.W.A.; Yazdanbakhsh, M.; Supali, T.

2017-01-01

Background: Emerging evidence suggests that helminth infections are associated with lower insulin resistance (IR). Current deworming programs might remove this helminth-associated protective effect. Therefore, we evaluated the anthelmintic treatment effect on changes in IR. Methods: We conducted a

Severe hypoglycaemia in a person with insulin autoimmune syndrome accompanied by insulin receptor anomaly type B.

Science.gov (United States)

Kato, T; Itoh, M; Hanashita, J; Itoi, T; Matsumoto, T; Ono, Y; Imamura, S; Hayakawa, N; Suzuki, A; Mizutani, Y; Uchigata, Y; Oda, N

2007-11-01

A rare case of the insulin autoimmune syndrome (IAS) accompanied by insulin receptor anomaly is reported. Antibodies to insulin and insulin receptor were determined in the patient with severe hypoglycaemia before and after the treatment with prednisolone. Titers of antibody to insulin and insulin receptors were 73.0% and 41.5%, respectively. Drug-induced lymphocyte stimulation tests were all negative for the suspicious drugs. Her HLA-DR was DRB1*0403/04051. Following steroid therapy, the formation of antibodies was suppressed and alleviated her symptoms. Scatchard analysis yielded findings specific to polyclonal antibodies. The changes in autoantibodies resulted in alleviation of the hypoglycemic symptoms as a result of steroid therapy.

Application of insulin-like growth factor-I and insulin release test in diabetes mellitus

International Nuclear Information System (INIS)

Chen Dong; Ma Yongxiu; Duan Wenruo

2003-01-01

The purpose of this study was to determine the role of insulin-like growth factor-I (IGF-I) and insulin release test (IRT) in understanding the extent of damage to ability of reducing blood sugar in different types of diabetes mellitus (DM) and in selection of treatment plan and adjustment of using drugs. OGTT, IRT and determination of IGF-I level of 67 normal subjects and 217 DM patients were performed. The result was analyzed comparatively. The level of IGF-I was negatively correlated with the level of fasting blood sugar, and positively correlated with the level of fasting insulin. Our conclusions are: There are two ways of reducing blood sugar: one is by insulin, and the other is by IGF-I. IRT can reflect the former better, and IGF-I the latter. The combination of these two is of significant value in diagnosis and treatment of DM

Biphasic insulin aspart 30/70 (BIAsp 30 in the treatment of type 1 and type 2 diabetes

Directory of Open Access Journals (Sweden)

Paul Valensi

2009-06-01

Full Text Available Paul ValensiDepartment of Endocrinology-Diabetology-Nutrition, Jean Verdier Hospital, AP-HP, Paris Nord University, CRNH-IdF, Bondy, FranceAbstract: The pharmacological advantages of the rapid-acting analog, insulin aspart, over human insulin have contributed to the widespread prescription of the premix, biphasic insulin aspart 30/70 (BIAsp 30, in type 1 (T1DM and type 2 diabetes (T2DM. This article reviews the available literature on the pharmacology, efficacy and safety of BIAsp 30 in T1DM and T2DM from an online search of the PubMed database. Following injection, BIAsp 30 reaches higher plasma insulin levels more quickly than human premix or basal insulin, giving effective reduction of postprandial hyperglycemia. In T1DM patients, randomized controlled trials (RCTs have shown that HbA1c reduction is similar, but postprandial glycemic control is better, with BIAsp 30 than with human insulin regimens. In T2DM patients, lowering of HbA1c and postprandial hyperglycemia with BIAsp 30 compare favorably with optimized oral antidiabetes drug treatment, insulin glargine, and, in obese patients, human premix. An increase in minor hypoglycemia with BIAsp 30 relative to basal insulin has been reported in T2DM patients, but major and nocturnal hypoglycemia rates are generally low. Findings from RCTs in T2DM patients are supported by large observational studies. In summary, BIAsp 30 once to three times daily represents a simple and effective tool for the modern management of diabetes.Keywords: biphasic insulin aspart, BIAsp 30, premix, type 1 diabetes, type 2 diabetes

Short-acting insulin analogues versus regular human insulin for adults with type 1 diabetes mellitus.

Science.gov (United States)

Fullerton, Birgit; Siebenhofer, Andrea; Jeitler, Klaus; Horvath, Karl; Semlitsch, Thomas; Berghold, Andrea; Plank, Johannes; Pieber, Thomas R; Gerlach, Ferdinand M

2016-06-30

Short-acting insulin analogue use for people with diabetes is still controversial, as reflected in many scientific debates. To assess the effects of short-acting insulin analogues versus regular human insulin in adults with type 1 diabetes. We carried out the electronic searches through Ovid simultaneously searching the following databases: Ovid MEDLINE(R), Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily and Ovid OLDMEDLINE(R) (1946 to 14 April 2015), EMBASE (1988 to 2015, week 15), the Cochrane Central Register of Controlled Trials (CENTRAL; March 2015), ClinicalTrials.gov and the European (EU) Clinical Trials register (both March 2015). We included all randomised controlled trials with an intervention duration of at least 24 weeks that compared short-acting insulin analogues with regular human insulins in the treatment of adults with type 1 diabetes who were not pregnant. Two review authors independently extracted data and assessed trials for risk of bias, and resolved differences by consensus. We graded overall study quality using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) instrument. We used random-effects models for the main analyses and presented the results as odds ratios (OR) with 95% confidence intervals (CI) for dichotomous outcomes. We identified nine trials that fulfilled the inclusion criteria including 2693 participants. The duration of interventions ranged from 24 to 52 weeks with a mean of about 37 weeks. The participants showed some diversity, mainly with regard to diabetes duration and inclusion/exclusion criteria. The majority of the trials were carried out in the 1990s and participants were recruited from Europe, North America, Africa and Asia. None of the trials was carried out in a blinded manner so that the risk of performance bias, especially for subjective outcomes such as hypoglycaemia, was present in all of the trials. Furthermore, several trials showed inconsistencies in

Testosterone treatment increases androgen receptor and aromatase gene expression in myotubes from patients with PCOS and controls, but does not induce insulin resistance

DEFF Research Database (Denmark)

Eriksen, Mette Brandt; Glintborg, Dorte; Nielsen, Michael Friberg Bruun

2014-01-01

Polycystic ovary syndrome (PCOS) is associated with insulin resistance and increased risk of type 2 diabetes. Skeletal muscle is the major site of insulin mediated glucose disposal and the skeletal muscle tissue is capable to synthesize, convert and degrade androgens. Insulin sensitivity is conse......Polycystic ovary syndrome (PCOS) is associated with insulin resistance and increased risk of type 2 diabetes. Skeletal muscle is the major site of insulin mediated glucose disposal and the skeletal muscle tissue is capable to synthesize, convert and degrade androgens. Insulin sensitivity...... is conserved in cultured myotubes (in vitro) from patients with PCOS, but the effect of testosterone on this insulin sensitivity is unknown. We investigated the effect of 7days testosterone treatment (100nmol/l) on glucose transport and gene expression levels of hormone receptors and enzymes involved...... in the synthesis and conversion of testosterone (HSD17B1, HSD17B2, CYP19A1, SRD5A1-2, AR, ER-α, HSD17B6 and AKR1-3) in myotubes from ten patients with PCOS and ten matched controls. Testosterone treatment significantly increased aromatase and androgen receptor gene expression levels in patients and controls...

Comparing effects of insulin analogues and human insulin on nocturnal glycaemia in hypoglycaemia-prone people with Type 1 diabetes

DEFF Research Database (Denmark)

Kristensen, P. L.; Tarnow, L.; Bay, C.

2017-01-01

. Conclusions: Treatment with insulin analogue reduces the occurrence of nocturnal hypoglycaemia assessed by nocturnal glucose profiles in people with Type 1 diabetes prone to severe hypoglycaemia. Nocturnal glucose profiles provide a more comprehensive assessment of clinical benefit of insulin regimens......Aims: To assess the difference between analogue and human insulin with regard to nocturnal glucose profiles and risk of hypoglycaemia in people with recurrent severe hypoglycaemia. Methods: A total of 72 people [46 men, mean ± sd age 54 ± 12 years, mean ± sd HbA1c 65 ± 12 mmol/mol (8.1 ± 1.1......%), mean ± sd duration of diabetes 30 ± 14 years], who participated in a 2-year randomized, crossover trial of basal-bolus therapy with insulin detemir/insulin aspart or human NPH insulin/human regular insulin (the HypoAna trial) were studied for 2 nights during each treatment. Venous blood was drawn...

Calcium phosphate-PEG-insulin-casein (CAPIC) particles as oral delivery systems for insulin.

Science.gov (United States)

Morçöl, T; Nagappan, P; Nerenbaum, L; Mitchell, A; Bell, S J D

2004-06-11

An oral delivery system for insulin was developed and functional activity was tested in a non-obese diabetic (NOD) mice model. Calcium phosphate particles containing insulin was synthesized in the presence of PEG-3350 and modified by aggregating the particles with caseins to obtain the calcium phosphate-PEG-insulin-casein (CAPIC) oral insulin delivery system. Single doses of CAPIC formulation were tested in NOD mice under fasting or fed conditions to evaluate the glycemic activity. The blood glucose levels were monitored every 1-2h for 12h following the treatments using an ACCU CHECK blood glucose monitoring system. Orally administered and subcutaneously injected free insulin solution served as controls in the study. Based on the results obtained we propose that: (1). the biological activity of insulin is preserved in CAPIC formulation; (2). insulin in CAPIC formulations, but not the free insulin, displays a prolonged hypoglycemic effect after oral administration to diabetic mice; (3). CAPIC formulation protects insulin from degradation while passing through the acidic environment of the GI track until it is released in the less acidic environment of the intestines where it can be absorbed in its biologically active form; (4). CAPIC formulation represents a new and unique oral delivery system for insulin and other macromolecules.

Defective insulin signaling pathway and increased glycogen synthase kinase-3 activity in the brain of diabetic mice: parallels with Alzheimer's disease and correction by insulin.

Science.gov (United States)

Jolivalt, C G; Lee, C A; Beiswenger, K K; Smith, J L; Orlov, M; Torrance, M A; Masliah, E

2008-11-15

We have evaluated the effect of peripheral insulin deficiency on brain insulin pathway activity in a mouse model of type 1 diabetes, the parallels with Alzheimer's disease (AD), and the effect of treatment with insulin. Nine weeks of insulin-deficient diabetes significantly impaired the learning capacity of mice, significantly reduced insulin-degrading enzyme protein expression, and significantly reduced phosphorylation of the insulin-receptor and AKT. Phosphorylation of glycogen synthase kinase-3 (GSK3) was also significantly decreased, indicating increased GSK3 activity. This evidence of reduced insulin signaling was associated with a concomitant increase in tau phosphorylation and amyloid beta protein levels. Changes in phosphorylation levels of insulin receptor, GSK3, and tau were not observed in the brain of db/db mice, a model of type 2 diabetes, after a similar duration (8 weeks) of diabetes. Treatment with insulin from onset of diabetes partially restored the phosphorylation of insulin receptor and of GSK3, partially reduced the level of phosphorylated tau in the brain, and partially improved learning ability in insulin-deficient diabetic mice. Our data indicate that mice with systemic insulin deficiency display evidence of reduced insulin signaling pathway activity in the brain that is associated with biochemical and behavioral features of AD and that it can be corrected by insulin treatment.

Insulin Detemir Causes Lesser Weight Gain in Comparison to Insulin Glargine: Role on Hypothalamic NPY and Galanin

Directory of Open Access Journals (Sweden)

Mohammad Ishraq Zafar

2014-01-01

Full Text Available Objective. Compared with other insulin analogues, insulin detemir induces less weight gain. This study investigated whether this effect was achieved by influencing the hypothalamic appetite regulators neuropeptide Y (NPY and galanin (GAL. Methods. Type  2 diabetic rat models were established with a high-fat diet and intraperitoneal injection of STZ. All rats were divided into NC, DM, DM+DE and DM+GLA groups. Glycemic levels of all study groups were checked at study onset and after 4 weeks of insulin treatment. Food intake and body weight were monitored during treatment. After 4 weeks, the hypothalamus of rats was examined for NPY and GAL mRNA and protein expression. Results. After 4 weeks of treatment, compared with the DM+GLA group, the DM+DE group exhibited less food intake (P<0.05 and less weight gain (P<0.05, but showed similar glycemic control. The expression of hypothalamic NPY and GAL at both mRNA and protein level were significantly lower (P<0.05 in the DM+DE group. Conclusion. Insulin detemir decreased food intake in type 2 diabetic rats, which led to reduced weight gain when compared to insulin glargine treatment. This effect is likely due to downregulation of hypothalamic NPY and GAL.

Metabolic effects of short-term GLP-1 treatment in insulin resistant heart failure patients

DEFF Research Database (Denmark)

Nielsen, Bent Roni Ranghøj; Wiggers, H; Halbirk, M

2012-01-01

calorimetry, forearm, and tracer methods.7 insulin resistant HF (EF 28%±2) patients completed the protocol. GLP-1 decreased plasma glucose levels (p=0.048) and improved glucose tolerance. 4 patients had hypoglycemic events during GLP-1 vs. none during placebo. GLP-1 treatment tended to increase whole body...

Acupuncture Alters Expression of Insulin Signaling Related Molecules and Improves Insulin Resistance in OLETF Rats

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Xin-Yu Huang

2016-01-01

Full Text Available To determine effect of acupuncture on insulin resistance in Otsuka Long-Evans Tokushima Fatty (OLETF rats and to evaluate expression of insulin signaling components. Rats were divided into three groups: Sprague-Dawley (SD rats, OLETF rats, and acupuncture+OLETF rats. Acupuncture was subcutaneously applied to Neiguan (PC6, Zusanli (ST36, and Sanyinjiao (SP6; in contrast, acupuncture to Shenshu (BL23 was administered perpendicularly. For Neiguan (PC6 and Zusanli (ST36, needles were connected to an electroacupuncture (EA apparatus. Fasting blood glucose (FPG was measured by glucose oxidase method. Plasma fasting insulin (FINS and serum C peptide (C-P were determined by ELISA. Protein and mRNA expressions of insulin signaling molecules were determined by Western blot and real-time RT-PCR, respectively. OLETF rats exhibit increased levels of FPG, FINS, C-P, and homeostasis model assessment-estimated insulin resistance (HOMA-IR, which were effectively decreased by acupuncture treatment. mRNA expressions of several insulin signaling related molecules IRS1, IRS2, Akt2, aPKCζ, and GLUT4 were decreased in OLETF rats compared to SD controls. Expression of these molecules was restored back to normal levels upon acupuncture administration. PI3K-p85α was increased in OLETF rats; this increase was also reversed by acupuncture treatment. Acupuncture improves insulin resistance in OLETF rats, possibly via regulating expression of key insulin signaling related molecules.

Insulin adherence behaviours and barriers in the multinational Global Attitudes of Patients and Physicians in Insulin Therapy study.

Science.gov (United States)

Peyrot, M; Barnett, A H; Meneghini, L F; Schumm-Draeger, P-M

2012-05-01

To examine patient and physician beliefs regarding insulin therapy and the degree to which patients adhere to their insulin regimens. Internet survey of 1250 physicians (600 specialists, 650 primary care physicians) who treat patients with diabetes and telephone survey of 1530 insulin-treated patients (180 with Type 1 diabetes, 1350 with Type 2 diabetes) in China, France, Japan, Germany, Spain, Turkey, the UK or the USA. One third (33.2%) of patients reported insulin omission/non-adherence at least 1 day in the last month, with an average of 3.3 days. Three quarters (72.5%) of physicians report that their typical patient does not take their insulin as prescribed, with a mean of 4.3 days per month of basal insulin omission/non-adherence and 5.7 days per month of prandial insulin omission/non-adherence. Patients and providers indicated the same five most common reasons for insulin omission/non-adherence: too busy; travelling; skipped meals; stress/emotional problems; public embarrassment. Physicians reported low patient success at initiating insulin in a timely fashion and adjusting insulin doses. Most physicians report that many insulin-treated patients do not have adequate glucose control (87.6%) and that they would treat more aggressively if not for concern about hypoglycaemia (75.5%). Although a majority of patients (and physicians) regard insulin treatment as restrictive, more patients see insulin treatment as having positive than negative impacts on their lives. Glucose control is inadequate among insulin-treated patients, in part attributable to insulin omission/non-adherence and lack of dose adjustment. There is a need for insulin regimens that are less restrictive and burdensome with lower risk of hypoglycaemia. © 2012 The Authors. Diabetic Medicine © 2012 Diabetes UK.

Awake, long-term intranasal insulin treatment does not affect object memory, odor discrimination, or reversal learning in mice.

Science.gov (United States)

Bell, Genevieve A; Fadool, Debra Ann

2017-05-15

Intranasal insulin delivery is currently being used in clinical trials to test for improvement in human memory and cognition, and in particular, for lessening memory loss attributed to neurodegenerative diseases. Studies have reported the effects of short-term intranasal insulin treatment on various behaviors, but less have examined long-term effects. The olfactory bulb contains the highest density of insulin receptors in conjunction with the highest level of insulin transport within the brain. Previous research from our laboratory has demonstrated that acute insulin intranasal delivery (IND) enhanced both short- and long-term memory as well as increased two-odor discrimination in a two-choice paradigm. Herein, we investigated the behavioral and physiological effects of chronic insulin IND. Adult, male C57BL6/J mice were intranasally treated with 5μg/μl of insulin twice daily for 30 and 60days. Metabolic assessment indicated no change in body weight, caloric intake, or energy expenditure following chronic insulin IND, but an increase in the frequency of meal bouts selectively in the dark cycle. Unlike acute insulin IND, which has been shown to cause enhanced performance in odor habituation/dishabituation and two-odor discrimination tasks in mice, chronic insulin IND did not enhance olfactometry-based odorant discrimination or olfactory reversal learning. In an object memory recognition task, insulin IND-treated mice did not perform differently than controls, regardless of task duration. Biochemical analyses of the olfactory bulb revealed a modest 1.3 fold increase in IR kinase phosphorylation but no significant increase in Kv1.3 phosphorylation. Substrate phosphorylation of IR kinase downstream effectors (MAPK/ERK and Akt signaling) proved to be highly variable. These data indicate that chronic administration of insulin IND in mice fails to enhance olfactory ability, object memory recognition, or a majority of systems physiology metabolic factors - as reported to

The impact of electronic education on metabolic control indicators in patients with diabetes who need insulin: a randomised clinical control trial.

Science.gov (United States)

Moattari, Marzieh; Hashemi, Maryam; Dabbaghmanesh, Mohammad H

2013-01-01

To determine the impact of electronic education on metabolic control indicators in patients with diabetes who were insulin dependent. Education can play an important role in controlling diabetes. Electronic (web-based, telehealth) education may be an efficient way to improve the patients' ability to control this disease. Randomised clinical control study. The participants in this clinical study were 48 insulin-dependent patients referred to diabetes centres in Shiraz, Iran. Serum concentrations of haemoglobin A(1C) , fasting blood sugar, triglycerides and high-density and low-density lipoprotein cholesterol were measured. Then the participants were divided randomly into control and experimental groups (n = 24). Participants in the experimental group received a specially designed electronic education programme for twelve weeks. The main components of the programme were a consultation service, quick answers to patients' questions, contact with the healthcare team and educational materials. At the end of the intervention period, all serum values were measured again in both groups. The data were compared using spss v 13·5 software. Serum concentrations of haemoglobin A(1C) (p education programme was useful in lowering two metabolic indicators of diabetes. Electronic education can be associated with increased health and patient satisfaction, and can eliminate the need to train personnel. © 2012 Blackwell Publishing Ltd.

Electron-beam flue-gas treatment system

International Nuclear Information System (INIS)

Aoki, Sinji; Suzuki, Ryoji

1994-01-01

The damage of forests in the world due to acid rain has become serious problems, and the development of high efficiency and economical desulfurization and denitration technologies for combustion exhaust gas has been desired. Japan leads the world in exhaust gas treatment technology. The conventional technologies have been the desulfurization by lime gypsum process and the denitration by ammonia catalytic reduction process. The solution by entirely new concept is the electron beam treatment technology for exhaust gas. This technology is a dry process without drain, and does not require catalyst. The byproduct from this technology was approved as a fertilizer. The electron beam treatment technology is called EBA (electron beam with ammonia). The exhaust gas treatment technology by electron beam process is constituted by the cooling of exhaust gas, ammonia addition, electron beam irradiation and the separation of byproduct. The features of the technology are the simultaneous removal of sulfur and nitrogen oxides, dry process, the facilities are simple and the operation is easy, easy following to load variation and the utilization of byproduct. The reaction mechanism of desulfurization and denitration, the course of development, the electron beam generator, and the verifying test are reported. (K.I.)

Role of sialic acid in insulin action and the insulin resistance of diabetes mellitus

International Nuclear Information System (INIS)

Salhanick, A.I.; Amatruda, J.M.

1988-01-01

Adipocytes treated with neuraminidase show markedly reduced responsiveness to insulin without any alteration in insulin binding. In addition, several studies have separately demonstrated both insulin resistance and decreases in membrane sialic acid content and associated biosynthetic enzymes in diabetes mellitus. In the present study, the authors investigated the role that sialic acid residues may play in insulin action and in the hepatic insulin resistance associated with nonketotic diabetes. Primary cultures of hepatocytes from normal rats treated with neuraminidase demonstrated a dose-dependent decrease in insulin-stimulated lipogenesis. At a concentration of neuraminidase that decreases insulin action by 50%, 23% of total cellular sialic acid content was released. Neuraminidase-releasable sialic acid was significantly decreased in hepatocytes from diabetic rats and this was associated with significant insulin resistance. Treatment of hepatocytes from diabetic rats with cytidine 5'-monophospho-N-acetylneuraminic acid (CMP-NANA) enhanced insulin responsiveness 39%. The enhanced insulin responsiveness induced by CMP-NANA was blocked by cytidine 5'-monophosphate (CMP) suggesting that the CMP-NANA effect was catalyzed by a cell surface sialyl-transferase. CMP reduced neuraminidase-releasable [ 14 C]sialic acid incorporation into hepatocytes by 43%. The data demonstrate a role for cell surface sialic acid residues in hepatic insulin action and support a role for decreased cell surface sialic acid residues in the insulin resistance of diabetes mellitus

Impaired insulin activation and dephosphorylation of glycogen synthase in skeletal muscle of women with polycystic ovary syndrome is reversed by pioglitazone treatment

DEFF Research Database (Denmark)

Glintborg, Dorte; Højlund, Kurt; Andersen, Nicoline Resen

2008-01-01

CONTEXT: Insulin resistance is a major risk factor for type 2 diabetes in women with polycystic ovary syndrome (PCOS). The molecular mechanisms underlying reduced insulin-mediated glycogen synthesis in skeletal muscle of patients with PCOS have not been established. SUBJECTS AND METHODS: We...... metabolically characterized by euglycemic-hyperinsulinemic clamps and indirect calorimetry. RESULTS: Reduced insulin-mediated glucose disposal (P .... No significant abnormalities in GSK-3alpha or -3beta were found in PCOS subjects. Pioglitazone treatment improved insulin-stimulated glucose metabolism and GS activity in PCOS (all P

WJD 5th Anniversary Special Issues（1）: Insulin Benefits of healthy adipose tissue in the treatment of diabetes

Institute of Scientific and Technical Information of China (English)

Subhadra; C; Gunawardana

2014-01-01

The major malfunction in diabetes mellitus is severe perturbation of glucose homeostasis caused by deficiency of insulin.Insulin deficiency is either absolute due to destruction or failure of pancreaticβcells,or relative due to decreased sensitivity of peripheral tissues to insulin.The primary lesion being related to insulin,treatments for diabetes focus on insulin replacement and/or increasing sensitivity to insulin.These therapies have their own limitations and complications,some of which can be life-threatening.For example,exogenous insulin administration can lead to fatal hypoglycemic episodes;islet/pancreas transplantation requires life-long immunosuppressive therapy;and anti-diabetic drugs have dangerous side effects including edema,heart failure and lactic acidosis.Thus the need remains for better safer long term treatments for diabetes.The ultimate goal in treating diabetes is to re-establish glucose homeostasis,preferably through endogenously generated hormones.Recent studies increasingly show that extra-pancreatic hormones,particularly those arising from adipose tissue,can compensate for insulin,or entirely replace the function of insulin under appropriate circumstances.Adipose tissue is a versatile endocrine organ that secretes a variety of hormones with far-reaching effects on overall metabolism.While unhealthy adipose tissue can exacerbate diabetes through limiting circulation and secreting of pro-inflammatory cytokines,healthy uninflamed adipose tissue secretes beneficial adipokines with hypoglycemic and anti-inflammatory properties,which can complement and/or compensate for the function of insulin.Administration of specific adipokines is known to alleviate both type 1 and 2 diabetes,and leptin mono-therapy is reported to reverse type 1 diabetes independent of insulin.Although specific adipokines may correct diabetes,administration of individual adipokines still carries risks similar to those of insulin monotherapy.Thus a better approach is to

Induction of insulin secretion in engineered liver cells by nitric oxide

Directory of Open Access Journals (Sweden)

Özcan Sabire

2007-10-01

Full Text Available Abstract Background Type 1 Diabetes Mellitus results from an autoimmune destruction of the pancreatic beta cells, which produce insulin. The lack of insulin leads to chronic hyperglycemia and secondary complications, such as cardiovascular disease. The currently approved clinical treatments for diabetes mellitus often fail to achieve sustained and optimal glycemic control. Therefore, there is a great interest in the development of surrogate beta cells as a treatment for type 1 diabetes. Normally, pancreatic beta cells produce and secrete insulin only in response to increased blood glucose levels. However in many cases, insulin secretion from non-beta cells engineered to produce insulin occurs in a glucose-independent manner. In the present study we engineered liver cells to produce and secrete insulin and insulin secretion can be stimulated via the nitric oxide pathway. Results Expression of either human insulin or the beta cell specific transcription factors PDX-1, NeuroD1 and MafA in the Hepa1-6 cell line or primary liver cells via adenoviral gene transfer, results in production and secretion of insulin. Although, the secretion of insulin is not significantly increased in response to high glucose, treatment of these engineered liver cells with L-arginine stimulates insulin secretion up to three-fold. This L-arginine-mediated insulin release is dependent on the production of nitric oxide. Conclusion Liver cells can be engineered to produce insulin and insulin secretion can be induced by treatment with L-arginine via the production of nitric oxide.

Oral treatment with γ-aminobutyric acid improves glucose tolerance and insulin sensitivity by inhibiting inflammation in high fat diet-fed mice.

Directory of Open Access Journals (Sweden)

Jide Tian

Full Text Available Adipocyte and β-cell dysfunction and macrophage-related chronic inflammation are critical for the development of obesity-related insulin resistance and type 2 diabetes mellitus (T2DM, which can be negatively regulated by Tregs. Our previous studies and those of others have shown that activation of γ-aminobutyric acid (GABA receptors inhibits inflammation in mice. However, whether GABA could modulate high fat diet (HFD-induced obesity, glucose intolerance and insulin resistance has not been explored. Here, we show that although oral treatment with GABA does not affect water and food consumption it inhibits the HFD-induced gain in body weights in C57BL/6 mice. Furthermore, oral treatment with GABA significantly reduced the concentrations of fasting blood glucose, and improved glucose tolerance and insulin sensitivity in the HFD-fed mice. More importantly, after the onset of obesity and T2DM, oral treatment with GABA inhibited the continual HFD-induced gain in body weights, reduced the concentrations of fasting blood glucose and improved glucose tolerance and insulin sensitivity in mice. In addition, oral treatment with GABA reduced the epididymal fat mass, adipocyte size, and the frequency of macrophage infiltrates in the adipose tissues of HFD-fed mice. Notably, oral treatment with GABA significantly increased the frequency of CD4(+Foxp3(+ Tregs in mice. Collectively, our data indicated that activation of peripheral GABA receptors inhibited the HFD-induced glucose intolerance, insulin resistance, and obesity by inhibiting obesity-related inflammation and up-regulating Treg responses in vivo. Given that GABA is safe for human consumption, activators of GABA receptors may be valuable for the prevention of obesity and intervention of T2DM in the clinic.

Insulin analogs with improved pharmacokinetic profiles.

Science.gov (United States)

Brange; Vølund

1999-02-01

The aim of insulin replacement therapy is to normalize blood glucose in order to reduce the complications of diabetes. The pharmacokinetics of the traditional insulin preparations, however, do not match the profiles of physiological insulin secretion. The introduction of the rDNA technology 20 years ago opened new ways to create insulin analogs with altered properties. Fast-acting analogs are based on the idea that an insulin with less tendency to self-association than human insulin would be more readily absorbed into the systemic circulation. Protracted-acting analogs have been created to mimic the slow, steady rate of insulin secretion in the fasting state. The present paper provides a historical review of the efforts to change the physicochemical and pharmacological properties of insulin in order to improve insulin therapy. The available clinical studies of the new insulins are surveyed and show, together with modeling results, that new strategies for optimal basal-bolus treatment are required for utilization of the new fast-acting analogs.

Four weeks of treatment with liraglutide reduces insulin dose without loss of glycemic control in type 1 diabetic patients with and without residual beta-cell function

DEFF Research Database (Denmark)

Kielgast, Urd; Krarup, Thure; Holst, Jens Juul

2011-01-01

OBJECTIVE To investigate the effect of 4 weeks of treatment with liraglutide on insulin dose and glycemic control in type 1 diabetic patients with and without residual ß-cell function. RESEARCH DESIGN AND METHODS Ten type 1 diabetic patients with residual ß-cell function (C-peptide positive) and 19.......1]; P Treatment with liraglutide in type 1 diabetic patients reduces insulin dose with improved or unaltered glycemic control....... activity was performed before (week 0) and during (week 4) treatment. Differences in insulin dose; HbA(1c); time spent with blood glucose 10, and 3.9-9.9 mmol/L; and body weight were evaluated. RESULTS Insulin dose decreased from 0.50 ± 0.06 to 0.31 ± 0.08 units/kg per day (P

Stimuli sensitive polymethacrylic acid microparticles (PMAA)--oral insulin delivery.

Science.gov (United States)

Victor, Sunita Prem; Sharma, Chandra P

2002-10-01

This study investigated polymethacrylic acid (PMAA) microparticles for controlled release of Insulin in oral administration. The microparticles were characterised by scanning electron microscopy (SEM) for morphological studies. The swelling behaviour and drug release profile in various pH media were studied. The % swelling of gels was found to be inversely related to the amount of crosslinker added. Inclusion complex of betaCD and Insulin was studied using polyacrylamide gel electrophoresis (PAGE). Optimum complexation was obtained in the ratio 100 mg betaCD: 200 IU Insulin. The release pattern of Insulin from Insulin-betaCD complex encapsulated PMAA microparticles showed release of Insulin for more than seven hours.

The insulin-like growth factor axis and collagen turnover during prednisolone treatment

DEFF Research Database (Denmark)

Wolthers, O D; Juul, A; Hansen, M

1994-01-01

Serum concentrations of insulin-like growth factor I (IGF-I) and insulin-like growth factor binding protein 3 (IGFBP-3), the carboxyterminal propeptide of type I collagen (PICP), the carboxyterminal pyridinoline crosslinked telopeptide of type I collagen (ICTP), and the aminoterminal propeptide...... of type III procollagen (PIIINP) were studied in 10 prepubertal children with asthma (mean age 9.0 years). The children were treated with 2.5 and 5.0 mg/day prednisolone in a randomised double blind crossover trial with run in, treatment, and washout periods of two weeks. No statistically significant...... effects on serum concentrations of IGF-I and IGFBP-3 were found. Dose related reductions of PICP, ICTP, and PIIINP were observed: the mean (SEM) reduction in PICP was 33.4 (26.3) and 68.4 (20.6) micrograms/l, in ICTP 2.5 (0.5) and 2.9 (0.6) micrograms/l, and in PIIINP 2.1 (0.7) and 3.1 (1.8) micrograms...

Combining insulins for optimal blood glucose control in type 1 and 2 diabetes: focus on insulin glulisine

Directory of Open Access Journals (Sweden)

Heather Ulrich

2007-07-01

Full Text Available Heather Ulrich1,4, Benjamin Snyder1,Satish K Garg1,2,31Barbara Davis Center for Childhood Diabetes; 2Department of Medicine; 3Pediatrics; 4Department of Clinical Pharmacy, School of Pharmacy, University of Colorado at Denver and Health Sciences Center, Denver, CO, USAAbstract: Normalization of blood glucose is essential for the prevention of diabetes mellitus (DM-related microvascular and macrovascular complications. Despite substantial literature to support the benefits of glucose lowering and clear treatment targets, glycemic control remains suboptimal for most people with DM in the United States. Pharmacokinetic limitations of conventional insulins have been a barrier to achieving treatment targets secondary to adverse effects such as hypoglycemia and weight gain. Recombinant DNA technology has allowed modification of the insulin molecule to produce insulin analogues that overcome these pharmacokinetic limitations. With time action profiles that more closely mimic physiologic insulin secretion, rapid acting insulin analogues (RAAs reduce post-prandial glucose excursions and hypoglycemia when compared to regular human insulin (RHI. Insulin glulisine (Apidra® is a rapid-acting insulin analogue created by substituting lysine for asparagine at position B3 and glutamic acid for lysine at position B29 on the B chain of human insulin. The quick absorption of insulin glulisine more closely reproduces physiologic first-phase insulin secretion and its rapid acting profile is maintained across patient subtypes. Clinical trials have demonstrated comparable or greater efficacy of insulin glulisine versus insulin lispro or RHI, respectively. Efficacy is maintained even when insulin glulisine is administered post-meal. In addition, glulisine appears to have a more rapid time action profile compared with insulin lispro across various body mass indexes (BMIs. The safety and tolerability profile of insulin glulisine is also comparable to that of insulin

Estrogen and insulin transport through the blood-brain barrier.

Science.gov (United States)

May, Aaron A; Bedel, Nicholas D; Shen, Ling; Woods, Stephen C; Liu, Min

2016-09-01

Obesity is associated with insulin resistance and reduced transport of insulin through the blood-brain barrier (BBB). Reversal of high-fat diet-induced obesity (HFD-DIO) by dietary intervention improves the transport of insulin through the BBB and the sensitivity of insulin in the brain. Although both insulin and estrogen (E2), when given alone, reduce food intake and body weight via the brain, E2 actually renders the brain relatively insensitive to insulin's catabolic action. The objective of these studies was to determine if E2 influences the ability of insulin to be transported into the brain, since the receptors for both E2 and insulin are found in BBB endothelial cells. E2 (acute or chronic) was systemically administered to ovariectomized (OVX) female rats and male rats fed a chow or a high-fat diet. Food intake, body weight and other metabolic parameters were assessed along with insulin entry into the cerebrospinal fluid (CSF). Acute E2 treatment in OVX female and male rats reduced body weight and food intake, and chronic E2 treatment prevented or partially reversed high-fat diet-induced obesity. However, none of these conditions increased insulin transport into the CNS; rather, chronic E2 treatment was associated less-effective insulin transport into the CNS relative to weight-matched controls. Thus, the reduction of brain insulin sensitivity by E2 is unlikely to be mediated by increasing the amount of insulin entering the CNS. Copyright © 2016 Elsevier Inc. All rights reserved.

Insulin Resistance

DEFF Research Database (Denmark)

Jensen, Benjamin Anderschou Holbech

Insulin resistance (IR) is escalating with alarming pace and is no longer restricted to westernized countries. As a forerunner for some of the most serious threats to human health including metabolic syndrome, cardiovascular diseases, and type 2-diabetes, the need for new treatment modalities...... interventions. We further show that improving the inflammatory toning, using fish oil as fat source, protects mice against diet induced obesity and -inflammation while preserving insulin sensitivity, even in the absence of free fatty acid receptor 4. Conversely, HFD-induced intestinal dysbiosis is associated...

Cost-effectiveness of once daily GLP-1 receptor agonist lixisenatide compared to bolus insulin both in combination with basal insulin for the treatment of patients with type 2 diabetes in Norway.

Science.gov (United States)

Huetson, Pernilla; Palmer, James L; Levorsen, Andrée; Fournier, Marie; Germe, Maeva; McLeod, Euan

2015-01-01

Lixisenatide is a potent, selective and short-acting once daily prandial glucagon-like peptide-1 receptor agonist which lowers glycohemoglobin and body weight by clinically significant amounts in patients with type 2 diabetes treated with basal insulin, with limited risk of hypoglycemia. To assess the cost-effectiveness of lixisenatide versus bolus insulin, both in combination with basal insulin, in patients with type 2 diabetes in Norway. The IMS CORE Diabetes Model, a non-product-specific and validated simulation model, was used to make clinical and cost projections. Transition probabilities, risk adjustments and the progression of complication risk factors were derived from the UK Prospective Diabetes Study, supplemented with Norwegian data. Patients were assumed to receive combination treatment with basal insulin, lixisenatide or bolus insulin therapy for 3 years, followed by intensification of a basal-bolus insulin regimen for their remaining lifetime. Simulated healthcare costs, taken from the public payer perspective, were derived from microcosting and diagnosis related groups, discounted at 4% per annum and reported in Norwegian krone (NOK). Productivity costs were also captured based on extractions from the Norwegian Labor and Welfare Administration. Health state utilities were derived from a systematic literature review. Sensitivity and scenario analyses were performed. Lixisenatide in combination with basal insulin was associated with increased quality-adjusted life years (QALYs) and reduced lifetime healthcare costs compared to bolus insulin in combination with basal insulin in patients with Type 2 diabetes, and can be considered dominant. The net monetary benefit of lixisenatide versus bolus insulin was NOK 39,369 per patient. Results were sensitive to discounting, the application of excess body weight associated disutility and uncertainty surrounding the changes in HbA1c. Lixisenatide may be considered an economically efficient therapy in combination

Insulin-induced translocation of IR to the nucleus in insulin responsive cells requires a nuclear translocation sequence.

Science.gov (United States)

Kesten, Dov; Horovitz-Fried, Miriam; Brutman-Barazani, Tamar; Sampson, Sanford R

2018-04-01

Insulin binding to its cell surface receptor (IR) activates a cascade of events leading to its biological effects. The Insulin-IR complex is rapidly internalized and then is either recycled back to the plasma membrane or sent to lysosomes for degradation. Although most of the receptor is recycled or degraded, a small amount may escape this pathway and migrate to the nucleus of the cell where it might be important in promulgation of receptor signals. In this study we explored the mechanism by which insulin induces IR translocation to the cell nucleus. Experiments were performed cultured L6 myoblasts, AML liver cells and 3T3-L1 adipocytes. Insulin treatment induced a rapid increase in nuclear IR protein levels within 2 to 5 min. Treatment with WGA, an inhibitor of nuclear import, reduced insulin-induced increases nuclear IR protein; IR was, however, translocated to a perinuclear location. Bioinformatics tools predicted a potential nuclear localization sequence (NLS) on IR. Immunofluorescence staining showed that a point mutation on the predicted NLS blocked insulin-induced IR nuclear translocation. In addition, blockade of nuclear IR activation in isolated nuclei by an IR blocking antibody abrogated insulin-induced increases in IR tyrosine phosphorylation and nuclear PKCδ levels. Furthermore, over expression of mutated IR reduced insulin-induced glucose uptake and PKB phosphorylation. When added to isolated nuclei, insulin induced IR phosphorylation but had no effect on nuclear IR protein levels. These results raise questions regarding the possible role of nuclear IR in IR signaling and insulin resistance. Copyright © 2018 Elsevier B.V. All rights reserved.

Treatment Dosing Patterns and Clinical Outcomes for Patients with Type 2 Diabetes Starting or Switching to Treatment with Insulin Glargine (300 Units per Milliliter) in a Real-World Setting: A Retrospective Observational Study.

Science.gov (United States)

Gupta, Shaloo; Wang, Hongwei; Skolnik, Neil; Tong, Liyue; Liebert, Ryan M; Lee, Lulu K; Stella, Peter; Cali, Anna; Preblick, Ronald

2018-01-01

Usage patterns and effectiveness of a longer-acting formulation of insulin glargine at a strength of 300 units per milliliter (Gla-300) have not been studied in real-world clinical practice. This study evaluated differences in dosing and clinical outcomes before and after Gla-300 treatment initiation in patients with type 2 diabetes starting or switching to treatment with Gla-300 to assess whether the benefits observed in clinical trials translate into real-world settings. This was a retrospective observational study using medical record data obtained by physician survey for patients starting treatment with insulin glargine at a strength of 100 units per milliliter (Gla-100) or Gla-300, or switching to treatment with Gla-300 from treatment with another basal insulin (BI). Differences in dosing and clinical outcomes before versus after treatment initiation or switching were examined by generalized linear mixed-effects models. Among insulin-naive patients starting BI treatment, no difference in the final titrated dose was observed in patients starting Gla-300 treatment versus those starting Gla-100 treatment [least-squares (LS) mean 0.43 units per kilogram vs 0.44 units per kilogram; P = 0.77]. Both groups had significant hemoglobin A 1c level reductions (LS mean 1.21 percentage points for Gla-300 and 1.12 percentage points for Gla-100 ; both P per kilogram before switch vs 0.58 units per kilogram after switch; P = 0.02). The mean hemoglobin A 1c level was significantly lower after switching than before switching (adjusted difference - 0.95 percentage points, 95% CI - 1.13 to - 0.78 percentage points ; P per patient-year were significantly lower (relative risk 0.17, 95% CI 0.11-0.26; P < 0.0001). Insulin-naive patients starting Gla-300 treatment had fewer hypoglycemic events, a similar hemoglobin A 1c level reduction, and no difference in insulin dose versus patients starting Gla-100 treatment. Patients switching to Gla-300 treatment from treatment with

Peripheral Insulin Doesn’t Alter Appetite of Broiler Chicks

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Lei Liu

2016-09-01

Full Text Available An experiment was conducted to investigate the effect of peripheral insulin treatment on appetite in chicks. Six-d-age chicks with ad libitum feeding or fasting for 3 h before injection received a subcutaneous injection of 0, 1, 3, 5, 10, or 20 IU of insulin or vehicle (saline. The results showed peripheral insulin treatment (1 to 20 IU did not alter significantly the feed intake in chicks under either ad libitum feeding or fasting conditions within 4 h (p>0.05. Compared with the control, plasma glucose concentration was significantly decreased after insulin treatment of 3, 5, 10, and 20 IU for 4 h in chicks with ad libitum feeding (p0.05. All results suggest peripheral administration of insulin has no effect on appetite in chicks.

Aerosolized liposomes with dipalmitoyl phosphatidylcholine enhance pulmonary absorption of encapsulated insulin compared with co-administered insulin.

Science.gov (United States)

Chono, Sumio; Togami, Kohei; Itagaki, Shirou

2017-11-01

We have previously shown that aerosolized liposomes with dipalmitoyl phosphatidylcholine (DPPC) enhance the pulmonary absorption of encapsulated insulin. In this study, we aimed to compare insulin encapsulated into the liposomes versus co-administration of empty liposomes and unencapsulated free insulin, where the DPCC liposomes would serve as absorption enhancer. The present study provides the useful information for development of noninvasive treatment of diabetes. Co-administration of empty DPPC liposomes and unencapsulated free insulin was investigated in vivo to assess the potential enhancement in protein pulmonary absorption. Co-administration was compared to DPPC liposomes encapsulating insulin, and free insulin. DPPC liposomes enhanced the pulmonary absorption of unencapsulated free insulin; however, the enhancing effect was lower than that of the DPPC liposomes encapsulating insulin. The mechanism of the pulmonary absorption of unencapsulated free insulin by DPPC liposomes involved the opening of epithelial cell space in alveolar mucosa, and not mucosal cell damage, similar to that of the DPPC liposomes encapsulating insulin. In an in vitro stability test, insulin in the alveolar mucus layer that covers epithelial cells was stable. These findings suggest that, although unencapsulated free insulin spreads throughout the alveolar mucus layer, the concentration of insulin released near the absorption surface is increased by the encapsulation of insulin into DPPC liposomes and the absorption efficiency is also increased. We revealed that the encapsulation of insulin into DPPC liposomes is more effective for pulmonary insulin absorption than co-administration of DPPC liposomes and unencapsulated free insulin.

Insulin Inclusion into a Tragacanth Hydrogel: An Oral Delivery System for Insulin

Science.gov (United States)

Vasiljevic, Todor

2018-01-01

Nanoparticles or microparticles created by physical complexation between two polyelectrolytes may have a prospective use as an excipient for oral insulin administration. Natural polymers such as tragacanth, alginate, dextran, pullulan, hyaluronic acid, gelatin and chitosan can be potential candidates for this purpose. In this research, insulin particles were prepared by the inclusion of insulin into a tragacanth hydrogel. The effect of the pH and concentration relationship involving polyelectrolytes offering individual particle size and zeta potential was assessed by zetasizer and scanning electron microscopy (SEM). Insulin–tragacanth interactions at varying pH (3.7, 4.3, 4.6, or 6), and concentration (0.1%, 0.5%, or 1% w/w) were evaluated by differential scanning calorimetry (DSC) and ATR Fourier transform infrared (ATR-FTIR) analysis. Individual and smaller particles, approximately 800 nm, were acquired at pH 4.6 with 0.5% of tragacanth. The acid gelation test indicated that insulin could be entrapped in the physical hydrogel of tragacanth. DSC thermograms of insulin–tragacanth showed shifts on the same unloaded tragacanth peaks and suggested polyelectrolyte–protein interactions at a pH close to 4.3–4.6. FTIR spectra of tragacanth–insulin complexes exhibited amide absorption bands featuring in the protein spectra and revealed the creation of a new chemical substance. PMID:29304023

Clinical experience with insulin detemir, biphasic insulin aspart and insulin aspart in people with type 2 diabetes: Results from the Mumbai cohort of the A1chieve study.

Science.gov (United States)

Talwalkar, P G; Gupta, Vishal; Kovil, Rajiv

2013-11-01

The A1chieve, a multicentric (28 countries), 24-week, non-interventional study evaluated the safety and effectiveness of insulin detemir, biphasic insulin aspart and insulin aspart in people with T2DM (n = 66,726) in routine clinical care across four continents. Data was collected at baseline, at 12 weeks and at 24 weeks. This short communication presents the results for patients enrolled from Mumbai, India. A total of 2112 patients were enrolled in the study. Four different insulin analogue regimens were used in the study. Patients had started on or were switched to biphasic insulin aspart (n = 1561), insulin detemir (n = 313), insulin aspart (n = 144), basal insulin plus insulin aspart (n = 53) and other insulin combinations (n = 41). At baseline glycaemic control was poor for both insulin naïve (mean HbA1c: 8.7%) and insulin user (mean HbA1c: 9.2%) groups. After 24 weeks of treatment, both the groups showed improvement in HbA1c (insulin naïve: -1.4%, insulin users: -1.8%). SADRs including major hypoglycaemic events or episodes did not occur in any of the study patients. Starting or switching to insulin analogues was associated with improvement in glycaemic control with a low rate of hypoglycaemia.

[Severe type A insulin resistance syndrome due to a mutation in the insulin receptor gene].

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Ros, P; Colino-Alcol, E; Grasso, V; Barbetti, F; Argente, J

2015-01-01

Insulin resistance syndromes without lipodystrophy are an infrequent and heterogeneous group of disorders with variable clinical phenotypes, associated with hyperglycemia and hyperinsulinemia. The three conditions related to mutations in the insulin receptor gene are leprechaunism or Donohue syndrome, Rabson-Mendenhall syndrome, and Type A syndrome. A case is presented on a patient diagnosed with type A insulin resistance, defined by the triad of extreme insulin resistance, acanthosis nigricans, and hyperandrogenism, carrying a heterozygous mutation in exon 19 of the insulin receptor gene coding for its tyrosine kinase domain that is crucial for the catalytic activity of the receptor. The molecular basis of the syndrome is reviewed, focusing on the structure-function relationships of the insulin receptor, knowing that the criteria for survival are linked to residual insulin receptor function. It is also pointed out that, although type A insulin resistance appears to represent a somewhat less severe condition, these patients have a high morbidity and their treatment is still unsatisfactory. Copyright © 2014 Asociación Española de Pediatría. Published by Elsevier Espana. All rights reserved.

Study on the changes of serum adiponectin (APN), insulin, C-reactive protein (CRP) and leptin levels after one year treatment in patients with type 2 diabetes

International Nuclear Information System (INIS)

Du Tongxin; Wang Zizheng; Wang Shukui; Li Yan; Fu Lei; Lin Yanli; Qu Wei; Qi Shaokang; Tao Xiaojun

2005-01-01

Objective: To investigate the β-cell function status and possible mechanism of insulin resistance in patients with type 2 diabetes through studies on the changes of serum APN, insulin, CRP, leptin, insulin antibody and glutamic acid decarboxylase antibody (GAD-Ab) levels after one year of treatment. Methods: Serum levels of the above four parameters and the positive rate of the two antibodies were measured (with CLIA, ELISA and RIA as appropriately) in 184 patients with type 2 diabetes and 30 controls as well as in 75 patients after one year of treatment. Results: The serum contents of insulin, leptin, CRP, insulin antibody in patients with type 2 diabetes were significantly higher (P<0.01) and APN levels significantly lower (P<0.001) than those in controls. Levels of APN were negatively correlated with those of the other parameters. In the 75 treated patients, levels of those parameters (with the exception of APN and insulin-antibody) decreased significantly. However, the APN levels were significantly increased (vs before treatment, P<0.001). Conclusion: Further study on the dynamic changes of these parameters in the diabetic patients might elucidate certain key-points in the pathogenesis of the disease. (authors)

Autophagy downregulation contributes to insulin resistance mediated injury in insulin receptor knockout podocytes in vitro

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Ying Xu

2016-04-01

Full Text Available It is unknown whether autophagy activity is altered in insulin resistant podocytes and whether autophagy could be a therapeutic target for diabetic nephropathy (DN. Here we used shRNA transfection to knockdown the insulin receptor (IR gene in cultured human immortalized podocytes as an in vitro insulin resistant model. Autophagy related proteins LC3, Beclin, and p62 as well as nephrin, a podocyte injury marker, were assessed using western blot and immunofluorescence staining. Our results show that autophagy is suppressed when podocytes lose insulin sensitivity and that treatment of rapamycin, an mTOR specific inhibitor, could attenuate insulin resistance induced podocytes injury via autophagy activation. The present study deepens our understanding of the role of autophagy in the pathogenesis of DN.

THE USE OF ULTRA-LONG-ACTING INSULIN ANALOGUE DEGLUDEC IN TYPE 1 DIABETES MELLITUS IN CLINICAL PRACTICE: THE INFLUENCE ON QUALITY OF LIFE AND SATISFACTION WITH TREATMENT

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M. F. Kalashnikova

2016-01-01

Full Text Available Background: Maintenance of stable glycemic control is an important prerequisite of effective treatment of patients with type 1 diabetes mellitus (DM. The ultra-long-acting basal insulin degludec allows for reduction of glycemic variability and for a substantial reduction in the rates of hypoglycemia with equivalent glycemic control. Evaluation of the impact of this novel insulin on diabetes-dependent quality of life and patient satisfactions with the treatment is necessary for comprehensive assessment of treatment efficacy.Aim: To study changes of glycated hemoglobin (HbA1c, rates of hypoglycemia, diabetes-dependent quality of life and treatment satisfaction in patients with type 1 DM, who have been switched to insulin degludec.Materials and methods: This open 12-week observational comparative study included 25  patients with type  1 DM (median age, 36 [20; 63] years, who were switched to insulin degludec in combination with a  ultra-short insulin analogue. The control group included 21 patients with type 1 DM (median age, 40 [23; 63] years, who continued their treatment with a long-acting insulin analogue glargine. At baseline and at week 12 after switching to insulin degludec, we assessed HbA1c level, mean insulin dose, depression score, diabetes-dependent quality of life and patient satisfaction with the treatment with the use of the Russian versions of the diabetes-specific questionnaires “Audit of Diabetes-Dependent Quality of life” (RuADDQoL, and “Diabetes Treatment Satisfaction Questionnaire” (DTSQ, respectively.Results: At 3 months, there was a significant reduction of the HbA1c levels in the main and the control groups to 7.57% (Ме 7.5 [7.1; 8.4]; р=0.03 and 8.18% (Ме 7.8% [7.4; 8.7]; р=0.04, respectively. The mean reduction of this parameter under treatment with degludec was slightly higher than under treatment with glargine (0.73 vs 0.57%, respectively, at 3 months the difference being statistically

Insulin autoimmune syndrome: case report

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Rodrigo Oliveira Moreira

Full Text Available CONTEXT: Insulin autoimmune syndrome (IAS, Hirata disease is a rare cause of hypoglycemia in Western countries. It is characterized by hypoglycemic episodes, elevated insulin levels, and positive insulin antibodies. Our objective is to report a case of IAS identified in South America. CASE REPORT: A 56-year-old Caucasian male patient started presenting neuroglycopenic symptoms during hospitalization due to severe trauma. Biochemical evaluation confirmed hypoglycemia and abnormally high levels of insulin. Conventional imaging examinations were negative for pancreatic tumor. Insulin antibodies were above the normal range. Clinical remission of the episodes was not achieved with verapamil and steroids. Thus, a subtotal pancreatectomy was performed due to the lack of response to conservative treatment and because immunosuppressants were contraindicated due to bacteremia. Histopathological examination revealed diffuse hypertrophy of beta cells. The patient continues to have high insulin levels but is almost free of hypoglycemic episodes.

Review and Update of Insulin Dependent Diabetes Mellitus

OpenAIRE

Gorrell, Jennifer Justice; Williams, Jennifer Schoelles; Powell, Paula

2003-01-01

The purpose of this article is to provide the health care practitioner with a comprehensive review of the pathophysiology and treatment of Type 1 Diabetes Mellitus. Traditionally, insulin has been administered via an insulin syringe. In the recent past, diabetes research has focused on developing more convenient insulin delivery devices and longer acting insulin's in hopes of increasing compliance with insulin therapy and improving the management of Type 1 diabetes in both children and adults...

Long-term rates of mitochondrial protein synthesis are increased in mouse skeletal muscle with high-fat feeding regardless of insulin-sensitizing treatment.

Science.gov (United States)

Newsom, Sean A; Miller, Benjamin F; Hamilton, Karyn L; Ehrlicher, Sarah E; Stierwalt, Harrison D; Robinson, Matthew M

2017-11-01

Skeletal muscle mitochondrial protein synthesis is regulated in part by insulin. The development of insulin resistance with diet-induced obesity may therefore contribute to impairments to protein synthesis and decreased mitochondrial respiration. Yet the impact of diet-induced obesity and insulin resistance on mitochondrial energetics is controversial, with reports varying from decreases to increases in mitochondrial respiration. We investigated the impact of changes in insulin sensitivity on long-term rates of mitochondrial protein synthesis as a mechanism for changes to mitochondrial respiration in skeletal muscle. Insulin resistance was induced in C57BL/6J mice using 4 wk of a high-fat compared with a low-fat diet. For 8 additional weeks, diets were enriched with pioglitazone to restore insulin sensitivity compared with nonenriched control low-fat or high-fat diets. Skeletal muscle mitochondrial protein synthesis was measured using deuterium oxide labeling during weeks 10-12 High-resolution respirometry was performed using palmitoyl-l-carnitine, glutamate+malate, and glutamate+malate+succinate as substrates for mitochondria isolated from quadriceps. Mitochondrial protein synthesis and palmitoyl- l-carnitine oxidation were increased in mice consuming a high-fat diet, regardless of differences in insulin sensitivity with pioglitazone treatment. There was no effect of diet or pioglitazone treatment on ADP-stimulated respiration or H 2 O 2 emission using glutamate+malate or glutamate+malate+succinate. The results demonstrate no impairments to mitochondrial protein synthesis or respiration following induction of insulin resistance. Instead, mitochondrial protein synthesis was increased with a high-fat diet and may contribute to remodeling of the mitochondria to increase lipid oxidation capacity. Mitochondrial adaptations with a high-fat diet appear driven by nutrient availability, not intrinsic defects that contribute to insulin resistance. Copyright © 2017 the

Twelve-Week Treatment With Liraglutide as Add-on to Insulin in Normal-Weight Patients With Poorly Controlled Type 1 Diabetes

DEFF Research Database (Denmark)

Frandsen, Christian S; Dejgaard, Thomas F; Holst, Jens J

2015-01-01

OBJECTIVE: This study investigated the efficacy and safety of once-daily liraglutide 1.2 mg versus placebo as add-on to insulin treatment in normal-weight patients with poorly controlled type 1 diabetes. RESEARCH DESIGN AND METHODS: In a randomized (1:1), double-blind, placebo-controlled design, 40...... patients with type 1 diabetes (HbA1c ≥8% [64 mmol/mol]) received once-daily liraglutide 1.2 mg or placebo for 12 weeks. Continuous glucose monitoring was performed before and at the end of treatment. The primary end point was change in HbA1c. Secondary end points included change in insulin dose, weight...... was more frequently associated with gastrointestinal adverse effects. The incidence of hypoglycemia did not differ between groups. CONCLUSIONS: Liraglutide significantly reduces body weight and insulin requirements but has no additional effect on HbA1c in normal-weight patients with type 1 diabetes...

Clinical experience with insulin detemir, biphasic insulin aspart and insulin aspart in people with type 2 diabetes: Results from the Casablanca cohort of the A 1 chieve study

Directory of Open Access Journals (Sweden)

Ahmed Farouqi

2013-01-01

Full Text Available Background: The A 1 chieve, a multicentric (28 countries, 24-week, non-interventional study evaluated the safety and effectiveness of insulin detemir, biphasic insulin aspart and insulin aspart in people with T2DM (n = 66,726 in routine clinical care across four continents. Materials and Methods: Data was collected at baseline, at 12 weeks and at 24 weeks. This short communication presents the results for patients enrolled from Casablanca, Morocco. Results: A total of 495 patients were enrolled in the study. Four different insulin analogue regimens were used in the study. Study patients had started on or were switched to biphasic insulin aspart (n = 231, insulin detemir (n = 151, insulin aspart (n = 19, basal insulin plus insulin aspart (n = 53 and other insulin combinations (n = 41. At baseline glycaemic control was poor for both insulin naïve (mean HbA 1 c: 10.2% and insulin user (mean HbA 1 c: 9.4% groups. After 24 weeks of treatment, both groups showed improvement in HbA 1 c (insulin naïve: −2.3%, insulin users: −1.8%. Major hypoglycaemia was observed in the insulin naïve group after 24 weeks. SADRs were reported in 1.2% of insulin naïve and 2.1% of insulin user groups. Conclusion: Starting or switching to insulin analogues was associated with improvement in glycaemic control with a low rate of hypoglycaemia.

Remission of insulin autoimmune syndrome in a patient with Grave's disease by treatment with methimazole.

Science.gov (United States)

Okabe, R; Inaba, M; Hosoi, M; Ishimura, E; Kumeda, Y; Nishizawa, Y; Morii, H

1999-06-01

The patient, a 24-year-old man, had suffered from hunger, sweating, tachycardia and palpitation for three years. He was diagnosed as having Graves' disease (GD) and treated with methimazole (MMI) for 3 months. He noted that palpitation and perspiration seemed to particularly occur when he was hungry, and thus he was examined to determine whether these symptoms were caused by hypoglycemia. As a markedly elevated immunoreactive insulin level and the presence of insulin antibody in serum were found, he was diagnosed as having insulin autoimmune syndrome (IAS). HLA typing revealed the patient to be positive for group Bw62/Cw4/DR4, which is reportedly a specific HLA type in MMI-treated euthyoroid GD patients with IAS. In spite of the continuation of MMI treatment, the % binding of IRI decreased and the hypoglycemic episode disappeared. In contrast to the previously reported MMI induced IAS in GD cases, MMI is unlikely to have exacerbated IAS in the present case, although his HLA combination is identical to that of the previous cases.

Expression of glycogen synthase and phosphofructokinase in muscle from type 1 (insulin-dependent) diabetic patients before and after intensive insulin treatment

DEFF Research Database (Denmark)

Vestergaard, H; Andersen, P H; Lund, S

1994-01-01

The aim of the present study was to determine whether short-term appropriate insulinization of Type 1 (insulin-dependent) diabetic patients in long-term poor glycaemic control (HbA1C > 9.5%) was associated with an adaptive regulation of the activity and gene expression of key proteins in muscle...... glycogen storage and glycolysis: glycogen synthase and phosphofructokinase, respectively. In nine diabetic patients biopsies of quadriceps muscle were taken before and 24-h after intensified insulin therapy and compared to findings in eight control subjects. Subcutaneous injections of rapid acting insulin...... were given at 3-h intervals to improve glycaemic control in diabetic patients (fasting plasma glucose decreased from 20.8 +/- 0.8 to 8.7 +/- 0.8 mmol/l whereas fasting serum insulin increased from 59 +/- 8 to 173 +/- 3 pmol/l). Before intensified insulin therapy, analysis of muscle biopsies from...

Efficacy and safety of dipeptidyl peptidase-4 inhibitors as an add-on to insulin treatment in patients with Type 2 diabetes

DEFF Research Database (Denmark)

Frandsen, Christian S.; Madsbad, S

2014-01-01

diabetes. METHODS: We searched the MEDLINE and PubMed databases to identify all randomized controlled clinical trials evaluating dipeptidyl peptidase-4 inhibitors as an add-on to insulin in patients with Type 2 diabetes, which were selected for review. The abstracts and posters of the recent annual...... and placebo treatment. CONCLUSION: Adding a dipeptidyl peptidase-4 inhibitor treatment to insulin has a moderate effect on HbA1c , a weight-neutral effect and a good safety profile. The risk of hypoglycaemia is not increased despite a significant improvement in HbA1c ....

Effect of chloroquine on insulin and glucose homoeostasis in normal subjects and patients with non-insulin-dependent diabetes mellitus.

Science.gov (United States)

Smith, G D; Amos, T A; Mahler, R; Peters, T J

1987-01-01

Plasma glucose, insulin, and C peptide concentrations were determined after an oral glucose load in normal subjects and in a group of patients with non-insulin-dependent diabetes mellitus before and during a short course of treatment with chloroquine. In the control group there was a small but significant reduction in fasting blood glucose concentration but overall glucose tolerance and hormone concentrations were unaffected. In contrast, the patients with non-insulin-dependent diabetes mellitus showed a significant improvement in their glucose tolerance, which paralleled the severity of their diabetes. This response seems to reflect decreased degradation of insulin rather than increased pancreatic output. These observations suggest that treatment with chloroquine or suitable analogues may be a new approach to the management of diabetes. PMID:3103729

Long-acting insulins alter milk composition and metabolism of lactating dairy cows.

Science.gov (United States)

Winkelman, L A; Overton, T R

2013-01-01

This study investigated the effect of 2 different types of long-acting insulin on milk production, milk composition, and metabolism in lactating dairy cows. Multiparous cows (n=30) averaging 88 d in milk were assigned to one of 3 treatments in a completely randomized design. Treatments consisted of control (C), Humulin-N (H; Eli Lilly and Company, Indianapolis, IN), and insulin glargine (L). The H and L treatments were administered twice daily at 12-h intervals via subcutaneous injection for 10d. Cows were milked twice daily, and milk composition was determined every other day. Mammary biopsies were conducted on d 11, and mammary proteins extracted from the biopsies were analyzed by Western blot for components of insulin and mammalian target of rapamycin signaling pathways. Treatment had no effect on dry matter intake or milk yield. Treatment with both forms of long-acting insulin increased milk protein content and tended to increase milk protein yield over the 10-d treatment period. Analysis of milk N fractions from samples collected on d 10 of treatment suggested that cows administered L tended to have higher yields of milk protein fractions than cows administered H. Milk fat content and yield tended to be increased for cows administered long-acting insulins. Lactose content and yields were decreased by treatment with long-acting insulins. Administration of long-acting insulins, particularly L, tended to shift milk fatty acid composition toward increased short- and medium-chain fatty acids and decreased long-chain fatty acids. Plasma concentrations of glucose and urea N were lower for cows administered long-acting insulins; interactions of treatment and sampling time were indicative of more pronounced effects of L than H on these metabolites. Concentrations of nonesterified fatty acids and insulin were increased in cows administered long-acting insulins. Decreased concentrations of urea N in both plasma and milk suggested more efficient use of N in cows

Impaired insulin-stimulated phosphorylation of Akt and AS160 in skeletal muscle of women with polycystic ovary syndrome is reversed by pioglitazone treatment

DEFF Research Database (Denmark)

Højlund, Kurt; Glintborg, Dorte; Andersen, Nicoline R

2008-01-01

, and we examined the effect of 16 weeks of treatment with pioglitazone in PCOS patients. RESULTS: Impaired insulin-mediated total (R(d)) oxidative and nonoxidative glucose disposal (NOGD) was paralleled by reduced insulin-stimulated Akt phosphorylation at Ser473 and Thr308 and AS160 phosphorylation......OBJECTIVE: Insulin resistance in skeletal muscle is a major risk factor for type 2 diabetes in women with polycystic ovary syndrome (PCOS). However, the molecular mechanisms underlying skeletal muscle insulin resistance and the insulin-sensitizing effect of thiazolidinediones in PCOS in vivo...... are less well characterized. RESEARCH DESIGN AND METHODS: We determined molecular mediators of insulin signaling to glucose transport in skeletal muscle biopsies of 24 PCOS patients and 14 matched control subjects metabolically characterized by euglycemic-hyperinsulinemic clamps and indirect calorimetry...

Potential of insulin nanoparticle formulations for oral delivery and diabetes treatment.

Science.gov (United States)

Wong, Chun Y; Al-Salami, Hani; Dass, Crispin R

2017-10-28

Nanoparticles have demonstrated significant advancements in potential oral delivery of insulin. In this publication, we review the current status of polymeric, inorganic and solid-lipid nanoparticles designed for oral administration of insulin. Firstly, the structure and physiological function of insulin are examined. Then, the efficiency and shortcomings of insulin nanoparticle are discussed. These include the susceptibility to digestive enzyme degradation, instability in the acidic pH environment, poor mucus diffusion and inadequate permeation through the gastrointestinal epithelium. In order to optimise the nanocarriers, the following considerations, including polymer nature, surface charge, size, polydispersity index and morphology of nanoparticles, have to be taken into account. Some novel designs such as chitosan-based glucose-responsive nanoparticles, layer by layer technique-based nanoparticles and zwitterion nanoparticles are being adopted to overcome the physiological challenges. The review ends with some future directions and challenges to be addressed for the success of oral delivery of insulin-loaded nanoparticle formulation. Copyright © 2017 Elsevier B.V. All rights reserved.

Clinical experience with insulin detemir, biphasic insulin aspart and insulin aspart in people with type 2 diabetes: Results from the Kolkata cohort of the A 1 chieve study

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Anirban Majumder

2013-01-01

Full Text Available Background: The A 1 chieve, a multicentric (28 countries, 24-week, non-interventional study evaluated the safety and effectiveness of insulin detemir, biphasic insulin aspart and insulin aspart in people with T2DM (n = 66,726 in routine clinical care across four continents. Materials and Methods: Data was collected at baseline, at 12 weeks and at 24 weeks. This short communication presents the results for patients enrolled from Kolkata, India. Results: A total of 576 patients were enrolled in the study. Four different insulin analogue regimens were used in the study. Patients had started on or were switched to biphasic insulin aspart (n = 417, insulin detemir (n = 70, insulin aspart (n = 55, basal insulin plus insulin aspart (n = 19 and other insulin combinations (n = 15. At baseline, glycaemic control was poor for both insulin naïve (mean HbA 1 c: 8.3% and insulin user (mean HbA 1 c: 8.6% groups. After 24 weeks of treatment, both the groups showed improvement in HbA 1 c (insulin naïve: −1.3%, insulin users: −1.4%. SADRs including major hypoglycaemic events or episodes did not occur in any of the study patients. Conclusion: Starting or switching to insulin analogues was associated with improvement in glycaemic control with a low rate of hypoglycaemia.

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

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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

Effect of insulin pump and continuous intravenous insulin on ketone body metabolism, blood gas indexes and stress state in patients with diabetic ketoacidosis

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Hui-Jin Shi

2017-09-01

Full Text Available Objective: To study the effect of insulin pump and continuous intravenous insulin on ketone body metabolism, blood gas indexes and stress state in patients with diabetic ketoacidosis. Methods: Patients with diabetic ketoacidosis who were treated in Meizhou Maternal and Child Heath Hospital between May 2014 and March 2017 were selected as the research subjects and randomly divided into the group A who received subcutaneous insulin infusion by insulin pump and the group B who received intravenous small-dose insulin injection by micropump. The indexes of ketone body, blood gas and stress were measured before and after treatment. Results: 12 h and 24 h after treatment, serum β-hydroxybutyrate, MDA, NE, ACTH and Cor contents of both groups of patients were significantly lower than those before treatment while pH, HCO3 - and base excess levels as well as serum SOD, GSH-Px, CAT and TAC contents were significantly higher than those before treatment, and serum β-hydroxybutyrate, MDA, NE, ACTH and Cor contents of group A were significantly lower than those of group B while pH, HCO3 - and base excess levels as well as serum SOD, GSH-Px, CAT and TAC contents were significantly higher than those of group B. Conclusion: Subcutaneous insulin infusion by insulin pump can improve ketone body metabolism, acidosis status and stress state in patients with diabetic ketoacidosis.

Treatment with continuous subcutaneous insulin infusion is associated with lower arterial stiffness

DEFF Research Database (Denmark)

Vestergaard Rosenlund, Signe; Theilade, Simone; Hansen, Tine Willum

2014-01-01

AIMS: To investigate the relationship between arterial stiffness and insulin treatment mode [continuous subcutaneous insulin infusion (CSII) versus multiple daily injections (MDI)] in type 1 diabetes patients. METHODS: Cross-sectional study, from 2009 to 2011, including 601 Caucasian type 1...... diabetes patients, 58 and 543 treated with CSII and MDI, respectively. Arterial stiffness was measured as pulse wave velocity (PWV) (SphygmoCor, AtCor Medical). Adjustment included gender, age, diabetes duration, HbA1c, heart rate, mean arterial pressure, P-creatinine, urinary albumin excretion rate (UAER......-treated patients were 48 versus 57 % men, 51 ± 11 versus 54 ± 13 years old (mean ± SD), had 33 ± 12 versus 32 ± 16 years diabetes duration and HbA1c 7.8 ± 0.9 % (62 ± 10 mmol/mol) versus 8.0 ± 1.2 % (64 ± 13 mmol/mol) (P ≥ 0.08 for all). PWV was lower in CSII- versus MDI-treated patients (9.3 ± 2.8 vs. 10.4 ± 3...

Relationship between insulin resistance and plasma endothelin in hypertension patients

International Nuclear Information System (INIS)

Duan Yongqiang; Wang Zuobing; Yu Hui; Cao Wei; Wang Jing; Li Xiaoqin

2011-01-01

To explore the relationship between plasma endothelin and hypertension insulin resistance, and the improvement of insulin resistance in hypertension patients treated with captopril and l-amlodipine, 25 patients with primary hypertension and impaired glucose tolerance were selected and treated by captopril and l-amlodipine. Systolic pressure, diastolic pressure, fasting blood glucose, insulin and insulin antibody were measured before and after treatment and compared with healthy controls. The results showed that the plasma ET-1 level in hypertension group was significantly higher than that of healthy controls (P<0.01), and he plasma ET-1 level was positively correlated with FPG, FINS, Anti-INS, HOMA-IR. The systolic pressure, diastolic pressure, fasting blood glucose, insulin, insulin antibody and insulin resistance index in hypertension patients were decreased significantly after treatment (P<0.05). There is a good correlation between endothelin and insulin resistance index in hypertension patients. Captopril and l-amlodipine had obvious improvement effect on insulin resistance in hypertension patients. (authors)

Modern basal insulins: an ongoing story or the start of a new era?

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Ivan Ivanovich Dedov

2015-11-01

Full Text Available Basal insulin represents an essential tool in the treatment of both type 1 and type 2 diabetes mellitus. The development of insulin analogues has improved the possibilities of diabetes treatment. Despite significant progress in understanding the physiology, chemistry, kinetics and action of insulin, currently available basal insulin products do not optimally mimic the endogenous profile of insulin. Although basal insulin analogues have some advantages over neutral protamine Hagedorn insulin in diabetes treatment, hypoglycaemia remains the main problem in the achievement of optimal glycaemic control in most patients with diabetes. These unmet clinical needs have stimulated the development of new basal insulin analogues with improved pharmacological profiles. This article reviews the specific characteristics of new long-acting insulin analogues to try and understand their benefits and limitations in the improvement of diabetes management and their possibilities in physiologic and safe insulin replacement.

Insulin gene therapy for type 1 diabetes mellitus.

Science.gov (United States)

Handorf, Andrew M; Sollinger, Hans W; Alam, Tausif

2015-04-01

Type 1 diabetes mellitus is an autoimmune disease resulting from the destruction of pancreatic β cells. Current treatments for patients with type 1 diabetes mellitus include daily insulin injections or whole pancreas transplant, each of which are associated with profound drawbacks. Insulin gene therapy, which has shown great efficacy in correcting hyperglycemia in animal models, holds great promise as an alternative strategy to treat type 1 diabetes mellitus in humans. Insulin gene therapy refers to the targeted expression of insulin in non-β cells, with hepatocytes emerging as the primary therapeutic target. In this review, we present an overview of the current state of insulin gene therapy to treat type 1 diabetes mellitus, including the need for an alternative therapy, important features dictating the success of the therapy, and current obstacles preventing the translation of this treatment option to a clinical setting. In so doing, we hope to shed light on insulin gene therapy as a viable option to treat type 1 diabetes mellitus.

Novel Simple Insulin Delivery Device Reduces Barriers to Insulin Therapy in Type 2 Diabetes: Results From a Pilot Study

OpenAIRE

Hermanns, Norbert; Lilly, Leslie C.; Mader, Julia K.; Aberer, Felix; Ribitsch, Anja; Kojzar, Harald; Warner, Jay; Pieber, Thomas R.

2015-01-01

Background: The PaQ® insulin delivery system is a simple-to-use patch-on device that provides preset basal rates and bolus insulin on demand. In addition to feasibility of use, safety, and efficacy (reported elsewhere), this study analyzed the impact of PaQ on patient-reported outcomes, including barriers to insulin treatment, diabetes-related distress, and attitudes toward insulin therapy in patients with type 2 diabetes on a stable multiple daily injection (MDI) regimen. Methods: This singl...

Insulin Inclusion into a Tragacanth Hydrogel: An Oral Delivery System for Insulin

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Mokhamad Nur

2018-01-01

Full Text Available Nanoparticles or microparticles created by physical complexation between two polyelectrolytes may have a prospective use as an excipient for oral insulin administration. Natural polymers such as tragacanth, alginate, dextran, pullulan, hyaluronic acid, gelatin and chitosan can be potential candidates for this purpose. In this research, insulin particles were prepared by the inclusion of insulin into a tragacanth hydrogel. The effect of the pH and concentration relationship involving polyelectrolytes offering individual particle size and zeta potential was assessed by zetasizer and scanning electron microscopy (SEM. Insulin–tragacanth interactions at varying pH (3.7, 4.3, 4.6, or 6, and concentration (0.1%, 0.5%, or 1% w/w were evaluated by differential scanning calorimetry (DSC and ATR Fourier transform infrared (ATR-FTIR analysis. Individual and smaller particles, approximately 800 nm, were acquired at pH 4.6 with 0.5% of tragacanth. The acid gelation test indicated that insulin could be entrapped in the physical hydrogel of tragacanth. DSC thermograms of insulin–tragacanth showed shifts on the same unloaded tragacanth peaks and suggested polyelectrolyte–protein interactions at a pH close to 4.3–4.6. FTIR spectra of tragacanth–insulin complexes exhibited amide absorption bands featuring in the protein spectra and revealed the creation of a new chemical substance.

Iontophoresis of monomeric insulin analogues in vitro: effects of insulin charge and skin pretreatment.

Science.gov (United States)

Langkjaer, L; Brange, J; Grodsky, G M; Guy, R H

1998-01-23

The aim of this study was to investigate the influence of association state and net charge of human insulin analogues on the rate of iontophoretic transport across hairless mouse skin, and the effect of different skin pretreatments on said transport. No insulin flux was observed with anodal delivery probably because of degradation at the Ag/AgCl anode. The flux during cathodal iontophoresis through intact skin was insignificant for human hexameric insulin, and only low and variable fluxes were observed for monomeric insulins. Using stripped skin on the other hand, the fluxes of monomeric insulins with two extra negative charges were 50-100 times higher than that of hexameric human insulin. Introducing three additional charges led to a further 2-3-fold increase in flux. Wiping the skin gently with absolute alcohol prior to iontophoresis resulted in a 1000-fold increase in transdermal transport of insulin relative to that across untreated skin, i.e. to almost the same level as stripping the skin. The alcohol pretreatment reduced the electrical resistance of the skin, presumably by lipid extraction. In conclusion, monomeric insulin analogues with at least two extra negative charges can be iontophoretically delivered across hairless mouse skin, whereas insignificant flux is observed with human, hexameric insulin. Wiping the skin with absolute alcohol prior to iontophoresis gave substantially improved transdermal transport of monomeric insulins resulting in clinically relevant delivery rates for basal treatment.

Fructose induced neurogenic hypertension mediated by overactivation of p38 MAPK to impair insulin signaling transduction caused central insulin resistance.

Science.gov (United States)

Cheng, Pei-Wen; Lin, Yu-Te; Ho, Wen-Yu; Lu, Pei-Jung; Chen, Hsin-Hung; Lai, Chi-Cheng; Sun, Gwo-Ching; Yeh, Tung-Chen; Hsiao, Michael; Tseng, Ching-Jiunn; Liu, Chun-Peng

2017-11-01

Type 2 diabetes are at a high risk of complications related to hypertension, and reports have indicated that insulin levels may be associated with blood pressure (BP). Fructose intake has recently been reported to promote insulin resistance and superoxide formation. The aim of this study is to investigate whether fructose intake can enhance superoxide generation and impair insulin signaling in the NTS and subsequently elevate BP in rats with fructose-induced hypertension. Treatment with fructose for 4 weeks increased the BP, serum fasting insulin, glucose, homeostatic model assessment-insulin resistance, and triglyceride levels and reduced the serum direct high-density lipoprotein level in the fructose group. The Tempol treatment recovered the fructose-induced decrease in nitric oxide production in the NTS. Immunoblotting and immunofluorescence analyses further showed that fructose increased the p38- and fructose-induced phosphorylation of insulin receptor substrate 1 (IRS1 S307 ) and suppressed Akt S473 and neuronal nitric oxide synthase phosphorylation. Similarly, fructose was able to impair insulin sensitivity and increase insulin levels in the NTS. Fructose intake also increased the production of superoxide in the NTS. The results of this study suggest that fructose might induce central insulin resistance and elevate BP by enhancing superoxide production and activating p38 phosphorylation in the NTS. Copyright © 2017 Elsevier Inc. All rights reserved.

Role of adipose tissue derived stem cells differentiated into insulin producing cells in the treatment of type I diabetes mellitus.

Science.gov (United States)

Amer, Mona G; Embaby, Azza S; Karam, Rehab A; Amer, Marwa G

2018-05-15

Generation of new β cells is an important approach in the treatment of type 1 diabetes mellitus (type 1 DM). Adipose tissue-derived stem cells (ADSCs) might be one of the best sources for cell replacement therapy for diabetes. Therefore, this work aimed to test the possible role of transplanted insulin-producing cells (IPCs) differentiated from ADSCs in treatment of streptozotocin (STZ) induced type I DM in rats. Type 1 DM was induced by single intra peritoneal injection with STZ (50 mg/kg BW). Half of the diabetic rats were left without treatment and the other half were injected with differentiated IPCs directly into the pancreas. ADSCs were harvested, cultured and identified by testing their phenotypes through flow cytometry. They were further subjected to differentiation into IPCs using differentiation medium. mRNA expression of pancreatic transcription factors (pdx1), insulin and glucose transporter-2 genes by real time PCR was done to detect the cellular differentiation and confirmed by stimulated insulin secretion. The pancreatic tissues from all groups were examined 2 months after IPC transplantation and were subjected to histological, Immunohistochemical and morphometric study. The differentiated IPCs showed significant expression of pancreatic β cell markers and insulin secretion in glucose dependent manner. Treatment with IPCs induced apparent regeneration, diffused proliferated islet cells and significant increase in C-peptide immune reaction. We concluded that transplantation of differentiated IPCs improved function and morphology of Islet cells in diabetic rats. Consequently, this therapy option may be a promising therapeutic approach to patient with type 1 DM if proven to be effective and safe. Copyright © 2018 Elsevier B.V. All rights reserved.

Glycine Increases Insulin Sensitivity and Glutathione Biosynthesis and Protects against Oxidative Stress in a Model of Sucrose-Induced Insulin Resistance

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Mohammed El-Hafidi

2018-01-01

Full Text Available Oxidative stress and redox status play a central role in the link between insulin resistance (IR and lipotoxicity in metabolic syndrome. This mechanistic link may involve alterations in the glutathione redox state. We examined the effect of glycine supplementation to diet on glutathione biosynthesis, oxidative stress, IR, and insulin cell signaling in liver from sucrose-fed (SF rats characterized by IR and oxidative stress. Our hypothesis is that the correction of glutathione levels by glycine treatment leads to reduced oxidative stress, a mechanism associated with improved insulin signaling and IR. Glycine treatment decreases the levels of oxidative stress markers in liver from SF rats and increases the concentrations of glutathione (GSH and γ-glutamylcysteine and the amount of γ-glutamylcysteine synthetase (γ-GCS, a key enzyme of GSH biosynthesis in liver from SF rats. In liver from SF rats, glycine also decreases the insulin-induced phosphorylation of insulin receptor substrate-1 (ISR-1 in serine residue and increases the phosphorylation of insulin receptor β-subunit (IR-β in tyrosine residue. Thus, supplementing diets with glycine to correct GSH deficiency and to reduce oxidative stress provides significant metabolic benefits to SF rats by improving insulin sensitivity.

Clinical experience with insulin detemir, biphasic insulin aspart and insulin aspart in people with type 2 diabetes: Results from the Northern Tunisia cohort of the A1chieve study

Science.gov (United States)

Blouza, Samira; Jamoussi, Henda

2013-01-01

Background: The A1chieve, a multicentric (28 countries), 24-week, non-interventional study evaluated the safety and effectiveness of insulin detemir, biphasic insulin aspart and insulin aspart in people with T2DM (n = 66,726) in routine clinical care across four continents. Materials and Methods: Data was collected at baseline, at 12 weeks and at 24 weeks. This short communication presents the results for patients enrolled from Northern Tunisia. Results: A total of 443 patients were enrolled in the study. Four different insulin analogue regimens were used in the study. Study patients had started on or were switched to biphasic insulin aspart (n = 137), insulin detemir (n = 243), insulin aspart (n = 11), basal insulin plus insulin aspart (n = 39) and other insulin combinations (n = 13). At baseline glycaemic control was poor for both insulin naïve (mean HbA1c: 10.2%) and insulin user (mean HbA1c: 9.8%) groups. After 24 weeks of treatment, both the study groups showed improvement in HbA1c (insulin naïve: −2.1%, insulin users: −0.9%). SADRs including major hypoglycaemic events or episodes did not occur in any of the study patients. Conclusion: Starting or switching to insulin analogues was associated with improvement in glycaemic control with a low rate of hypoglycaemia. PMID:24404473

Clinical experience with insulin detemir, biphasic insulin aspart and insulin aspart in people with type 2 diabetes: Results from the Northern Tunisia cohort of the A 1 chieve study

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Samira Blouza

2013-01-01

Full Text Available Background: The A 1 chieve, a multicentric (28 countries, 24-week, non-interventional study evaluated the safety and effectiveness of insulin detemir, biphasic insulin aspart and insulin aspart in people with T2DM (n = 66,726 in routine clinical care across four continents. Materials and Methods: Data was collected at baseline, at 12 weeks and at 24 weeks. This short communication presents the results for patients enrolled from Northern Tunisia. Results: A total of 443 patients were enrolled in the study. Four different insulin analogue regimens were used in the study. Study patients had started on or were switched to biphasic insulin aspart (n = 137, insulin detemir (n = 243, insulin aspart (n = 11, basal insulin plus insulin aspart (n = 39 and other insulin combinations (n = 13. At baseline glycaemic control was poor for both insulin naïve (mean HbA 1 c: 10.2% and insulin user (mean HbA 1 c: 9.8% groups. After 24 weeks of treatment, both the study groups showed improvement in HbA 1 c (insulin naïve: −2.1%, insulin users: −0.9%. SADRs including major hypoglycaemic events or episodes did not occur in any of the study patients. Conclusion: Starting or switching to insulin analogues was associated with improvement in glycaemic control with a low rate of hypoglycaemia.

Targeting VEGF-B as a novel treatment for insulin resistance and type 2 diabetes.

Science.gov (United States)

Hagberg, Carolina E; Mehlem, Annika; Falkevall, Annelie; Muhl, Lars; Fam, Barbara C; Ortsäter, Henrik; Scotney, Pierre; Nyqvist, Daniel; Samén, Erik; Lu, Li; Stone-Elander, Sharon; Proietto, Joseph; Andrikopoulos, Sofianos; Sjöholm, Ake; Nash, Andrew; Eriksson, Ulf

2012-10-18

The prevalence of type 2 diabetes is rapidly increasing, with severe socioeconomic impacts. Excess lipid deposition in peripheral tissues impairs insulin sensitivity and glucose uptake, and has been proposed to contribute to the pathology of type 2 diabetes. However, few treatment options exist that directly target ectopic lipid accumulation. Recently it was found that vascular endothelial growth factor B (VEGF-B) controls endothelial uptake and transport of fatty acids in heart and skeletal muscle. Here we show that decreased VEGF-B signalling in rodent models of type 2 diabetes restores insulin sensitivity and improves glucose tolerance. Genetic deletion of Vegfb in diabetic db/db mice prevented ectopic lipid deposition, increased muscle glucose uptake and maintained normoglycaemia. Pharmacological inhibition of VEGF-B signalling by antibody administration to db/db mice enhanced glucose tolerance, preserved pancreatic islet architecture, improved β-cell function and ameliorated dyslipidaemia, key elements of type 2 diabetes and the metabolic syndrome. The potential use of VEGF-B neutralization in type 2 diabetes was further elucidated in rats fed a high-fat diet, in which it normalized insulin sensitivity and increased glucose uptake in skeletal muscle and heart. Our results demonstrate that the vascular endothelium can function as an efficient barrier to excess muscle lipid uptake even under conditions of severe obesity and type 2 diabetes, and that this barrier can be maintained by inhibition of VEGF-B signalling. We propose VEGF-B antagonism as a novel pharmacological approach for type 2 diabetes, targeting the lipid-transport properties of the endothelium to improve muscle insulin sensitivity and glucose disposal.

S961, an insulin receptor antagonist causes hyperinsulinemia, insulin-resistance and depletion of energy stores in rats

Energy Technology Data Exchange (ETDEWEB)

Vikram, Ajit [Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), SAS Nagar, Mohali, Punjab 160 062 (India); Jena, Gopabandhu, E-mail: gbjena@gmail.com [Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER), SAS Nagar, Mohali, Punjab 160 062 (India)

2010-07-23

Research highlights: {yields}Insulin receptor antagonist S961 causes hyperglycemia, hyperinsulinemia and insulin resistance in rats. {yields}Peroxysome-proliferator-activated-receptor-gamma agonist pioglitazone improves S961 induced hyperglycemia and glucose intolerance. {yields}Long term treatment with insulin receptor antagonist S961 results in the decreased adiposity and hepatic glycogen content. {yields}Improvement in the hyperglycemia and glucose intolerance by pioglitazone clearly demonstrates that S961 treated rats can be successfully used to screen the novel therapeutic interventions having potential to improve glucose disposal through receptor independent mechanisms. -- Abstract: Impairment in the insulin receptor signaling and insulin mediated effects are the key features of type 2 diabetes. Here we report that S961, a peptide insulin receptor antagonist induces hyperglycemia, hyperinsulinemia ({approx}18-fold), glucose intolerance and impairment in the insulin mediated glucose disposal in the Sprague-Dawley rats. Further, long-term S961 treatment (15 day, 10 nM/kg/day) depletes energy storage as evident from decrease in the adiposity and hepatic glycogen content. However, peroxysome-proliferator-activated-receptor-gamma (PPAR{gamma}) agonist pioglitazone significantly (P < 0.001) restored S961 induced hyperglycemia (196.73 {+-} 16.32 vs. 126.37 {+-} 27.07 mg/dl) and glucose intolerance ({approx}78%). Improvement in the hyperglycemia and glucose intolerance by pioglitazone clearly demonstrates that S961 treated rats can be successfully used to screen the novel therapeutic interventions having potential to improve glucose disposal through receptor independent mechanisms. Further, results of the present study reconfirms and provide direct evidence to the crucial role of insulin receptor signaling in the glucose homeostasis and fuel metabolism.

Luminal uptake and intracellular transport of insulin in renal proximal tubules

International Nuclear Information System (INIS)

Hellfritzsch, M.; Christensen, E.I.; Sonne, O.

1986-01-01

It is generally accepted that proteins taken up from the renal tubular fluid are transported into lysosomes in proximal tubule cells. Recently, however, it has been postulated that insulin in isolated perfused rat kidneys did not accumulate in lysosomes but to a certain degree in the Golgi region. The present study was undertaken to investigate the intracellular handling of biologically unaltered insulin in rat renal proximal tubule cells. Rats were prepared for in vivo micropuncture and either a colloidal gold insulin complex or insulin monoiodinated in the A-14 position ( 125 I-insulin) was microinfused into proximal tubules. After 5, 10, 25 or 60 min the tubules were fixed by microinfusion of glutaraldehyde and processed for electron microscopy or electron microscope autoradiography. A qualitative analysis of tubules infused with colloidal gold insulin or 125 I-insulin showed that insulin was taken up by endocytosis and transported to lysosomes, and a quantitative autoradiographic analysis of the 125 I-insulin microinfused tubules showed that the grain density after five min was significantly increased for endocytic vacuoles and for lysosomes. After 60 min the grain density was still significant over lysosomes. The accumulation of grains was non-significant over all other areas analyzed at any time. This study shows that insulin is taken up from the luminal side of the proximal tubule by endocytosis and transported to the lysosomes. There was no significant transport to the Golgi region

Quercetin suppresses insulin receptor signaling through inhibition of the insulin ligand–receptor binding and therefore impairs cancer cell proliferation

Energy Technology Data Exchange (ETDEWEB)

Wang, Feng [Department of Gastroenterology, The Tenth People’s Hospital of Shanghai, Tongji University, Shanghai 200072 (China); Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX 77030 (United States); Yang, Yong, E-mail: yyang@houstonmethodist.org [Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX 77030 (United States); Department of Medicine, Weill Cornell Medical College, New York, NY 10065 (United States)

2014-10-03

Graphical abstract: - Highlights: • Quercetin inhibits insulin ligand–receptor interactions. • Quercetin reduces downstream insulin receptor signaling. • Quercetin blocks insulin induced glucose uptake. • Quercetin suppresses insulin stimulated cancer cell proliferation and tumor growth. - Abstract: Although the flavonoid quercetin is known to inhibit activation of insulin receptor signaling, the inhibitory mechanism is largely unknown. In this study, we demonstrate that quercetin suppresses insulin induced dimerization of the insulin receptor (IR) through interfering with ligand–receptor interactions, which reduces the phosphorylation of IR and Akt. This inhibitory effect further inhibits insulin stimulated glucose uptake due to decreased cell membrane translocation of glucose transporter 4 (GLUT4), resulting in impaired cancer cell proliferation. The effect of quercetin in inhibiting tumor growth was also evident in an in vivo model, indicating a potential future application for quercetin in the treatment of cancers.

Quercetin suppresses insulin receptor signaling through inhibition of the insulin ligand–receptor binding and therefore impairs cancer cell proliferation

International Nuclear Information System (INIS)

Wang, Feng; Yang, Yong

2014-01-01

Graphical abstract: - Highlights: • Quercetin inhibits insulin ligand–receptor interactions. • Quercetin reduces downstream insulin receptor signaling. • Quercetin blocks insulin induced glucose uptake. • Quercetin suppresses insulin stimulated cancer cell proliferation and tumor growth. - Abstract: Although the flavonoid quercetin is known to inhibit activation of insulin receptor signaling, the inhibitory mechanism is largely unknown. In this study, we demonstrate that quercetin suppresses insulin induced dimerization of the insulin receptor (IR) through interfering with ligand–receptor interactions, which reduces the phosphorylation of IR and Akt. This inhibitory effect further inhibits insulin stimulated glucose uptake due to decreased cell membrane translocation of glucose transporter 4 (GLUT4), resulting in impaired cancer cell proliferation. The effect of quercetin in inhibiting tumor growth was also evident in an in vivo model, indicating a potential future application for quercetin in the treatment of cancers

Clinical experience with insulin detemir, biphasic insulin aspart and insulin aspart in people with type 2 diabetes: Results from the Rajasthan cohort of the A 1 chieve study

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Akhil Joshi

2013-01-01

Full Text Available Background: The A 1 chieve, a multicentric (28 countries, 24-week, non-interventional study evaluated the safety and effectiveness of insulin detemir, biphasic insulin aspart and insulin aspart in people with T2DM (n = 66,726 in routine clinical care across four continents. Materials and Methods: Data was collected at baseline, at 12 weeks and at 24 weeks. This short communication presents the results for patients enrolled from Rajasthan, India. Results: A total of 477 patients were enrolled in the study. Four different insulin analogue regimens were used in the study. Patients had started on or were switched to biphasic insulin aspart (n = 340, insulin detemir (n = 90, insulin aspart (n = 37, basal insulin plus insulin aspart (n = 7 and other insulin combinations (n = 2. At baseline glycaemic control was poor for both insulin naïve (mean HbA 1 c: 8.3% and insulin user (mean HbA 1 c: 8.4% groups. After 24 weeks of treatment, both the groups showed improvement in HbA 1 c (insulin naïve: −0.9%, insulin users: −1.2%. Major hypoglycaemic events decreased from 0.5 events/patient-year to 0.0 events/patient-year in insulin naïve group while no change from baseline (1.3 events/patients-year was observed for insulin users. SADRs were not reported in any of the study patients. Conclusion: Starting or switching to insulin analogues was associated with improvement in glycaemic control with a low rate of hypoglycaemia.

Insulin induces airway smooth muscle contraction

NARCIS (Netherlands)

Schaafsma, D.; Gosens, R.; Ris, J. M.; Zaagsma, J.; Meurs, H.; Nelemans, S. A.

Background and purpose: Recently, the use of inhaled insulin formulations for the treatment of type I and type II diabetes has been approved in Europe and in the United States. For regular use, it is critical that airway function remains unimpaired in response to insulin exposure. Experimental

Interaction between exogenous insulin, endogenous insulin, and glucose in type 2 diabetes patients.

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Janukonyté, Jurgita; Parkner, Tina; Bruun, Niels Henrik; Lauritzen, Torsten; Christiansen, Jens Sandahl; Laursen, Torben

2015-05-01

Little is known about the influence of exogenous insulin and actual glucose levels on the release of endogenous insulin in insulin-treated type 2 diabetes mellitus (T2DM) patients. This study investigated the interaction among serum endogenous insulin (s-EI), serum exogenous insulin aspart (s-IAsp), and blood glucose levels in an experimental short-term crossover design. Eight T2DM patients (63.52 years old; range, 49-69 years; mean body mass index, 28.8±3.8 kg/m(2)) were randomized to treatment with individual fixed doses of insulin aspart (0.5-1.5 IU/h) as a continuous subcutaneous insulin infusion (CSII) during a 10-h period on two occasions with different duration of hyperglycemia: (1) transient hyperglycemia for 2 h (visit TH) and (2) continuous hyperglycemia for 12 h (visit CH). During steady state the variances of plasma glucose (p-glucose), s-IAsp, and s-EI were equal within visit TH and within visit CH, but variances were significantly higher during visit CH compared with visit TH. The s-IAsp reached lower levels at visit CH compared with visit TH (test for slope=1, P=0.005). The s-EI depended on p-glucose in a nonlinear fashion during the first 100 min of both visits when s-IAsp was undetectable (adjusted R(2)=0.9). A complex but statistically significant interaction among s-IAsp, s-EI, p-glucose, and patients was observed during measurable s-IAsp levels (adjusted R(2)=0.70). Endogenous and exogenous insulin showed higher variation during continuous hyperglycemia. Significantly lower levels of exogenous insulin were observed following CSII during continuous hyperglycemia compared with transient hyperglycemia. Endogenous insulin levels could in a complex way be explained by an individual interaction among p-glucose and serum exogenous insulin, if present.

Effectiveness of insulin glargine in type 2 diabetes mellitus patients failing glycaemic control with premixed insulin: Adriatic countries data meta-analysis.

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Cigrovski Berkovic, Maja; Petrovski, Goran; Grulovic, Natasa

2016-10-01

Type 2 diabetes mellitus (T2DM) is a progressive disease, often requiring exogenous insulin therapy and treatment intensification. Despite new therapies, most patients do not reach the recommended HbA1c targets, among them a significant proportion of patients on premixed insulins. The aim was to summarize published data in Adriatic countries on effectiveness of insulin glargine based therapy in type 2 diabetic patients suboptimally controlled on premix insulin. A meta-analysis was carried out in major medical databases up to April 2014, focusing on Adriatic region. We searched observational studies with duration of at least 6 months, evaluating effectiveness and safety of insulin glargine (IGlar), in combination with OAD or bolus insulin in patients with T2 failing premixed insulin therapy. Outcomes included values of HbA1c, fasting blood glucose and two hours post-prandial glucose concentration as well as changes in body mass index after at least 6 months of study duration. Three prospective, observational, multicentric trials (698 patients in total) were included. The basal bolus regimen with glargine significantly reduced HbA1c (Mean Difference, MD=2.27, CI [1.76, 2.78]), fasting glucose (MD=5.15, CI [4.86, 5.44]) and 2-hours postprandial glucose concentration (MD=6.94, CI [6.53, 7.34]). No significant changes were found in BMI after switching from premixes to IGlar based treatment. Insulin glargine based therapy following premix failure is efficacious and safe option of type 2 diabetes treatment intensification.

Structure and dynamics of spin-labeled insulin entrapped in a silica matrix by the sol-gel method.

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Vanea, E; Gruian, C; Rickert, C; Steinhoff, H-J; Simon, V

2013-08-12

The structure and conformational dynamics of insulin entrapped into a silica matrix was monitored during the sol to maturated-gel transition by electron paramagnetic resonance (EPR) spectroscopy. Insulin was successfully spin-labeled with iodoacetamide and the bifunctional nitroxide reagent HO-1944. Room temperature continuous wave (cw) EPR spectra of insulin were recorded to assess the mobility of the attached spin labels. Insulin conformation and its distribution within the silica matrix were studied using double electron-electron resonance (DEER) and low-temperature cw-EPR. A porous oxide matrix seems to form around insulin molecules with pore diameters in the order of a few nanometers. Secondary structure of the encapsulated insulin investigated by Fourier transform infrared spectroscopy proved a high structural integrity of insulin even in the dried silica matrix. The results show that silica encapsulation can be used as a powerful tool to effectively isolate and functionally preserve biomolecules during preparation, storage, and release.

Effects of one year treatment of sibutramine on insulin resistance parameters in type 2 diabetic patients.

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Derosa, Giuseppe; Maffioli, Pamela; Ferrari, Ilaria; Palumbo, Ilaria; Randazzo, Sabrina; D'Angelo, Angela; Cicero, Arrigo F G

2010-01-01

Comparison of the effects of one year treatment with sibutramine compared to placebo on insulin resistance parameters, body weight, glycemic control, and lipid profile, in type 2 diabetic patients. Two hundred and forty-six patients with uncontrolled type 2 diabetes mellitus in therapy with different oral hypoglycemic agents or insulin were enrolled in this study and randomised to take sibutramine 10 mg or placebo for one year. We evaluated at baseline, and after 3, 6, 9, and 12 months these parameters: homeostasis model assessment insulin resistance index (HOMA-IR), retinol binding protein-4 (RBP-4), resistin, visfatin, and high sensitivity-C reactive protein (Hs-CRP), body weight, body mass index (BMI), glycated hemoglobin (HbA(₁c)), fasting plasma glucose (FPG), post-prandial plasma glucose (PPG), fasting plasma insulin (FPI), total cholesterol (TC), low density lipoprotein-cholesterol (LDL-C), high density lipoprotein-cholesterol (HDL-C), and triglycerides (T(g)). A faster decrease of HOMA-IR, resistin, and RBP-4 was recorded with sibutramine compared to the control group. We observed a significant decrease of Hs-CRP in both groups, and a faster improvement of HbA(₁c), FPG and PPG with sibutramine compared to the control group; furthermore we recorded a decrease of FPI, TC, LDL-C, body weight, and BMI in the sibutramine group, but not in the control group. Sibutramine gave a faster improvement of insulin resistance parameters and glycemic control compared to placebo; furthermore sibutramine gave also an improvement of lipid profile, and body weight.

Patient safety and minimizing risk with insulin administration - role of insulin degludec.

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Aye, Myint M; Atkin, Stephen L

2014-01-01

Diabetes is a lifelong condition requiring ongoing medical care and patient self-management. Exogenous insulin therapy is essential in type 1 diabetes and becomes a necessity in patients with longstanding type 2 diabetes who fail to achieve optimal control with lifestyle modification, oral agents, and glucagon-like peptide 1-based therapy. One of the risks that hinders insulin use is hypoglycemia. Optimal insulin therapy should therefore minimize the risk of hypoglycemia while improving glycemic control. Insulin degludec (IDeg) is a novel basal insulin that, following subcutaneous injection, assembles into a depot of soluble multihexamer chains. These subsequently release IDeg monomers that are absorbed at a slow and steady rate into the circulation, with the terminal half-life of IDeg being ~25 hours. Thus, it requires only once-daily dosing unlike other basal insulin preparations that often require twice-daily dosing. Despite its long half-life, once-daily IDeg does not cause accumulation of insulin in the circulation after reaching steady state. IDeg once a day will produce a steady-state profile with a lower peak:trough ratio than other basal insulins. In clinical trials, this profile translates into a lower frequency of nocturnal hypoglycemia compared with insulin glargine, as well as an ability to allow some flexibility in dose timing without compromising efficacy and safety. Indeed, a study that tested the extremes of dosing intervals of 8 and 40 hours showed no detriment in either glycemic control or hypoglycemic frequency versus insulin glargine given at the same time each day. While extreme flexibility in dose timing is not recommended, these findings are reassuring. This may be particularly beneficial to elderly patients, patients with learning difficulties, or others who have to rely on health-care professionals for their daily insulin injections. Further studies are required to confirm whether this might benefit adherence to treatment, reduce long

Proinsulin C-peptide interferes with insulin fibril formation

International Nuclear Information System (INIS)

Landreh, Michael; Stukenborg, Jan-Bernd; Willander, Hanna; Söder, Olle; Johansson, Jan; Jörnvall, Hans

2012-01-01

Highlights: ► Insulin and C-peptide can interact under insulin fibril forming conditions. ► C-peptide is incorporated into insulin aggregates and alters aggregation lag time. ► C-peptide changes insulin fibril morphology and affects backbone accessibility. ► C-peptide may be a regulator of fibril formation by β-cell granule proteins. -- Abstract: Insulin aggregation can prevent rapid insulin uptake and cause localized amyloidosis in the treatment of type-1 diabetes. In this study, we investigated the effect of C-peptide, the 31-residue peptide cleaved from proinsulin, on insulin fibrillation at optimal conditions for fibrillation. This is at low pH and high concentration, when the fibrils formed are regular and extended. We report that C-peptide then modulates the insulin aggregation lag time and profoundly changes the fibril appearance, to rounded clumps of short fibrils, which, however, still are Thioflavine T-positive. Electrospray ionization mass spectrometry also indicates that C-peptide interacts with aggregating insulin and is incorporated into the aggregates. Hydrogen/deuterium exchange mass spectrometry further reveals reduced backbone accessibility in insulin aggregates formed in the presence of C-peptide. Combined, these effects are similar to those of C-peptide on islet amyloid polypeptide fibrillation and suggest that C-peptide has a general ability to interact with amyloidogenic proteins from pancreatic β-cell granules. Considering the concentrations, these peptide interactions should be relevant also during physiological secretion, and even so at special sites post-secretory or under insulin treatment conditions in vivo.

Proinsulin C-peptide interferes with insulin fibril formation

Energy Technology Data Exchange (ETDEWEB)

Landreh, Michael [Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 77 Stockholm (Sweden); Stukenborg, Jan-Bernd [Department of Women' s and Children' s Health, Astrid Lindgren Children' s Hospital, Pediatric Endocrinology Unit, Karolinska Institutet and University Hospital, S-17176 Stockholm (Sweden); Willander, Hanna [KI-Alzheimer' s Disease Research Center, NVS Department, Karolinska Institutet, S-141 86 Stockholm (Sweden); Soeder, Olle [Department of Women' s and Children' s Health, Astrid Lindgren Children' s Hospital, Pediatric Endocrinology Unit, Karolinska Institutet and University Hospital, S-17176 Stockholm (Sweden); Johansson, Jan [KI-Alzheimer' s Disease Research Center, NVS Department, Karolinska Institutet, S-141 86 Stockholm (Sweden); Department of Anatomy, Physiology and Biochemistry, Swedish University of Agricultural Sciences, S-751 23 Uppsala (Sweden); Joernvall, Hans, E-mail: Hans.Jornvall@ki.se [Department of Medical Biochemistry and Biophysics, Karolinska Institutet, S-171 77 Stockholm (Sweden)

2012-02-17

Highlights: Black-Right-Pointing-Pointer Insulin and C-peptide can interact under insulin fibril forming conditions. Black-Right-Pointing-Pointer C-peptide is incorporated into insulin aggregates and alters aggregation lag time. Black-Right-Pointing-Pointer C-peptide changes insulin fibril morphology and affects backbone accessibility. Black-Right-Pointing-Pointer C-peptide may be a regulator of fibril formation by {beta}-cell granule proteins. -- Abstract: Insulin aggregation can prevent rapid insulin uptake and cause localized amyloidosis in the treatment of type-1 diabetes. In this study, we investigated the effect of C-peptide, the 31-residue peptide cleaved from proinsulin, on insulin fibrillation at optimal conditions for fibrillation. This is at low pH and high concentration, when the fibrils formed are regular and extended. We report that C-peptide then modulates the insulin aggregation lag time and profoundly changes the fibril appearance, to rounded clumps of short fibrils, which, however, still are Thioflavine T-positive. Electrospray ionization mass spectrometry also indicates that C-peptide interacts with aggregating insulin and is incorporated into the aggregates. Hydrogen/deuterium exchange mass spectrometry further reveals reduced backbone accessibility in insulin aggregates formed in the presence of C-peptide. Combined, these effects are similar to those of C-peptide on islet amyloid polypeptide fibrillation and suggest that C-peptide has a general ability to interact with amyloidogenic proteins from pancreatic {beta}-cell granules. Considering the concentrations, these peptide interactions should be relevant also during physiological secretion, and even so at special sites post-secretory or under insulin treatment conditions in vivo.

Detecting insulin resistance in polycystic ovary syndrome: purposes and pitfalls.

Science.gov (United States)

Legro, Richard S; Castracane, V Daniel; Kauffman, Robert P

2004-02-01

Approximately 50% to 70% of all women with polycystic ovary syndrome (PCOS) have some degree of insulin resistance, and this hormone insensitivity probably contributes to the hyperandrogenism that is responsible for the signs and symptoms of PCOS. Although uncertainty exists, early detection and treatment of insulin resistance in this population could ultimately reduce the incidence or severity of diabetes mellitus, dyslipidemia, hypertension, and cardiovascular disease. Even if that proves to be the case, there are still several problems with our current approach to insulin sensitivity assessment in PCOS, including the apparent lack of consensus on what defines PCOS and "normal" insulin sensitivity, ethnic and genetic variability, the presence of other factors contributing to insulin resistance such as obesity, stress, and aging, and concern about whether simplified models of insulin sensitivity have the precision to predict treatment needs, responses, and future morbidity. Although the hyperinsulinemic-euglycemic clamp technique is the gold standard for measuring insulin sensitivity, it is too expensive, time-consuming, and labor-intensive to be of practical use in an office setting. Homeostatic measurements (fasting glucose/insulin ratio or homeostatic model assessment [HOMA] value) and minimal model tests (particularly the oral glucose tolerance test [OGTT]) represent the easiest office-based assessments of insulin resistance in the PCOS patient. The OGTT is probably the best simple, office-based method to assess women with PCOS because it provides information about both insulin resistance and glucose intolerance. The diagnosis of glucose intolerance holds greater prognostic and treatment implications. All obese women with PCOS should be screened for the presence of insulin resistance by looking for other stigmata of the insulin resistance syndrome such as hypertension, dyslipidemia, central obesity, and glucose intolerance.

Identifying and meeting the challenges of insulin therapy in type 2 diabetes

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Sorli C

2014-07-01

Full Text Available Christopher Sorli,1,* Michael K Heile2,*1Billings Clinic Research Center, Billings, MT, USA; 2The Family Medical Group Glenway, Cincinnati, OH, USA*Both authors contributed equally to this workAbstract: Type 2 diabetes mellitus (T2DM is a chronic illness that requires clinical recognition and treatment of the dual pathophysiologic entities of altered glycemic control and insulin resistance to reduce the risk of long-term micro- and macrovascular complications. Although insulin is one of the most effective and widely used therapeutic options in the management of diabetes, it is used by less than one-half of patients for whom it is recommended. Clinician-, patient-, and health care system-related challenges present numerous obstacles to insulin use in T2DM. Clinicians must remain informed about new insulin products, emerging technologies, and treatment options that have the potential to improve adherence to insulin therapy while optimizing glycemic control and mitigating the risks of therapy. Patient-related challenges may be overcome by actively listening to the patient's fears and concerns regarding insulin therapy and by educating patients about the importance, rationale, and evolving role of insulin in individualized self-treatment regimens. Enlisting the services of Certified Diabetes Educators and office personnel can help in addressing patient-related challenges. Self-management of diabetes requires improved patient awareness regarding the importance of lifestyle modifications, self-monitoring, and/or continuous glucose monitoring, improved methods of insulin delivery (eg, insulin pens, and the enhanced convenience and safety provided by insulin analogs. Health care system-related challenges may be improved through control of the rising cost of insulin therapy while making it available to patients. To increase the success rate of treatment of T2DM, the 2012 position statement from the American Diabetes Association and the European

A Systematic Review on Insulin Overdose Cases

DEFF Research Database (Denmark)

Johansen, Nicklas Järvelä; Christensen, Mikkel Bring

2018-01-01

A large overdose of insulin is a serious health matter. Information concerning administration and duration of intravenous (IV) glucose, other treatment options or complications beside hypoglycaemia following large insulin overdoses is not readily apparent from the literature. This article...

Melatonin-Mediated Intracellular Insulin during 2-Deoxy-d-glucose Treatment Is Reduced through Autophagy and EDC3 Protein in Insulinoma INS-1E Cells

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Han Sung Kim

2016-01-01

Full Text Available 2-DG triggers glucose deprivation without altering other nutrients or metabolic pathways and then activates autophagy via activation of AMPK and endoplasmic reticulum (ER stress. We investigated whether 2-DG reduced intracellular insulin increased by melatonin via autophagy/EDC3 in insulinoma INS-1E cells. p-AMPK and GRP78/BiP level were significantly increased by 2-DG in the presence/absence of melatonin, but IRE1α level was reduced in 2-DG treatment. Levels of p85α, p110, p-Akt (Ser473, Thr308, and p-mTOR (Ser2481 were also significantly reduced by 2-DG in the presence/absence of melatonin. Mn-SOD increased with 2-DG plus melatonin compared to groups treated with/without melatonin alone. Bcl-2 was decreased and Bax increased with 2-DG plus melatonin. LC3II level increased with 2-DG treatment in the presence/absence of melatonin. Intracellular insulin production increased in melatonin plus 2-DG but reduced in treatment with 2-DG with/without melatonin. EDC3 was increased by 2-DG in the presence/absence of melatonin. Rapamycin, an mTOR inhibitor, increased GRP78/BiP and EDC3 levels in a dose-dependent manner and subsequently resulted in a decrease in intracellular production of insulin. These results suggest that melatonin-mediated insulin synthesis during 2-DG treatment involves autophagy and EDC3 protein in rat insulinoma INS-1E cells and subsequently results in a decrease in intracellular production of insulin.

Effects of insulin combined with idebenone on blood-brain barrier permeability in diabetic rats.

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Sun, Yan-Na; Liu, Li-Bo; Xue, Yi-Xue; Wang, Ping

2015-04-01

This study investigates the effect of insulin combined with idebenone on blood-brain barrier (BBB) permeability in experimental streptozotocin-induced diabetic rats as well as the underlying mechanisms. With a diabetic rat model, we show that insulin and idebenone normalize body weight and water intake and restore BBB permeability and that their combination displays a synergistic effect. The results from transmission electron microscopy show that the combination of insulin and idebenone significantly closed the tight junction (TJ) in diabetic rats. The results from Western blotting in diabetic rats show that the upregulation of TJ-associated proteins occludin, and zonula occludens (ZO)-1 caused by the combination of insulin and idebenone is more remarkable than that with either agent alone. In addition, the activations of reactive oxygen species (ROS) and advanced glycation end products (AGEs) and the expression levels of receptors for advanced glycation end-products (RAGE) and nuclear factor-κB (NF-κB) were significantly decreased after treatment with insulin and idebenone in diabetic rats. These results suggest that the combination of insulin and idebenone could decrease the BBB permeability in diabetic rats by upregulating the expression of occludin, claudin-5, and ZO-1 and that the ROS/AGE/RAGE/NF-κB signal pathway might be involved in the process. © 2014 Wiley Periodicals, Inc.

S961, an insulin receptor antagonist causes hyperinsulinemia, insulin-resistance and depletion of energy stores in rats

International Nuclear Information System (INIS)

Vikram, Ajit; Jena, Gopabandhu

2010-01-01

Research highlights: →Insulin receptor antagonist S961 causes hyperglycemia, hyperinsulinemia and insulin resistance in rats. →Peroxysome-proliferator-activated-receptor-gamma agonist pioglitazone improves S961 induced hyperglycemia and glucose intolerance. →Long term treatment with insulin receptor antagonist S961 results in the decreased adiposity and hepatic glycogen content. →Improvement in the hyperglycemia and glucose intolerance by pioglitazone clearly demonstrates that S961 treated rats can be successfully used to screen the novel therapeutic interventions having potential to improve glucose disposal through receptor independent mechanisms. -- Abstract: Impairment in the insulin receptor signaling and insulin mediated effects are the key features of type 2 diabetes. Here we report that S961, a peptide insulin receptor antagonist induces hyperglycemia, hyperinsulinemia (∼18-fold), glucose intolerance and impairment in the insulin mediated glucose disposal in the Sprague-Dawley rats. Further, long-term S961 treatment (15 day, 10 nM/kg/day) depletes energy storage as evident from decrease in the adiposity and hepatic glycogen content. However, peroxysome-proliferator-activated-receptor-gamma (PPARγ) agonist pioglitazone significantly (P < 0.001) restored S961 induced hyperglycemia (196.73 ± 16.32 vs. 126.37 ± 27.07 mg/dl) and glucose intolerance (∼78%). Improvement in the hyperglycemia and glucose intolerance by pioglitazone clearly demonstrates that S961 treated rats can be successfully used to screen the novel therapeutic interventions having potential to improve glucose disposal through receptor independent mechanisms. Further, results of the present study reconfirms and provide direct evidence to the crucial role of insulin receptor signaling in the glucose homeostasis and fuel metabolism.

Aβ-Induced Insulin Resistance and the Effects of Insulin on the Cholesterol Synthesis Pathway and Aβ Secretion in Neural Cells.

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Najem, Dema; Bamji-Mirza, Michelle; Yang, Ze; Zhang, Wandong

2016-06-01

Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) toxicity, tau pathology, insulin resistance, neuroinflammation, and dysregulation of cholesterol homeostasis, all of which play roles in neurodegeneration. Insulin has polytrophic effects on neurons and may be at the center of these pathophysiological changes. In this study, we investigated possible relationships among insulin signaling and cholesterol biosynthesis, along with the effects of Aβ42 on these pathways in vitro. We found that neuroblastoma 2a (N2a) cells transfected with the human gene encoding amyloid-β protein precursor (AβPP) (N2a-AβPP) produced Aβ and exhibited insulin resistance by reduced p-Akt and a suppressed cholesterol-synthesis pathway following insulin treatment, and by increased phosphorylation of insulin receptor subunit-1 at serine 612 (p-IRS-S612) as compared to parental N2a cells. Treatment of human neuroblastoma SH-SY5Y cells with Aβ42 also increased p-IRS-S612, suggesting that Aβ42 is responsible for insulin resistance. The insulin resistance was alleviated when N2a-AβPP cells were treated with higher insulin concentrations. Insulin increased Aβ release from N2a-AβPP cells, by which it may promote Aβ clearance. Insulin increased cholesterol-synthesis gene expression in SH-SY5Y and N2a cells, including 24-dehydrocholesterol reductase (DHCR24) and 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR) through sterol-regulatory element-binding protein-2 (SREBP2). While Aβ42-treated SH-SY5Y cells exhibited increased HMGCR expression and c-Jun phosphorylation as pro-inflammatory responses, they also showed down-regulation of neuro-protective/anti-inflammatory DHCR24. These results suggest that Aβ42 may cause insulin resistance, activate JNK for c-Jun phosphorylation, and lead to dysregulation of cholesterol homeostasis, and that enhancing insulin signaling may relieve the insulin-resistant phenotype and the dysregulated cholesterol-synthesis pathway to promote A�

Liraglutide increases FGF-21 activity and insulin sensitivity in high fat diet and adiponectin knockdown induced insulin resistance.

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Mengliu Yang

Full Text Available BACKGROUND: Liraglutide is a glucagon-like peptide-1 analogue that stimulates insulin secretion and improves β-cell function. However, it is not clear whether liraglutide achieves its glucose lowering effect only by its known effects or whether other as yet unknown mechanisms are involved. The aim of this study was to examine the effects of liraglutide on Fibroblast growth factor-21 (FGF-21 activity in High-fat diet (HFD fed ApoE(-/- mice with adiponectin (Acrp30 knockdown. METHOD: HFD-fed ApoE(-/- mice were treated with adenovirus vectors expressing shAcrp30 to produce insulin resistance. Hyperinsulinemic-euglycemic clamp studies were performed to evaluate insulin sensitivity of the mouse model. QRT-PCR and Western blot were used to measure the mRNA and protein expression of the target genes. RESULTS: The combination of HFD, ApoE deficiency, and hypoadiponectinemia resulted in an additive effect on insulin resistance. FGF-21 mRNA expressions in both liver and adipose tissues were significantly increased while FGF-21 receptor 1 (FGFR-1 and β-Klotho mRNA levels in adipose tissue, as well as FGFR-1-3 and β-Klotho mRNA levels in liver were significantly decreased in this model. Liraglutide treatment markedly improved insulin resistance and increased FGF-21 expression in liver and FGFR-3 in adipose tissue, restored β-Klotho mRNA expression in adipose tissue as well as FGFR-1-3, β-Klotho levels and phosphorylation of FGFR1 up to the levels observed in control mice in liver. Liraglutide treatment also further increased FGF-21 proteins in liver and plasma. In addition, as shown by hyperinsulinemic-euglycemic clamp, liraglutide treatment also markedly improved glucose metabolism and insulin sensitivity in these animals. CONCLUSION: These findings demonstrate an additive effect of HFD, ApoE deficiency, and adiponectin knockdown on insulin resistance and unveil that the regulation of glucose metabolism and insulin sensitivity by liraglutide may be

FACTORS AFFECTING THE DEPOSITION OF AEROSOLIZED INSULIN

Science.gov (United States)

AbstractBackground The inhalation of insulin for absorption into the bloodstream via the lung seems to be a promising technique for the treatment of diabetes mellitus. A fundamental issue to be resolved in the development of such insulin aerosol delivery systems is their...

Time and Costs of Insulin Treatment in the Care of Newly Registered Type 2 Diabetes Patients in Diabetes Clinics across Japan (JDDM 22

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Mariko Oishi

2011-01-01

Full Text Available Aims To study the time and costs of insulin treatment of newly registered outpatients with Type 2 diabetes mellitus (T2DM. Methods In total, 355 patients with T2DM were registered on their first visit to one of 11 diabetes clinics across Japan. Of these, 313 were not being treated with insulin (the non-insulin group, whereas 42 were (the insulin group. In the insulin group, 26 were already on insulin at the first visit, whereas 16 were started on insulin after their first visit. The time and costs involved in the care were recorded over the following 5 months. Results In the first 3 months, considerable time was expended in both groups, with the time spent by physicians a little (but significantly longer for the insulin group. The total time expended by all care providers was approximately 1.3-fold greater for the insulin compared with the non-insulin group. The total cost and total cost/min for the insulin group was almost twice that for the non-insulin group. Over the 5-month period, mean HbA 1c in the non-insulin group improved from 8.0% to 6.5%, with 72% achieving a glycemic target of HbA 1c ≤ 6.5%. In contrast, in the insulin group, mean HbA 1c improved from 9.4% to 7.6%, with only 39% achieving the target. There were no reports of major hypoglycemic events in either group and body mass index remained stable. Conclusions The insulin therapy for T2DM can be achieved safely and effectively at outpatient clinics, even though it requires considerably more time and resources than non-insulin therapy.

Fibroblast growth factor 21 improves insulin sensitivity and synergizes with insulin in human adipose stem cell-derived (hASC adipocytes.

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Darwin V Lee

Full Text Available Fibroblast growth factor 21 (FGF21 has evolved as a major metabolic regulator, the pharmacological administration of which causes weight loss, insulin sensitivity and glucose control in rodents and humans. To understand the molecular mechanisms by which FGF21 exerts its metabolic effects, we developed a human in vitro model of adipocytes to examine crosstalk between FGF21 and insulin signaling. Human adipose stem cell-derived (hASC adipocytes were acutely treated with FGF21 alone, insulin alone, or in combination. Insulin signaling under these conditions was assessed by measuring tyrosine phosphorylation of insulin receptor (InsR, insulin receptor substrate-1 (IRS-1, and serine 473 phosphorylation of Akt, followed by a functional assay using 14C-2-deoxyglucose [14C]-2DG to measure glucose uptake in these cells. FGF21 alone caused a modest increase of glucose uptake, but treatment with FGF21 in combination with insulin had a synergistic effect on glucose uptake in these cells. The presence of FGF21 also effectively lowered the insulin concentration required to achieve the same level of glucose uptake compared to the absence of FGF21 by 10-fold. This acute effect of FGF21 on insulin signaling was not due to IR, IGF-1R, or IRS-1 activation. Moreover, we observed a substantial increase in basal S473-Akt phosphorylation by FGF21 alone, in contrast to the minimal shift in basal glucose uptake. Taken together, our data demonstrate that acute co-treatment of hASC-adipocytes with FGF21 and insulin can result in a synergistic improvement in glucose uptake. These effects were shown to occur at or downstream of Akt, or separate from the canonical insulin signaling pathway.

Lack of effect of long-term amlodipine on insulin sensitivity and plasma insulin in obese patients with essential hypertension

DEFF Research Database (Denmark)

de Courten, Maximilian; Ferrari, P; Schneider, M

1993-01-01

Method of Bergman, fasting plasma insulin and glucose concentrations, serum total triglyceride and lipoprotein cholesterol fractions, and blood pressure in 20 obese, non-diabetic patients with essential hypertension before and after 6 weeks of placebo and again after 6 months of amlodipine. Ten patients......To evaluate the effects of long-term treatment antihypertensive with the dihydropyridine calcium antagonist amlodipine on insulin sensitivity, plasma insulin, and lipoprotein metabolism in obese hypertensive patients. We measured the insulin sensitivity index (SI), determined by the Minimal Model...... [mean body mass index (BMI) 30.2 kg.m-2] had been on prior treatment with a thiazide diuretic in low dosage and/or a beta-adrenoceptor blocker (group A), and 10 matched patients [BMI 31.8 kg.m-2] had been previously untreated (group B). Amlodipine was started in a dose of 5 mg and was increased to 10 mg...

Basal insulin analogues in the treatment of diabetes mellitus: What progress have we made?

OpenAIRE

Kalra, Sanjay

2015-01-01

Over the past few decades, continuous progress has been made in the development of insulin therapy. Basal insulins were developed around 60 years ago. However, existing basal insulins were found to have limitations. An ideal basal insulin should have the following properties viz. longer duration of action, a flat time-action profile, low day-to-day glycaemic variability, and the potential for flexible dosing. Basal insulins have advanced over the years, from lectin and neutral protamine Haged...

Comparison of liraglutide plus basal insulin and basal-bolus insulin therapy (BBIT) for glycemic control, body weight stability, and treatment satisfaction in patients treated using BBIT for type 2 diabetes without severe insulin deficiency: A randomized prospective pilot study.

Science.gov (United States)

Yamamoto, Saki; Hayashi, Toshiyuki; Ohara, Makoto; Goto, Satoshi; Sato, Jun; Nagaike, Hiroe; Fukase, Ayako; Sato, Nobuko; Hiromura, Munenori; Tomoyasu, Masako; Nakanishi, Noriko; Lee, Soushou; Osamura, Anna; Yamamoto, Takeshi; Fukui, Tomoyasu; Hirano, Tsutomu

2018-03-26

We examined whether 0.9 mg/day liraglutide plus basal insulin (Lira-basal) is superior to basal-bolus insulin therapy (BBIT) for type 2 diabetes (T2DM) without severe insulin deficiency as determined by glucagon stimulation. Fifty patients receiving BBIT were enrolled in this 24-week, prospective, randomized, open-labeled study. After excluding subjects with fasting C-peptide immunoreactivity (CPR) basal (n = 12) or continued BBIT (n = 13). Primary endpoint was change in HbA1c. Secondary endpoints were changes in body weight (BW), 7-point self-monitored blood glucose (SMBG), and Diabetes Treatment Satisfaction Questionnaire status (DTSQs) scores. The Lira-basal group demonstrated reduced HbA1c, whereas the BBIT group showed no change. BW was reduced in the Lira-basal group but increased in the BBIT group. The Lira-basal group also exhibited significantly reduced pre-breakfast and pre-lunch SMBG. DTSQs scores improved in the Lira-basal group but not the BBIT group. Plasma lipids, liver function, and kidney function were not significantly changed in either group. Lira-basal therapy is superior to BBIT for T2DM without severe insulin deficiency. This study was registered with UMIN Clinical Trials Registry (UMIN000028313). Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

Development of a Rapid Insulin Assay by Homogenous Time-Resolved Fluorescence.

Directory of Open Access Journals (Sweden)

Zachary J Farino

Full Text Available Direct measurement of insulin is critical for basic and clinical studies of insulin secretion. However, current methods are expensive and time-consuming. We developed an insulin assay based on homogenous time-resolved fluorescence that is significantly more rapid and cost-effective than current commonly used approaches. This assay was applied effectively to an insulin secreting cell line, INS-1E cells, as well as pancreatic islets, allowing us to validate the assay by elucidating mechanisms by which dopamine regulates insulin release. We found that dopamine functioned as a significant negative modulator of glucose-stimulated insulin secretion. Further, we showed that bromocriptine, a known dopamine D2/D3 receptor agonist and newly approved drug used for treatment of type II diabetes mellitus, also decreased glucose-stimulated insulin secretion in islets to levels comparable to those caused by dopamine treatment.

Inflammation-induced microvascular insulin resistance is an early event in diet-induced obesity

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Zhao, Lina; Fu, Zhuo; Wu, Jing; Aylor, Kevin W.; Barrett, Eugene J.; Cao, Wenhong

2015-01-01

Endothelial dysfunction and vascular insulin resistance usually coexist and chronic inflammation engenders both. In the present study, we investigate the temporal relationship between vascular insulin resistance and metabolic insulin resistance. We assessed insulin responses in all arterial segments, including aorta, distal saphenous artery and the microvasculature, as well as the metabolic insulin responses in muscle in rats fed on a high-fat diet (HFD) for various durations ranging from 3 days to 4 weeks with or without sodium salicylate treatment. Compared with controls, HFD feeding significantly blunted insulin-mediated Akt (protein kinase B) and eNOS [endothelial nitric oxide (NO) synthase] phosphorylation in aorta in 1 week, blunted vasodilatory response in small resistance vessel in 4 weeks and microvascular recruitment in as early as 3 days. Insulin-stimulated whole body glucose disposal did not begin to progressively decrease until after 1 week. Salicylate treatment fully inhibited vascular inflammation, prevented microvascular insulin resistance and significantly improved muscle metabolic responses to insulin. We conclude that microvascular insulin resistance is an early event in diet-induced obesity and insulin resistance and inflammation plays an essential role in this process. Our data suggest microvascular insulin resistance contributes to the development of metabolic insulin resistance in muscle and muscle microvasculature is a potential therapeutic target in the prevention and treatment of diabetes and its related complications. PMID:26265791

Effect of chloroquine on insulin and glucose homoeostasis in normal subjects and patients with non-insulin-dependent diabetes mellitus.

OpenAIRE

Smith, G D; Amos, T A; Mahler, R; Peters, T J

1987-01-01

Plasma glucose, insulin, and C peptide concentrations were determined after an oral glucose load in normal subjects and in a group of patients with non-insulin-dependent diabetes mellitus before and during a short course of treatment with chloroquine. In the control group there was a small but significant reduction in fasting blood glucose concentration but overall glucose tolerance and hormone concentrations were unaffected. In contrast, the patients with non-insulin-dependent diabetes melli...

Effect of insulin degludec versus insulin glargine on glycemic control and daily fasting blood glucose variability in insulin-naïve Japanese patients with type 2 diabetes: I'D GOT trial.

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Aso, Yoshimasa; Suzuki, Kunihiro; Chiba, Yasuko; Sato, Minoru; Fujita, Nobuya; Takada, Yoshihisa; Murano, Shunichi; Kuroda, Hisamoto

2017-08-01

Insulin degludec (IDeg) is an ultra-long-acting insulin that has a smooth time/action profile over more than 42h. The present study compared the effects of IDeg and insulin glargine (IGlar) on HbA1c reduction and on within-subject day-to-day variability of fasting blood glucose (FBG) in insulin-naïve patients with type 2 diabetes. Eligible patients were randomly allocated at a 3:1 ratio to receive once-daily IDeg (n=31) or IGlar (n=12). Both basal insulins were administered before breakfast and titrated to achieve a target FBG <110mg/dl. The primary endpoints were the change in HbA1c from baseline to 24weeks of treatment, as well as the standard deviation (SD) and coefficient of variation (CV) of FBG from 8 to 12weeks and from 20 to 24weeks. Secondary endpoints included the QOL evaluated by the Diabetes Therapy-Related QOL questionnaire. After 24weeks, HbA1c was decreased by 1.6% in the IDeg group and 1.7% in the IGlar at the same insulin dosage. At 24weeks, FBG was significantly lower in the IDeg group than in the IGlar group and the CV of FBG was significantly smaller in the IDeg group. The frequency of total and severe hypoglycemic episodes did not differ between the groups. In the IDeg group, QOL showed significant improvement regarding anxiety and dissatisfaction with treatment. Treatment with IDeg or IGlar achieved similar improvement in glycemic control in insulin-naïve patients with type 2 diabetes. The day-to-day variation of FBG was smaller in patients receiving IDeg. Copyright © 2017. Published by Elsevier B.V.

Deregulation of brain insulin signaling in Alzheimer's disease.

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Chen, Yanxing; Deng, Yanqiu; Zhang, Baorong; Gong, Cheng-Xin

2014-04-01

Contrary to the previous belief that insulin does not act in the brain, studies in the last three decades have demonstrated important roles of insulin and insulin signal transduction in various functions of the central nervous system. Deregulated brain insulin signaling and its role in molecular pathogenesis have recently been reported in Alzheimer's disease (AD). In this article, we review the roles of brain insulin signaling in memory and cognition, the metabolism of amyloid β precursor protein, and tau phosphorylation. We further discuss deficiencies of brain insulin signaling and glucose metabolism, their roles in the development of AD, and recent studies that target the brain insulin signaling pathway for the treatment of AD. It is clear now that deregulation of brain insulin signaling plays an important role in the development of sporadic AD. The brain insulin signaling pathway also offers a promising therapeutic target for treating AD and probably other neurodegenerative disorders.

Insulin resistance in therapeutic clinic

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Anna V. Pashentseva

2017-09-01

Full Text Available Today an obesity became the global epidemic striking both children, and adults and represents one of the most important problems of health care worldwide. Excess accumulation of fatty tissue is resulted by insulin resistance and a compensatory hyperinsulinaemia which are the main predictors of development of a diabetes mellitus type 2. Insulin resistance is also one of key links of a pathogenesis of such diseases as cardiovascular pathology, not-alcoholic fatty liver disease, a polycystic ovary syndrome, gestational diabetes and many others. Depression of sensitivity of tissues to insulin can be physiological reaction of an organism to stress factors and pathological process. The endogenic reasons also take part in development of insulin resistance besides factors of the external environment. The role of genetic predisposition, a subclinical inflammation of fatty tissue, thyroid hormones, adipokines and vitamin D in formation of this pathological process is studied. As insulin resistance takes part in a pathogenesis of various diseases, methods of its diagnostics and correction are of great importance in therapeutic practice. At purpose of treatment it is worth giving preference to the drugs which are positively influencing sensitivity of tissues to insulin.

Insulin initiation in patients with type 2 diabetes mellitus

DEFF Research Database (Denmark)

Vaag, Allan; Lund, Søren

2012-01-01

This review addresses the apparent disconnect between international guideline recommendations, real-life clinical practice and the results of clinical trials, with regard to the initiation of insulin using basal (long-acting) or premixed insulin analogues in patients with type 2 diabetes (T2D...... and monitoring regimens. Enforced intensification of unrealistic complex treatment regimens and glycaemic targets may theoretically worsen the psychological well-being in some patients. More simple and sustainable treatment regimens and guidelines are urgently needed. As for the use of insulin in T2D...

Insulin pump treatment; increasing prevalence, and predictors for better metabolic outcome in Danish children and adolescents with type 1 diabetes

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Olsen, Birthe; Johannesen, J; Fredheim, S

2015-01-01

glucose (SMBG) measurements, a higher number of daily boluses, and a higher percentage of bolus insulin were all related to a lower HbA1c. CONCLUSION: The percentage of children on pumps (CSII) is CSII treatment is associated with a significantly lower Hba1c, achieved just after treatment initiation...

Pure Insulin Nanoparticle Agglomerates for Pulmonary Delivery

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Bailey, Mark M.; Gorman, Eric M.; Munson, Eric J.; Berkland, Cory J.

2009-01-01

Diabetes is a set of diseases characterized by defects in insulin utilization, either through autoimmune destruction of insulin-producing cells (Type I) or insulin resistance (Type II). Treatment options can include regular injections of insulin, which can be painful and inconvenient, often leading to low patient compliance. To overcome this problem, novel formulations of insulin are being investigated, such as inhaled aerosols. Sufficient deposition of powder in the peripheral lung to maximize systemic absorption requires precise control over particle size and density, with particles between 1 and 5 μm in aerodynamic diameter being within the respirable range. Insulin nanoparticles were produced by titrating insulin dissolved at low pH up to the pI of the native protein, and were then further processed into microparticles using solvent displacement. Particle size, crystallinity, dissolution properties, structural stability, and bulk powder density were characterized. We have demonstrated that pure drug insulin microparticles can be produced from nanosuspensions with minimal processing steps without excipients, and with suitable properties for deposition in the peripheral lung. PMID:18959432

Increased skeletal muscle capillarization enhances insulin sensitivity

DEFF Research Database (Denmark)

Åkerström, Thorbjörn; Laub, Lasse; Vedel, Kenneth

2014-01-01

Increased skeletal muscle capillarization is associated with improved glucose tolerance and insulin sensitivity. However, a possible causal relationship has not previously been identified. We therefore investigated whether increased skeletal muscle capillarization increases insulin sensitivity....... Skeletal muscle specific angiogenesis was induced by adding the α1-adrenergic receptor antagonist Prazosin to the drinking water of Sprague Dawley rats (n=33) while 34 rats served as controls. Insulin sensitivity was measured ≥40 h after termination of the 3-week Prazosin treatment, which ensured...... that Prazosin was cleared from the blood stream. Whole-body insulin sensitivity was measured in conscious, unrestrained rats by hyperinsulinemic euglycemic clamp. Tissue specific insulin sensitivity was assessed by administration of 2-deoxy-[(3)H]-Glucose during the plateau phase of the clamp. Whole...

Luminal and basolateral uptake of insulin in isolated perfused, proximal tubules

International Nuclear Information System (INIS)

Nielsen, S.; Nielsen, J.T.; Christensen, E.I.

1987-01-01

The present study was performed to quantitate compare the luminal and the peritubular uptake of 125 I-insulin in isolated, perfused, proximal tubules from rabbit kidneys. 125 I-insulin was added in physiological concentrations to either the perfusate or the bath fluid for 30 min. The luminal uptake in 30 min averaged 0.76 pg/mm at physiological concentrations and 18.0 pg/mm at high insulin concentrations. About 15-41% of the absorbed insulin was digested and 125 I-insulin at physiological and high concentrations in the bath was 0.136 and 0.318 pg, respectively. The data indicates that insulin is bound/absorbed at the basolateral membranes both by a saturable specific mechanism and a nonspecific, nonsaturable mechanism. The basolateral absorption constituted 15.2 and 1.8% of the total tubular extraction of insulin at physiological and high insulin concentrations, respectively. Electron microscope autoradiography showed that, after luminal as well as basolateral endocytosis, insulin was exclusively accumulated in endocytic vacuoles and lysosomes

Cancer risk among insulin users: comparing analogues with human insulin in the CARING five-country cohort study.

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But, Anna; De Bruin, Marie L; Bazelier, Marloes T; Hjellvik, Vidar; Andersen, Morten; Auvinen, Anssi; Starup-Linde, Jakob; Schmidt, Marjanka K; Furu, Kari; de Vries, Frank; Karlstad, Øystein; Ekström, Nils; Haukka, Jari

2017-09-01

The aim of this work was to investigate the relationship between use of certain insulins and risk for cancer, when addressing the limitations and biases involved in previous studies. National Health Registries from Denmark (1996-2010), Finland (1996-2011), Norway (2005-2010) and Sweden (2007-2012) and the UK Clinical Practice Research Datalink database (1987-2013) were used to conduct a cohort study on new insulin users (N = 327,112). By using a common data model and semi-aggregate approach, we pooled individual-level records from five cohorts and applied Poisson regression models. For each of ten cancer sites studied, we estimated the rate ratios (RRs) by duration (≤0.5, 0.5-1, 1-2, 2-3, 3-4, 4-5, 5-6 and >6 years) of cumulative exposure to insulin glargine or insulin detemir relative to that of human insulin. A total of 21,390 cancer cases occurred during a mean follow-up of 4.6 years. No trend with cumulative treatment time for insulin glargine relative to human insulin was observed in risk for any of the ten studied cancer types. Of the 136 associations tested in the main analysis, only a few increased and decreased risks were found: among women, a higher risk was observed for colorectal (RR 1.54, 95% CI 1.06, 2.25) and endometrial cancer (RR 1.78, 95% CI 1.07, 2.94) for ≤0.5 years of treatment and for malignant melanoma for 2-3 years (RR 1.92, 95% CI 1.02, 3.61) and 4-5 years (RR 3.55, 95% CI 1.68, 7.47]); among men, a lower risk was observed for pancreatic cancer for 2-3 years (RR 0.34, 95% CI 0.17, 0.66) and for liver cancer for 3-4 years (RR 0.36, 95% CI 0.14, 0.94) and >6 years (RR 0.22, 95% CI 0.05, 0.92). Comparisons of insulin detemir with human insulin also showed no consistent differences. The present multi-country study found no evidence of consistent differences in risk for ten cancers for insulin glargine or insulin detemir use compared with human insulin, at follow-up exceeding 5 years.

Insulin initiation status of primary care physicians in Turkey, barriers to insulin initiation and knowledge levels about insulin therapy: A multicenter cross-sectional study.

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Ates, Elif; Set, Turan; Saglam, Zuhal; Tekin, Nil; Karatas Eray, Irep; Yavuz, Erdinc; Sahin, Mustafa Kursat; Selcuk, Engin Burak; Cadirci, Dursun; Cubukcu, Mahcube

2017-10-01

Our aim was to evaluate the insulin initiation status, barriers to insulin initiation and knowledge levels about treatment administered by primary care physicians (PCP). We conducted our study in accordance with a multicenter, cross-sectional design in Turkey, between July 2015 and July 2016. A questionnaire inquiring demographic features, status of insulin initiation, obstacles to insulin initiation and knowledge about therapy of the PCPs was administered during face-to-face interviews. 84 PCPs (19%) (n=446, mean age=41.5±8.4years, 62.9% male and 90.0% ministry certified family physicians) initiated insulin therapy in the past. Most of the stated primary barriers (51.9%, n=230) were due to the physicians. The most relevant barrier was "lack of clinical experience" with a rate of 19% (n=84 of the total). The average total knowledge score was 5.7±2.0 for the family medicine specialist, and 3.8±2.1 for the ministry certified family physicians (p=0.000, maximum knowledge score could be 10). The status of insulin initiation in Turkey by the primary care physicians is inadequate. Medical education programs and health care systems may require restructuring to facilitate insulin initiation in primary care. Copyright © 2017 Primary Care Diabetes Europe. Published by Elsevier Ltd. All rights reserved.

Application of electron beam irradiation. 4. Treatment of pollutants by electron beam irradiation

International Nuclear Information System (INIS)

Tokunaga, Okihiro; Arai, Hidehiko

1994-01-01

Electron beam irradiation is capable of dissolving and removing pollutants, such as sulfur oxides, nitrogen oxides, and organic compounds, by easy production of OH radicals in flue gas and water. This paper deals with current status in the search for techniques for treating flue gas and waste water, using electron beam irradiation. Pilot tests have been conducted during the period 1991-1994 for the treatment of flue gas caused by coal and garbage burning and road tunnels. Firstly, techniques for cleaning flue gas with electron beams are outlined, with special reference to their characteristics and process of research development. Secondly, the application of electron beam irradiation in the treatment of waste water is described in terms of the following: (1) disinfection of sewage, (2) cleaning of water polluted with toxic organic compounds, (3) treatment for eliminating sewage sludge, (4) promotion of sewage sludge sedimentation, (5) disinfection and composting of sewage sludge, and (6) regeneration of activated carbon used for the treatment of waste water. (N.K.)

Association of insulin treatment versus oral hypoglycaemic agents with diabetic retinopathy and its severity in type 2 diabetes patients in Cameroon, sub-Saharan Africa.

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Jingi, Ahmadou M; Noubiap, Jean Jacques N; Essouma, Mickael; Bigna, Jean Joel R; Nansseu, Jobert Richie N; Ellong, Augustin; Mvogo, Côme Ebana

2016-10-01

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disease associated with multiple macro and microvascular complications, diabetic retinopathy (DR) being the commonest one. Recent literature has reported an increased risk of DR with insulin use. We carried out a cross-sectional study at the Ophthalmology Department of the Douala General Hospital (DGH) during a 2-year period to explore the association between insulin treatment and both DR and its severity as compared with oral hypoglycemic agents (OHAs) in Cameroonian T2DM patients aged ≥35 years, and who were all screened for DR through eye examination including exhaustive retinal evaluation. In total, medical files of 134 T2DM patients were analyzed. The frequency of DR was 54.1% among patients on OHA and 73.9% among those on insulin treatment, giving an overall frequency of 57.5%. There were significantly more OHA treated patients than insulin treated patients (82.8% vs . 17.2%, Phistory of hypertension, alcohol misuse, and current tobacco smoking. DR was almost significantly more frequent in T2DM patients under insulin regimen than in patients under OHA [73.9% vs . 54.1%; odds ratio (OR) 2.4; 95% confidence interval (CI), 0.9-6.6; P=0.06]. Proliferative diabetic retinopathy (PDR) was significantly more observed in insulin treated patients than in OHA treated patients (34.8% vs . 15.3%; OR 2.95; 95% CI, 1.1-8; P=0.035). Irrespective of staging, the frequency of diabetic macular edema (DME) was significantly higher in the insulin group than in the OHA group (43.5% vs . 19.8%; OR 3.1; 95% CI, 1.2-8; P=0.019). Compared with OHA, insulin therapy may be associated with DR, DR severity and DME in these T2DM sub-Saharan African patients.

Application of 3C insulin pump system in combination with non-invasive ventilation in the treatment of a patient with type 2 diabetes and obstructive sleep apnea syndrome.

Science.gov (United States)

Dong, Peng; Xu, Jing; Wang, Junhong; Zhang, Chunhong

2018-03-01

We observed the curative effect of the 3C insulin system in combination with non-invasive ventilation in a patient with type 2 diabetes and obstructive sleep apnea syndrome (OSAS). The 3C insulin pump is a system of devices that closely monitors and effectively regulates blood glucose levels. Non-invasive ventilation has been shown to be an effective treatment for OSAS. A type 2 diabetes patient with concomitant OSAS was treated with a 3C insulin pump system for real-time continuous glucose monitoring and nocturnal non-invasive ventilation for OSAS. Treatment-induced diabetic remission with improved sleep and reduced hypoglycemic episodes was achieved. Therefore, the 3C insulin pump system, in combination with non-invasive ventilation, is an effective treatment for type 2 diabetes patients with concomitant OSAS. © 2017 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.

Insulin at pH 2: structural analysis of the conditions promoting insulin fibre formation.

Science.gov (United States)

Whittingham, Jean L; Scott, David J; Chance, Karen; Wilson, Ashley; Finch, John; Brange, Jens; Guy Dodson, G

2002-04-26

When insulin solutions are subjected to acid, heat and agitation, the normal pattern of insulin assembly (dimers-->tetramers-->hexamers) is disrupted; the molecule undergoes conformational changes allowing it to follow an alternative aggregation pathway (via a monomeric species) leading to the formation of insoluble amyloid fibres. To investigate the effect of acid pH on the conformation and aggregation state of the protein, the crystal structure of human insulin at pH 2.1 has been determined to 1.6 A resolution. The structure reveals that the native fold is maintained at low pH, and that the molecule is still capable of forming dimers similar to those found in hexameric insulin structures at higher pH. Sulphate ions are incorporated into the molecule and the crystal lattice where they neutralise positive charges on the protein, stabilising its structure and facilitating crystallisation. The sulphate interactions are associated with local deformations in the protein, which may indicate that the structure is more plastic at low pH. Transmission electron microscopy analysis of insulin fibres reveals that the appearance of the fibres is greatly influenced by the type of acid employed. Sulphuric acid produces distinctive highly bunched, truncated fibres, suggesting that the sulphate ions have a sophisticated role to play in fibre formation, rather as they do in the crystal structure. Analytical ultracentrifugation studies show that in the absence of heating, insulin is predominantly dimeric in mineral acids, whereas in acetic acid the equilibrium is shifted towards the monomer. Hence, the effect of acid on the aggregation state of insulin is also complex. These results suggest that acid conditions increase the susceptibility of the molecule to conformational change and dissociation, and enhance the rate of fibrillation by providing a charged environment in which the attractive forces between the protein molecules is increased. (c) 2002 Elsevier Science Ltd.

Reversal of the toxic effects of cachectin by concurrent insulin administration.

Science.gov (United States)

Fraker, D L; Merino, M J; Norton, J A

1989-06-01

Rats treated with recombinant human tumor necrosis factor-cachectin, 100 micrograms/kg ip twice daily for 5 consecutive days, had a 56% decrease in food intake, a 54% decrease in nitrogen balance, and a 23-g decrease in body weight gain vs. saline-treated controls. Concurrent neutral protamine hagedorn insulin administration of 2 U/100 g sc twice daily reversed all of these changes to control levels without causing any treatment deaths. The improvement seen with insulin was dose independent. Five days of cachectin treatment caused a severe interstitial pneumonitis, periportal inflammation in the liver, and an increase in wet organ weight in the heart, lungs, kidney, and spleen. Concurrent insulin treatment led to near total reversal of these histopathologic changes. Cachectin treatment did not significantly change blood glucose levels from control values of 130-140 mg/dl, but insulin plus cachectin caused a significant decrease in blood glucose from 1 through 12 h after injection. Administration of high-dose insulin can near totally reverse the nutritional and histopathologic toxicity of sublethal doses of cachectin in rats.

Metabolism and insulin signaling in common metabolic disorders and inherited insulin resistance.

Science.gov (United States)

Højlund, Kurt

2014-07-01

synthesis was at least equally strong. Moreover, we found a correlation between plasma adiponectin and insulin activation of GS. This result is supported by a number of recent studies of animal models and muscle cell lines, which have shown that adiponectin augments insulin action on enzymes in the insulin signaling cascade. In contrast, we observed no differences in the abundance or activity of AMPK in obesity, type 2 diabetes, PCOS or inherited insulin resistance. This indicates that reduced insulin sensitivity in these conditions is not mediated via abnormal AMPK activity. The results from these studies demonstrate that the well-established abnormalities in insulin action on glucose uptake and glycogen synthesis are reflected by defects in insulin signaling to these cellular processes in type 2 diabetes, obesity, and PCOS, and as expected also in inherited insulin resistance caused by a mutation in INSR. In common metabolic disorders, low plasma adiponectin may contribute to insulin resistance and defects in insulin signaling, whereas in inherited insulin resistance a normal plasma adiponectin and reduced insulin clearance could contribute to maintain a sufficient activation of the insulin signaling cascade. The insight gained from these studies have improved our understanding of the molecular mechanisms underlying insulin resistance in skeletal muscle of humans, and can form the basis for further studies, which can lead to the development of treatment that more directly targets insulin resistance, and hence reduce the risk of type 2 diabetes and cardiovascular disease.

Self-assembled lecithin/chitosan nanoparticles for oral insulin delivery: preparation and functional evaluation

Science.gov (United States)

Liu, Liyao; Zhou, Cuiping; Xia, Xuejun; Liu, Yuling

2016-01-01

Purpose Here, we investigated the formation and functional properties of self-assembled lecithin/chitosan nanoparticles (L/C NPs) loaded with insulin following insulin–phospholipid complex preparation, with the aim of developing a method for oral insulin delivery. Methods Using a modified solvent-injection method, insulin-loaded L/C NPs were obtained by combining insulin–phospholipid complexes with L/C NPs. The nanoparticle size distribution was determined by dynamic light scattering, and morphologies were analyzed by cryogenic transmission electron microscopy. Fourier transform infrared spectroscopy analysis was used to disclose the molecular mechanism of prepared insulin-loaded L/C NPs. Fast ultrafiltration and a reversed-phase high-performance liquid chromatography assay were used to separate free insulin from insulin entrapped in the L/C NPs, as well as to measure the insulin-entrapment and drug-loading efficiencies. The in vitro release profile was obtained, and in vivo hypoglycemic effects were evaluated in streptozotocin-induced diabetic rats. Results Our results indicated that insulin-containing L/C NPs had a mean size of 180 nm, an insulin-entrapment efficiency of 94%, and an insulin-loading efficiency of 4.5%. Cryogenic transmission electron microscopy observations of insulin-loaded L/C NPs revealed multilamellar structures with a hollow core, encircled by several bilayers. In vitro analysis revealed that insulin release from L/C NPs depended on the L/C ratio. Insulin-loaded L/C NPs orally administered to streptozotocin-induced diabetic rats exerted a significant hypoglycemic effect. The relative pharmacological bioavailability following oral administration of L/C NPs was 6.01%. Conclusion With the aid of phospholipid-complexation techniques, some hydrophilic peptides, such as insulin, can be successfully entrapped into L/C NPs, which could improve oral bioavailability, time-dependent release, and therapeutic activity. PMID:26966360

Autoimmune Hypoglycemia in a Patient with Characterization of Insulin Receptor Autoantibodies

Directory of Open Access Journals (Sweden)

Suk Chon

2011-02-01

Full Text Available BackgroundType B insulin resistance syndrome is a manifestation of autoantibodies to the insulin receptor that results in severe hyperglycemia and acanthosis nigricans. However, the mechanisms by which these autoantibodies induce hypoglycemia are largely unknown. In this paper, we report the case of patient with type B insulin resistance syndrome who presented with frequent severe fasting hypoglycemia and acanthosis nigricans.MethodsTo evaluate the mechanism of hypoglycemia, we measured the inhibition of insulin binding to erythrocytes and IM9 lymphocytes in a sample of the patient's dialyzed serum before and after immunosuppressive therapy.ResultsIn the patient's pre-treatment serum IgG, the binding of 125I-insulin to erythrocytes was markedly inhibited in a dose-dependent manner until the cold insulin level reached 10-9 mol/L. We also observed dose-dependent inhibition of insulin binding to IM9 lymphocytes, which reached approximately 82% inhibition and persisted even when diluted 1:20. After treatment with glucocorticoids, insulin-erythrocyte binding activity returned to between 70% and 80% of normal, while the inhibition of insulin-lymphocyte binding was reduced by 17%.ConclusionWe treated a patient with type B insulin resistance syndrome showing recurrent fasting hypoglycemia with steroids and azathioprine. We characterized the patient's insulin receptor antibodies by measuring the inhibition of insulin binding.

Insulin and insulin signaling play a critical role in fat induction of insulin resistance in mouse

Science.gov (United States)

Ning, Jie; Hong, Tao; Yang, Xuefeng; Mei, Shuang; Liu, Zhenqi; Liu, Hui-Yu

2011-01-01

The primary player that induces insulin resistance has not been established. Here, we studied whether or not fat can cause insulin resistance in the presence of insulin deficiency. Our results showed that high-fat diet (HFD) induced insulin resistance in C57BL/6 (B6) mice. The HFD-induced insulin resistance was prevented largely by the streptozotocin (STZ)-induced moderate insulin deficiency. The STZ-induced insulin deficiency prevented the HFD-induced ectopic fat accumulation and oxidative stress in liver and gastrocnemius. The STZ-induced insulin deficiency prevented the HFD- or insulin-induced increase in hepatic expression of long-chain acyl-CoA synthetases (ACSL), which are necessary for fatty acid activation. HFD increased mitochondrial contents of long-chain acyl-CoAs, whereas it decreased mitochondrial ADP/ATP ratio, and these HFD-induced changes were prevented by the STZ-induced insulin deficiency. In cultured hepatocytes, we observed that expressions of ACSL1 and -5 were stimulated by insulin signaling. Results in cultured cells also showed that blunting insulin signaling by the PI3K inhibitor LY-294002 prevented fat accumulation, oxidative stress, and insulin resistance induced by the prolonged exposure to either insulin or oleate plus sera that normally contain insulin. Finally, knockdown of the insulin receptor prevented the oxidative stress and insulin resistance induced by the prolonged exposure to insulin or oleate plus sera. Together, our results show that insulin and insulin signaling are required for fat induction of insulin resistance in mice and cultured mouse hepatocytes. PMID:21586696

Adiposity in Children Born Small for Gestational Age Is Associated With β-Cell Function, Genetic Variants for Insulin Resistance, and Response to Growth Hormone Treatment

DEFF Research Database (Denmark)

Thankamony, Ajay; Jensen, Rikke Beck; O'Connell, Susan M

2016-01-01

-ray absorptiometry. The main outcome measures were treatment-related changes in height, IGF-1 standard deviation score, insulin sensitivity, insulin secretion, and disposition index. Combined multiallele gene scores based on single nucleotide polymorphisms with known associations with lower insulin sensitivity (gene...... (baseline vs 1-year z-scores, -0.26 ± 1.2 vs -1.23 ± 1.54; P IGF-1 responses (p-trends = .042), first-year height gains (B [95% confidence interval], 0.61 cm/y [0.28,0.95]; P

Insulin resistance is not conserved in myotubes established from women with PCOS.

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Mette Eriksen

2010-12-01

Full Text Available Polycystic ovary syndrome (PCOS is the most common endocrine disorder among premenopausal women, who often develop insulin resistance. We tested the hypothesis that insulin resistance in skeletal muscle of patients with polycystic ovary syndrome (PCOS is an intrinsic defect, by investigating the metabolic characteristics and gene expression of in vitro differentiated myotubes established from well characterized PCOS subjects.Using radiotracer techniques, RT-PCR and enzyme kinetic analysis we examined myotubes established from PCOS subjects with or without pioglitazone treatment, versus healthy control subjects who had been extensively metabolically characterized in vivo. Results. Myotubes established from PCOS and matched control subjects comprehensively expressed all insulin-sensitive biomarkers; glucose uptake and oxidation, glycogen synthesis and lipid uptake. There were no significant differences between groups either at baseline or during acute insulin stimulation, although in vivo skeletal muscle was insulin resistant. In particular, we found no evidence for defects in insulin-stimulated glycogen synthase activity between groups. Myotubes established from PCOS patients with or without pioglitazone treatment also showed no significant differences between groups, neither at baseline nor during acute insulin stimulation, although in vivo pioglitazone treatment significantly improved insulin sensitivity. Consistently, the myotube cultures failed to show differences in mRNA levels of genes previously demonstrated to differ in PCOS patients with or without pioglitazone treatment (PLEK, SLC22A16, and TTBK.These results suggest that the mechanisms governing insulin resistance in skeletal muscle of PCOS patients in vivo are not primary, but rather adaptive.ClinicalTrials.gov NCT00145340.

Insulin inhalation for diabetic patients: Nursing considerations

Directory of Open Access Journals (Sweden)

Hanan Mohammed Mohammed

2016-04-01

Full Text Available Scientific knowledge has advanced to enable the development of inhaled insulin. It is a form of diabetes medication administered via the pulmonary system that studies have shown to be efficacious in the treatment of both type 1 and type 2 diabetes. Inhaled insulin is a new, safe means to deliver insulin that may increase patient compliance with insulin therapy, helping them to achieve optimal glycemic control and possibly reducing their risk of developing cardiovascular complications. However, diabetes is a chronic illness requiring lifetime intervention. Empowering patients with the knowledge of the diabetes disease process may give them the confidence to be more autonomous in managing their diabetes. HIIP gives nurse practitioners a new option that may improve their patients’ acceptance of insulin therapy, and improve glycemic control.

Studies on insulin secretion and insulin resistance in non-insulin-dependent diabetes in young Indians

International Nuclear Information System (INIS)

Naidoo, C.

1986-01-01

Patients with Non-insulin-dependent diabetes mellitus (NIDDM) have defects in insulin secretion and insulin action. In the discrete genetic syndrome of NIDDY (non-insulin-dependent diabetes in the young), the situation is less clear and these aspects is the subject of this thesis. This study included Indian pasients with three generation transmission of NIDDM via one parent. The insulin and C-peptide responses to oral and intravenous glucose in patients with NIDDY were studied. The insulin and glucose responses to non-glucose secretogogues glucagon, tolbutamide and arginine, in NIDDY were also investigated. The following aspects with regard to insulin resistance in NIDDY were examined: glucose and free fatty acid response to intravenous insulin administration, insulin binding to circulating erythrocytes and monocytes, 125 I-insulin binding to the solubilized erythrocyte membrane receptor and 125 I-insulin binding to fibroblasts in culture

Studies on insulin secretion and insulin resistance in non-insulin-dependent diabetes in young Indians

Energy Technology Data Exchange (ETDEWEB)

Naidoo, C

1986-01-01

Patients with Non-insulin-dependent diabetes mellitus (NIDDM) have defects in insulin secretion and insulin action. In the discrete genetic syndrome of NIDDY (non-insulin-dependent diabetes in the young), the situation is less clear and these aspects is the subject of this thesis. This study included Indian pasients with three generation transmission of NIDDM via one parent. The insulin and C-peptide responses to oral and intravenous glucose in patients with NIDDY were studied. The insulin and glucose responses to non-glucose secretogogues glucagon, tolbutamide and arginine, in NIDDY were also investigated. The following aspects with regard to insulin resistance in NIDDY were examined: glucose and free fatty acid response to intravenous insulin administration, insulin binding to circulating erythrocytes and monocytes, /sup 125/I-insulin binding to the solubilized erythrocyte membrane receptor and /sup 125/I-insulin binding to fibroblasts in culture.

Potensi Terapeutik Fibroblast Growth Factor 21 terhadap Resistensi Insulin

Directory of Open Access Journals (Sweden)

Kurniasari Kurniasari

2015-12-01

Full Text Available Fibroblast growth factor 21 (FGF21 merupakan salah satu dari anggota FGF yang berperansebagai faktor endokrin. Hepar dan jaringan adiposa merupakan tempat kerja utama FGF21.Ekspresi FGF21 di hepar diatur oleh peroxisome proliferator activated receptor alpha (PPARαsedangkan di jaringan adiposa diatur oleh peroxisome proliferator activated receptor gamma(PPARγ. Kedua faktor transkripsi tersebut terlibat dalam metabolisme karbohidrat dan lipid. Padaresistensi insulin terdapat hiperglikemia, hiperinsulinemia, dan dislipidemia. Pemberian FGF21pada berbagai studi in vivo dan in vitro telah menunjukan potensi FGF21 dalam mengatasi kelainanakibat resistensi insulin sekaligus meningkatkan sensitivitas jaringan terhadap insulin. Kata kunci: FGF21, PPARγ, PPARα, resistensi insulin Fibroblast Growth Factor 21 (FGF21 Potension in InsulinResistance Treatment Abstract Fibroblast growth factor 21 (FGF21 is a member of FGF family that plays a role as endocrinefactor. Liver and adipose tissue are major target of FGF21. The expression of FGF21 in liveris regulated by peroxisome proliferator activated receptor alpha (PPARα, while peroxisomeproliferator activated receptor gamma (PPARγ regulate FGF21 expression in adipose tissue.Both transcription factors are involved in carbohydrate and lipid metabolism. Hyperglycemia,hyperinsulinemia, and dyslipidemia are observed in insulin resistance. Treatment with FGF21 inin vitro and in vivo study showed that FGF21 have the potential to overcome insulin resistance aswell as increasing tissue’s sensitivity towards insulin. Keywords: FGF21, PPARγ, PPARα, insulin resistance Normal 0 false false false IN X-NONE X-NONE

Insulin resistance and polycystic ovary syndrome.

Science.gov (United States)

Galluzzo, Aldo; Amato, Marco Calogero; Giordano, Carla

2008-09-01

Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in humans, affecting approximately 7-8% of women of reproductive age. Despite the criteria adopted, PCOS is considered to be a predominantly hyperandrogenetic syndrome and the evaluation of metabolic parameters and insulin sensitivity is not mandatory. Most women with PCOS also exhibit features of the metabolic syndrome, including insulin resistance, obesity and dyslipidaemia. While the association with type 2 diabetes is well established, whether the incidence of cardiovascular disease is increased in women with PCOS remains unclear. Acknowledging the strong impact of insulin-resistance in the genesis of PCOS could be helpful not only to make the diagnosis more robust, but also for conferring better cardiovascular risk prevention. Several current studies support a strong recommendation that women with PCOS should undergo comprehensive evaluation for the metabolic syndrome and recognized cardiovascular risk factors, and receive appropriate treatment as needed. Lifestyle modifications remain the first-line therapy for all obese women with PCOS. However, many of these women do not lose weight easily. Insulin-sensitizing drugs are discussed as a promising and unique therapeutic option for the chronic treatment of PCOS.

The course of diabetic retinopathy during treatment with continuous subcutaneous insulin infusion

NARCIS (Netherlands)

Hooymans, Johanna Martina Maria

1986-01-01

The aim of this prospective study was to investigate the effect of normalization of blood sugar regulation by continuous subcutaneous insulin infusion (CSII) on the course of diabetic retinopathy in insulin-dependent (type I) diabetic patients. Zie: Summary

Comparison of treatment with continuous subcutaneous insulin infusion versus multiple daily insulin injections with bolus calculator in patients with type 1 diabetes.

Science.gov (United States)

Pérez-García, L; Goñi-Iriarte, M J; García-Mouriz, M

2015-01-01

A study of the glycemic control, quality of life, and fear and perception of hypoglycemia by comparing continuous subcutaneous insulin infusion (CSII) group with multiple daily inyections (MDI) with bolus calculator group. This is a retrospective cohort study with following up during the first 12 months that CSII group (n=30) begins the use of "bolus wizard" and the MDI-calculator (n=30) group begins the use of the bolus calculator (Accu-Chek(®) Aviva Expert). HbA1c (3, 6 and 12 months). Questionnaires used: EsDQOL (quality of life), FH-15 (fear of hypoglycemia), and Clarke (perception of hypoglycemia). T Student and nonparametric tests. The average reduction in HbA1c during the study was significantly higher in CSII group (-0.56±0.84%) compared with the MDI group (0.097±0.94%), P=.028. The average basal insulin dose was significantly higher in the MDI group (at baseline, 6 and 12 months). No significant differences were found between the 2 treatment groups after analyzing the EsDQOL, FH-15 and Clarke questionnaires. In the CSII group, perceived quality of life assessed by the EsDQOL questionnaire was found to be better at the end of the study than at the beginning of using the insulin pump. The average reduction in HbA1c was significantly higher in the CSII group. In the CSII group, perceived quality of life was better at the end of the study than at the beginning. Copyright © 2014 SEEN. Published by Elsevier España, S.L.U. All rights reserved.

Ultrastructural evidence for the accumulation of insulin in nuclei of intact 3T3-L1 adipocytes by an insulin-receptor mediated process

International Nuclear Information System (INIS)

Smith, R.M.; Jarett, L.

1987-01-01

Monomeric ferritin-labeled insulin (F/sub m/-Ins), a biologically active, electron-dense marker of occupied insulin receptors, was used to characterize the internalization of insulin in 3T3-L1 adipocytes. F/sub m/-Ins bound specifically to insulin receptors and was internalized in a time- and temperature-dependent manner. In the nucleus, several F/sub m/-Ins particles usually were found in the same general location-near nuclear pores, associated with the periphery of the condensed chromatin. Addition of a 250-fold excess of unlabeled insulin or incubation at 15 0 C reduced the number of F/sub m/-Ins particles found in nuclei after 90 min by 99% or 92%, respectively. Nuclear accumulation of unlabeled ferritin was only 2% of that found with F/sub m/-Ins after 90 min at 37 0 C. Biochemical experiments utilizing 125 I-labeled insulin and subcellular fractionation indicated that intact 3T3-L1 adipocytes internalized insulin rapidly and that ≅ 3% of the internalized ligand accumulated in nuclei after 1 hr. These data provide biochemical and high-resolution ultrastructural evidence that 3T3-L1 adipocytes accumulate potentially significant amounts of insulin in nuclei by an insulin receptor-mediated process. The transport of insulin or the insulin-receptor complex to nuclei in this cell or in others may be directly involved in the long-term biological effects of insulin - in particular, in the control of DNA and RNA synthesis

Insulin resistance in brain and possible therapeutic approaches.

Science.gov (United States)

Cetinkalp, Sevki; Simsir, Ilgin Y; Ertek, Sibel

2014-01-01

Although the brain has long been considered an insulin-independent organ, recent research has shown that insulin has significant effects on the brain, where it plays a role in maintaining glucose and energy homeostasis. To avoid peripheral insulin resistance, the brain may act via hypoinsulinemic responses, maintaining glucose metabolism and insulin sensitivity within its own confines; however, brain insulin resistance may develop due to environmental factors. Insulin has two important functions in the brain: controlling food intake and regulating cognitive functions, particularly memory. Notably, defects in insulin signaling in the brain may contribute to neurodegenerative disorders. Insulin resistance may damage the cognitive system and lead to dementia states. Furthermore, inflammatory processes in the hypothalamus, where insulin receptors are expressed at high density, impair local signaling systems and cause glucose and energy metabolism disorders. Excessive caloric intake and high-fat diets initiate insulin and leptin resistance by inducing mitochondrial dysfunction and endoplasmic reticulum stress in the hypothalamus. This may lead to obesity and diabetes mellitus (DM). Exercise can enhance brain and hypothalamic insulin sensitivity, but it is the option least preferred and/or continuously practiced by the general population. Pharmacological treatments that increase brain and hypothalamic insulin sensitivity may provide new insights into the prevention of dementia disorders, obesity, and type 2 DM in the future.

SGLT2 inhibitors provide an effective therapeutic option for diabetes complicated with insulin antibodies.

Science.gov (United States)

Hayashi, Akinori; Takano, Koji; Kawai, Sayuki; Shichiri, Masayoshi

2016-01-01

Diabetes mellitus complicated with insulin antibodies is rare in clinical practice but usually difficult to control. A high amount of insulin antibodies, especially with low affinity and high binding capacity, leads to unstable glycemic control characterized by hyperglycemia unresponsive to large volume of insulin and unanticipated hypoglycemia. There are several treatment options, such as changing insulin preparation, immunosupression with glucocorticoids, and plasmapheresis, most of which are of limited efficacy. Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a novel class of drug which decrease renal glucose reabsorption and lowers plasma glucose level independent of insulin action. We report here a case with diabetes complicated with insulin antibodies who was effectively controlled by an SGLT2 inhibitor. A 47-year-old man with type 2 diabetes treated with insulin had very poor glycemic control characterized by postprandial hyperglycemia unresponsive to insulin therapy and repetitive hypoglycemia due to insulin antibodies. Treatment with ipragliflozin, an SGLT2 inhibitor, improved HbA1c from 8.4% to 6.0% and glycated albumin from 29.4% to 17.9%. Continuous glucose monitoring revealed improvement of glycemic profile (average glucose level from 212 mg/dL to 99 mg/dL and glycemic standard deviation from 92 mg/dL to 14 mg/dL) with disappearance of hypoglycemic events. This treatment further ameliorated the characteristics of insulin antibodies and resulted in reduced insulin requirement. SGLT2 inhibitors may offer an effective treatment option for managing the poor glycemic control in diabetes complicated with insulin antibodies.

Effects of intraperitoneal insulin versus subcutaneous insulin administration on sex hormone-binding globulin concentrations in patients with type 1 diabetes mellitus

Directory of Open Access Journals (Sweden)

M Boering

2016-06-01

Full Text Available Aims Elevated sex hormone-binding globulin (SHBG concentrations have been described in patients with type 1 diabetes mellitus (T1DM, probably due to low portal insulin concentrations. We aimed to investigate whether the route of insulin administration, continuous intraperitoneal insulin infusion (CIPII, or subcutaneous (SC, influences SHBG concentrations among T1DM patients. Methods Post hoc analysis of SHBG in samples derived from a randomized, open-labeled crossover trial was carried out in 20 T1DM patients: 50% males, mean age 43 (±13 years, diabetes duration 23 (±11 years, and hemoglobin A1c (HbA1c 8.7 (±1.1 (72 (±12 mmol/mol. As secondary outcomes, testosterone, 17-β-estradiol, luteinizing hormone (LH, and follicle-stimulating hormone (FSH were analyzed. Results Estimated mean change in SHBG was −10.3nmol/L (95% CI: −17.4, −3.2 during CIPII and 3.7nmol/L (95% CI: −12.0, 4.6 during SC insulin treatment. Taking the effect of treatment order into account, the difference in SHBG between therapies was −6.6nmol/L (95% CI: −17.5, 4.3; −12.7nmol/L (95% CI: −25.1, −0.4 for males and −1.7nmol/L (95% CI: −24.6, 21.1 for females, respectively. Among males, SHBG and testosterone concentrations changed significantly during CIPII; −15.8nmol/L (95% CI: −24.2, −7.5 and −8.3nmol/L (95% CI: −14.4, −2.2, respectively. The difference between CIPII and SC insulin treatment was also significant for change in FSH 1.2U/L (95% CI: 0.1, 2.2 among males. Conclusions SHBG concentrations decreased significantly during CIPII treatment. Moreover, the difference in change between CIPII and SC insulin therapy was significant for SHBG and FSH among males. These findings support the hypothesis that portal insulin administration influences circulating SHBG and sex steroids.

Dapagliflozin as an adjunct therapy to insulin in the treatment of patients with type 1 diabetes mellitus

OpenAIRE

Tamez, Hector E.; Tamez, Alejandra L.; Garza, Lucas A.; Hernandez, Mayra I.; Polanco, Ana C.

2015-01-01

We have evaluated the efficacy of dapagliflozin in patients with type 1 diabetes mellitus (DM1) without adequate control. We expected that adding dapagliflozin to this population on top of their base treatment would lower their HbA1c levels. We conducted a pragmatic, open, 24-week study of treatment with 10 mg of oral dapagliflozin in patients with DM1 and chronic hyperglycemia. We evaluated glycemic control, lipid profile, weight, and insulin dose. Safety was assessed by adverse event report...

EFFECT OF INSULIN ON ENDOCRINE PANCREAS FUNCTION DURING LATE PREGNANCY IN THE RAT

NARCIS (Netherlands)

WIJKSTRA, S; MOES, H; SCHUILING, GA; KOITER, TR

To partly or completely satisfy the increasing demand for insulin, pregnant rats were infused SC with human insulin (2.4 or 4.8 IU/day) from day 14 to day 20 of gestation. Cyclic control rats underwent the same procedure of 6 days of insulin-treatment. During the treatment all,stoups of rats were

Effects of 12 weeks' treatment with a proton pump inhibitor on insulin secretion, glucose metabolism and markers of cardiovascular risk in patients with type 2 diabetes

DEFF Research Database (Denmark)

Hove, K D; Brøns, Charlotte; Færch, Kai Erik Vinther

2013-01-01

Recent studies suggest that proton pump inhibitor treatment may increase insulin secretion and improve glucose metabolism in type 2 diabetes. In a randomised double-blind prospective placebo-controlled 2 × 2 factorial study, we examined the effect of esomeprazole on insulin secretion, HbA(1c...

InsuOnline, an Electronic Game for Medical Education on Insulin Therapy: A Randomized Controlled Trial With Primary Care Physicians

Science.gov (United States)

2017-01-01

Background Most patients with diabetes mellitus (DM) are followed by primary care physicians, who often lack knowledge or confidence to prescribe insulin properly. This contributes to clinical inertia and poor glycemic control. Effectiveness of traditional continuing medical education (CME) to solve that is limited, so new approaches are required. Electronic games are a good option, as they can be very effective and easily disseminated. Objective The objective of our study was to assess applicability, user acceptance, and educational effectiveness of InsuOnline, an electronic serious game for medical education on insulin therapy for DM, compared with a traditional CME activity. Methods Primary care physicians (PCPs) from South of Brazil were invited by phone or email to participate in an unblinded randomized controlled trial and randomly allocated to play the game InsuOnline, installed as an app in their own computers, at the time of their choice, with minimal or no external guidance, or to participate in a traditional CME session, composed by onsite lectures and cases discussion. Both interventions had the same content and duration (~4 h). Applicability was assessed by the number of subjects who completed the assigned intervention in each group. Insulin-prescribing competence (factual knowledge, problem-solving skills, and attitudes) was self-assessed through a questionnaire applied before, immediately after, and 3 months after the interventions. Acceptance of the intervention (satisfaction and perceived importance for clinical practice) was also assessed immediately after and 3 months after the interventions, respectively. Results Subjects’ characteristics were similar between groups (mean age 38, 51.4% [69/134] male). In the game group, 69 of 88 (78%) completed the intervention, compared with 65 of 73 (89%) in the control group, with no difference in applicability. Percentage of right answers in the competence subscale, which was 52% at the baseline in both

Insulin resistance and improvements in signal transduction.

Science.gov (United States)

Musi, Nicolas; Goodyear, Laurie J

2006-02-01

Type 2 diabetes and obesity are common metabolic disorders characterized by resistance to the actions of insulin to stimulate skeletal muscle glucose disposal. Insulin-resistant muscle has defects at several steps of the insulin-signaling pathway, including decreases in insulin-stimulated insulin receptor and insulin receptor substrate-1 tyrosine phosphorylation, and phosphatidylinositol 3-kinase (PI 3-kinase) activation. One approach to increase muscle glucose disposal is to reverse/improve these insulin-signaling defects. Weight loss and thiazolidinediones (TZDs) improve glucose disposal, in part, by increasing insulin-stimulated insulin receptor and IRS-1 tyrosine phosphorylation and PI 3-kinase activity. In contrast, physical training and metformin improve whole-body glucose disposal but have minimal effects on proximal insulin-signaling steps. A novel approach to reverse insulin resistance involves inhibition of the stress-activated protein kinase Jun N-terminal kinase (JNK) and the protein tyrosine phosphatases (PTPs). A different strategy to increase muscle glucose disposal is by stimulating insulin-independent glucose transport. AMP-activated protein kinase (AMPK) is an enzyme that works as a fuel gauge and becomes activated in situations of energy consumption, such as muscle contraction. Several studies have shown that pharmacologic activation of AMPK increases glucose transport in muscle, independent of the actions of insulin. AMPK activation is also involved in the mechanism of action of metformin and adiponectin. Moreover, in the hypothalamus, AMPK regulates appetite and body weight. The effect of AMPK to stimulate muscle glucose disposal and to control appetite makes it an important pharmacologic target for the treatment of type 2 diabetes and obesity.

Childhood obesity and insulin resistance: how should it be managed?

Science.gov (United States)

Ho, Mandy; Garnett, Sarah P; Baur, Louise A

2014-12-01

Concomitant with the rise in global pediatric obesity in the past decades, there has been a significant increase in the number of children and adolescents with clinical signs of insulin resistance. Given insulin resistance is the important link between obesity and the associated metabolic abnormalities and cardiovascular risk, clinicians should be aware of high risk groups and treatment options. As there is no universally accepted biochemical definition of insulin resistance in children and adolescents, identification and diagnosis of insulin resistance usually relies on clinical features such as acanthosis nigricans, polycystic ovary syndrome, hypertension, dyslipidemia, and nonalcoholic fatty liver disease. Treatment for reducing insulin resistance and other obesity-associated comorbidities should focus on changes in health behaviors to achieve effective weight management. Lifestyle interventions incorporating dietary change, increased physical activity, and decreased sedentary behaviors, with the involvement of family and adoption of a developmentally appropriate approach, should be used as the first line treatment. Current evidence suggests that the primary objective of dietary interventions should be to reduce total energy intake and a combination of aerobic and resistance training should be encouraged. Metformin can be used in conjunction with a lifestyle intervention program in obese adolescents with clinical insulin resistance to achieve weight loss and to improve insulin sensitivity. Ongoing evaluation and research are required to explore optimal protocol and long-term effectiveness of lifestyle interventions, as well as to determine whether the improvements in insulin sensitivity induced by lifestyle interventions and weight loss will lead to a clinical benefit including reduced cardiovascular morbidity and mortality.

Clinical experience with insulin detemir type 2 diabetes mellitus, biphasic insulin aspart and insulin aspart in people with type 2 diabetes: Results from the Rabat-Sale-Zemmour-Zaer Region cohort of the A1chieve study.

Science.gov (United States)

Chraibi, Abdelmjid; Belmejdoub, Ghizlane

2013-11-01

The A1chieve, a multicentric (28 countries), 24-week, non-interventional study evaluated the safety and effectiveness of insulin detemir, biphasic insulin aspart and insulin aspart in people with T2DM (n = 66 726) in routine clinical care across four continents. Data was collected at baseline, at 12 weeks and at 24 weeks. This short communication presents the results for patients enrolled from Rabat-Sale-Zemmour-Zaer region, Morocco. A total of 424 patients were enrolled in the study. Four different insulin analogue regimens were used in the study. Study patients had started on or were switched to biphasic insulin aspart (n = 177), insulin detemir (n = 150), insulin aspart (n = 11), basal insulin plus insulin aspart (n = 45) and other insulin combinations (n = 41). At baseline glycaemic control was poor for both insulin naïve (mean HbA1c: 10.1%) and insulin user (mean HbA1c: 9.4%) groups. After 24 weeks of treatment, all the study groups showed improvement in HbA1c (insulin naïve: -2.5%, insulin users: -1.8%). Major hypoglycaemia was observed in the insulin user group after 24 weeks (0.1 events/patient-year). SADRs were reported in 0.5% of insulin users. Starting or switching to insulin analogues was associated with improvement in glycaemic control with a low rate of hypoglycaemia.

Insulin initiation and intensification in patients with T2DM for the primary care physician

Directory of Open Access Journals (Sweden)

Unger J

2011-06-01

Full Text Available Jeff UngerCatalina Research Institute, Chino, CA, USAAbstract: Type 2 diabetes mellitus (T2DM is characterized by both insulin resistance and inadequate insulin secretion. All patients with the disease require treatment to achieve and maintain the target glycosylated hemoglobin (A1C level of 6.5%–7%. Pharmacological management of T2DM typically begins with the introduction of oral medications, and the majority of patients require exogenous insulin therapy at some point in time. Primary care physicians play an essential role in the management of T2DM since they often initiate insulin therapy and intensify regimens over time as needed. Although insulin therapy is prescribed on an individualized basis, treatment usually begins with basal insulin added to a background therapy of oral agents. Prandial insulin injections may be added if glycemic targets are not achieved. Treatments may be intensified over time using patient-friendly titration algorithms. The goal of insulin intensification within the primary care setting is to minimize patients' exposure to chronic hyperglycemia and weight gain, and reduce patients' risk of hypoglycemia, while achieving individualized fasting, postprandial, and A1C targets. Simplified treatment protocols and insulin delivery devices allow physicians to become efficient prescribers of insulin intensification within the primary care arena.Keywords: diabetes, basal, bolus, regimens, insulin analogs, structured glucose testing

Frequency and risk factors of severe hypoglycemia in insulin-treated type 2 diabetes

DEFF Research Database (Denmark)

Akram, Kamran; Pedersen-Bjergaard, Ulrik; Borch-Johnsen, Knut

2006-01-01

Intensive treatment regimens including early initiation of insulin treatment are important to prevent late complications in type 2 diabetes. The assumed risk of severe hypoglycemia (SH) is a major barrier to initiation of insulin treatment. To assess the relevance of this risk we evaluated...... the frequency of SH as reported in the literature. Using Medline and Embase search we identified 11 studies (5 retrospective and 6 prospective) including at least 50 patients with insulin-treated type 2 diabetes followed for at least 6 months in which frequency of SH was reported. The incidence of SH....... Only few studies looked into the impact of risk factors on the rate of SH. Impaired hypoglycemia awareness, high age, long duration of diabetes and insulin therapy increased the risk, while no association was found with HbA1c and insulin dose. The present knowledge of SH in insulin-treated type 2...

Sulfonylurea in combination with insulin is associated with increased mortality compared with a combination of insulin and metformin in a retrospective Danish nationwide study

DEFF Research Database (Denmark)

Mogensen, Ulrik M; Andersson, Charlotte; Fosbøl, Emil L

2015-01-01

AIMS/HYPOTHESIS: Individual sulfonylureas (SUs) and metformin have, in some studies, been associated with unequal hypoglycaemic, cardiovascular and mortality risks when used as monotherapy in type 2 diabetes. We investigated the outcomes in patients treated with different combinations of SUs...... and insulin vs a combination of metformin and insulin in a retrospective nationwide study. METHODS: All Danish individuals using dual therapy with SU + insulin or metformin + insulin without prior myocardial infarction (MI) or stroke were followed from 1 January 1997 to 31 December 2009 in nationwide...... + insulin and 16,910 used metformin + insulin. Patients receiving metformin + insulin were younger and had less comorbidity and a longer history of glucose-lowering treatment. SU + insulin was associated with higher mortality rates compared with metformin + insulin (76-126 vs 23 per 1,000 person...

Degludec insulin: A novel basal insulin

OpenAIRE

Kalra, Sanjay; Unnikrishnan, Ambika Gopalakrishnan; Baruah, Manash; Kalra, Bharti

2011-01-01

This paper reviews a novel insulin analogue, degludec, which has the potential to emerge as an ideal basal insulin. It reviews the limitations of existing basal insulin and analogues, and highlights the need for a newer molecule. The paper discusses the potential advantages of degludec, while reviewing its pharmacologic and clinical studies done so far. The paper assesses the potential role of insulin degludec and degludec plus in clinical diabetes practice.

[The use of continuous subcutaneous insulin infusion (CSII) with personal insulin pumps in the treatment of children and adolescents with diabetes type 1].

Science.gov (United States)

Jarosz-Chobot, Przemysława

2004-01-01

This paper sums up recently published researches on the continuous subcutaneous insulin infusion (CSII) with the use of insulin pump in children and adolescents with diabetes type 1. Obtaining a balance in the organism metabolism in childhood and adolescence diabetology is nowadays one of the most important rules of the diabetes management in children. One of the modern ways to achieve that goal is the intensive insulin therapy model with use of the insulin pump. In this paper the advantages and disadvantages as well as the indications and contraindications for the CSII in children and adolescents with diabetes are widely discussed.

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.

Interleukin-1β inhibits insulin signaling and prevents insulin-stimulated system A amino acid transport in primary human trophoblasts.

Science.gov (United States)

Aye, Irving L M H; Jansson, Thomas; Powell, Theresa L

2013-12-05

Interleukin-1β (IL-1β) promotes insulin resistance in tissues such as liver and skeletal muscle; however the influence of IL-1β on placental insulin signaling is unknown. We recently reported increased IL-1β protein expression in placentas of obese mothers, which could contribute to insulin resistance. In this study, we tested the hypothesis that IL-1β inhibits insulin signaling and prevents insulin-stimulated amino acid transport in cultured primary human trophoblast (PHT) cells. Cultured trophoblasts isolated from term placentas were treated with physiological concentrations of IL-1β (10pg/ml) for 24h. IL-1β increased the phosphorylation of insulin receptor substrate-1 (IRS-1) at Ser307 (inhibitory) and decreased total IRS-1 protein abundance but did not affect insulin receptor β expression. Furthermore, IL-1β inhibited insulin-stimulated phosphorylation of IRS-1 (Tyr612, activation site) and Akt (Thr308) and prevented insulin-stimulated increase in PI3K/p85 and Grb2 protein expression. IL-1β alone stimulated cRaf (Ser338), MEK (Ser221) and Erk1/2 (Thr202/Tyr204) phosphorylation. The inflammatory pathways nuclear factor kappa B and c-Jun N-terminal kinase, which are involved in insulin resistance, were also activated by IL-1β treatment. Moreover, IL-1β inhibited insulin-stimulated System A, but not System L amino acid uptake, indicating functional impairment of insulin signaling. In conclusion, IL-1β inhibited the insulin signaling pathway by inhibiting IRS-1 signaling and prevented insulin-stimulated System A transport, thereby promoting insulin resistance in cultured PHT cells. These findings indicate that conditions which lead to increased systemic maternal or placental IL-1β levels may attenuate the effects of maternal insulin on placental function and consequently fetal growth. Published by Elsevier Ireland Ltd.

Insulin sensitizers in adolescents with polycystic ovary syndrome.

Science.gov (United States)

LE, Trang N; Wickham, Edmond P; Nestler, John E

2017-10-01

Polycystic ovary syndrome (PCOS) is the most common disorder of androgen excess in women of reproductive age. The diagnosis of PCOS can be more challenging in adolescents than in adult women given significant overlap between normal puberty and the signs of PCOS, including acne, menstrual irregularity, and polycystic ovarian morphology. Optimal treatments for adult women with PCOS vary depending on patient risk factors and reproductive goals, but mainly include hormonal contraception and insulin sensitizers. There is continued interest in targeting the intrinsic insulin resistance that contributes to metabolic and hormonal derangements associated with PCOS. The vast majority of published data on insulin sensitizing PCOS treatments are reported in adult women; these have included weight loss, metformin, thiazolidinediones, and the inositols. Furthermore, there is also a small but growing body of evidence in support of the use of insulin sensitizers in adolescents, with or without oral contraceptives. Discussion of the available treatments, including benefits, potential side effects, and incorporation of patient and family preferences is critical in developing a plan of care aimed at achieving patient-important improvements in PCOS signs and symptoms while addressing the longer-term cardiometabolic risks associated with the syndrome.

Solid waste electron beam treatment

International Nuclear Information System (INIS)

Chmielewski, A.G.

1998-01-01

The possible applications of electron accelerators for solid waste treatment are discussed in the report. The elaborated technologies allow to recycle of materials (e.g. cellulosic materials in municipal waste), improve their hygienic standards (agricultural usage of sludge from municipal waste water treatment) and reduce harmful to environment chemical usage (cellulose degradation). These are environment friendly advanced technologies which meets demands waste recycling. (author)

Solid waste electron beam treatment

Energy Technology Data Exchange (ETDEWEB)

Chmielewski, A G

1998-07-01

The possible applications of electron accelerators for solid waste treatment are discussed in the report. The elaborated technologies allow to recycle of materials (e.g., cellulosic materials in municipal waste), improve their hygienic standards (agricultural usage of sludge from municipal waste water treatment) and reduce harmful to environment chemical usage (cellulose degradation). These are environment friendly advanced technologies which meets demands waste recycling. (author)

High power electron accelerators for flue gas treatment

International Nuclear Information System (INIS)

Zimek, Z.

2011-01-01

Flue gas treatment process based on electron beam application for SO 2 and NO x removal was successfully demonstrated in number of laboratories, pilot plants and industrial demonstration facilities. The industrial scale application of an electron beam process for flue gas treatment requires accelerators modules with a beam power 100-500 kW and electron energy range 0.8-1.5 MeV. The most important accelerator parameters for successful flue gas radiation technology implementation are related to accelerator reliability/availability, electrical efficiency and accelerator price. Experience gained in high power accelerators exploitation in flue gas treatment industrial demonstration facility was described and high power accelerator constructions have been reviewed. (author)

Insulin secretion and insulin action in non-insulin-dependent diabetes mellitus: which defect is primary?

Science.gov (United States)

Reaven, G M

1984-01-01

Defects in both insulin secretion and insulin action exist in patients with non-insulin-dependent diabetes mellitus (NIDDM). The loss of the acute plasma insulin response to intravenous glucose is seen in patients with relatively mild degrees of fasting hyperglycemia, but patients with severe fasting hyperglycemia also demonstrate absolute hypoinsulinemia in response to an oral glucose challenge. In contrast, day-long circulating insulin levels are within normal limits even in severely hyperglycemic patients with NIDDM. The relationship between NIDDM and insulin action in NIDDM is less complex, and is a characteristic feature of the syndrome. This metabolic defect is independent of obesity, and the severity of the resistance to insulin-stimulated glucose uptake increases with magnitude of hyperglycemia. Control of hyperglycemia with exogenous insulin ameliorates the degree of insulin resistance, and reduction of insulin resistance with weight loss in obese patients with NIDDM leads to an enhanced insulin response. Since neither therapeutic intervention is capable of restoring all metabolic abnormalities to normal, these observations do not tell us which of these two defects is primarily responsible for the development of NIDDM. Similarly, the observation that most patients with impaired glucose tolerance are hyperinsulinemic and insulin resistant does not prove that insulin resistance is the primary defect in NIDDM. In conclusion, reduction in both insulin secretion and action is seen in patients with NIDDM, and the relationship between these two metabolic abnormalities is very complex.(ABSTRACT TRUNCATED AT 250 WORDS)

Exhaust gas treatment by electron beam irradiation

International Nuclear Information System (INIS)

Shibamura, Yokichi; Suda, Shoichi; Kobayashi, Toshiki

1991-01-01

Among global environmental problems, atmospheric pollution has been discussed since relatively old days, and various countermeasures have been taken, but recently in connection with acid rain, the efficient and economical treatment technology is demanded. As the denitration and desulfurization technology for the exhaust gas from the combustion of fossil fuel, the incineration of city trash and internal combustion engines, three is the treatment method by electron beam irradiation. By irradiating electron beam to exhaust gas, nitrogen oxides and sulfur oxides are oxidized to nitric acid and sulfuric acid, and by promoting the neutralization of these acids with injected alkali, harmless salts are recovered. This method has the merit that nitrogen oxides and surfur oxides can be removed efficiently with a single system. In this report, as for the exhaust gas treatment by electron beam irradiation, its principle, features, and the present status of research and development are described, and in particular, the research on the recent exhaust gas treatment in city trash incineration is introduced. This treatment method is a dry process, accordingly, waste water disposal is unnecessary. The reaction products are utilized as fertilizer, and waste is not produced. (K.I.)

Antibody-Mediated Extreme Insulin Resistance: A Report of Three Cases.

Science.gov (United States)

Kim, Han Na; Fesseha, Betiel; Anzaldi, Laura; Tsao, Allison; Galiatsatos, Panagis; Sidhaye, Aniket

2018-01-01

Type 2 diabetes mellitus is characterized by relative insulin deficiency and insulin resistance. Features suggesting severe insulin resistance include acanthosis nigricans, hyperandrogenism, weight loss, and recurrent hospital admissions for diabetic ketoacidosis. In rare circumstances, hyperglycemia persists despite administration of massive doses of insulin. In these cases, it is important to consider autoimmune etiologies for insulin resistance, such as type B insulin resistance and insulin antibody-mediated extreme insulin resistance, which carry high morbidity and mortality if untreated. Encouragingly, immunomodulatory regimens have recently been published that induce remission at high rates. We describe 3 cases of extreme insulin resistance mediated by anti-insulin receptor autoantibodies or insulin autoantibodies. All cases were effectively treated with an immunomodulatory regimen. Although cases of extreme insulin resistance are rare, it is important to be aware of autoimmune causes, recognize suggestive signs and symptoms, and pursue appropriate diagnostic evaluation. Prompt treatment with immunomodulators is key to restoring euglycemia in patients with autoimmune etiologies of insulin resistance. Copyright © 2018 Elsevier Inc. All rights reserved.

Insulin in the nervous system and the mind: Functions in metabolism, memory, and mood.

Science.gov (United States)

Lee, Seung-Hwan; Zabolotny, Janice M; Huang, Hu; Lee, Hyon; Kim, Young-Bum

2016-08-01

Insulin, a pleotrophic hormone, has diverse effects in the body. Recent work has highlighted the important role of insulin's action in the nervous system on glucose and energy homeostasis, memory, and mood. Here we review experimental and clinical work that has broadened the understanding of insulin's diverse functions in the central and peripheral nervous systems, including glucose and body weight homeostasis, memory and mood, with particular emphasis on intranasal insulin. Implications for the treatment of obesity, type 2 diabetes, dementia, and mood disorders are discussed in the context of brain insulin action. Intranasal insulin may have potential in the treatment of central nervous system-related metabolic disorders.

Interaction between the p21ras GTPase activating protein and the insulin receptor

NARCIS (Netherlands)

Pronk, G.J.; Medema, R.H.; Burgering, B.M.T.; Clark, R.; McCormick, F.; Bos, J.L.

1992-01-01

We investigated the involvement of the p21ras-GTPase activating protein (GAP) in insulin-induced signal transduction. In cells overexpressing the insulin receptor, we did not observe association between GAP and the insulin receptor after insulin treatment nor the phosphorylation of GAP on tyrosine

Clinical experience with insulin detemir type 2 diabetes mellitus, biphasic insulin aspart and insulin aspart in people with type 2 diabetes: Results from the Rabat-Sale-Zemmour-Zaer Region cohort of the A 1 chieve study

Directory of Open Access Journals (Sweden)

Abdelmjid Chraibi

2013-01-01

Full Text Available Background: The A 1 chieve, a multicentric (28 countries, 24-week, non-interventional study evaluated the safety and effectiveness of insulin detemir, biphasic insulin aspart and insulin aspart in people with T2DM (n = 66 726 in routine clinical care across four continents. Materials and Methods: Data was collected at baseline, at 12 weeks and at 24 weeks. This short communication presents the results for patients enrolled from Rabat-Sale-Zemmour-Zaer region, Morocco. Results: A total of 424 patients were enrolled in the study. Four different insulin analogue regimens were used in the study. Study patients had started on or were switched to biphasic insulin aspart (n = 177, insulin detemir (n = 150, insulin aspart (n = 11, basal insulin plus insulin aspart (n = 45 and other insulin combinations (n = 41. At baseline glycaemic control was poor for both insulin naïve (mean HbA 1 c: 10.1% and insulin user (mean HbA 1 c: 9.4% groups. After 24 weeks of treatment, all the study groups showed improvement in HbA 1 c (insulin naïve: −2.5%, insulin users: −1.8%. Major hypoglycaemia was observed in the insulin user group after 24 weeks (0.1 events/patient-year. SADRs were reported in 0.5% of insulin users. Conclusion: Starting or switching to insulin analogues was associated with improvement in glycaemic control with a low rate of hypoglycaemia.

Insulin fibrillation: The influence and coordination of Zn2+

DEFF Research Database (Denmark)

Frankær, Christian Grundahl; Sønderby, Pernille; Bang, Maria Blanner

2017-01-01

fibrils has been debated for some years. We have therefore investigated the influence and binding geometry of zinc in fibrillated insulin using extended X-ray absorption fine-structure and X-ray absorption near-edge structure spectroscopy. The results were validated with fibre diffraction, Transmission...... Electron Microscopy and Thioflavin T fluorescence measurements. It is well-known that Zn2+ ions coordinate and stabilize the hexameric forms of insulin. However, this study is the first to show that zinc indeed binds to the insulin fibrils. Furthermore, zinc influences the kinetics and the morphology...... of the fibrils. It also shows that zinc coordinates to histidine residues in an environment, which is similar to the coordination seen in the insulin R6 hexamers, where three histidine residues and a chloride ion is coordinating the zinc....

Aspartame Administration and Insulin Treatment Altered Brain Levels of CYP2E1 and CYP3A2 in Streptozotocin-Induced Diabetic Rats.

Science.gov (United States)

Nosti-Palacios, Rosario; Gómez-Garduño, Josefina; Molina-Ortiz, Dora; Calzada-León, Raúl; Dorado-González, Víctor Manuel; Vences-Mejía, Araceli

2014-07-01

This study demonstrates that aspartame consumption and insulin treatment in a juvenile diabetic rat model leads to increase in cytochrome P450 (CYP) 2E1 and CYP3A2 isozymes in brain. Diabetes mellitus was induced in postweaned 21-day-old Wistar male rat by streptozotocin. Animals were randomly assigned to one of the following groups: untreated control, diabetic (D), D-insulin, D-aspartame, or the D-insulin + aspartame-treated group. Brain and liver tissue samples were used to analyze the activity of CYP2E1 and CYP3A2 and protein levels. Our results indicate that combined treatment with insulin and aspartame in juvenile diabetic rats significantly induced CYP2E1 in the cerebrum and cerebellum without modifying it in the liver, while CYP3A2 protein activity increased both in the brain and in the liver. The induction of CYP2E1 in the brain could have important in situ toxicological effects, given that this CYP isoform is capable of bioactivating various toxic substances. Additionally, CYP3A2 induction in the liver and brain could be considered a decisive factor in the variation of drug response and toxicity. © The Author(s) 2014.

The effects of increasing doses of 2 preparations of long-acting insulin on short-term plasma profiles of glucose and insulin in lactating dairy cows.

Science.gov (United States)

Winkelman, L A; Overton, T R

2012-12-01

Two experiments were conducted to investigate effects of administering increasing doses of 2 different preparations of long-acting insulin on the 24-h profiles of plasma glucose and insulin concentrations in mid lactation dairy cows. The 2 separately analyzed experiments investigated the effects administering either Humulin N (H), a neutral protamine Hagedorn insulin, or insulin glargine (Lantus, L), an insulin analog, at doses of 0 (control), 0.1, 0.2, and 0.4 IU/kg of body weight in a randomized complete block design. Sixteen cows (237±11 d in milk for H; 213±10 d in milk for L; mean ± SD) were used for each insulin preparation, resulting in n=4 for each dose within insulin preparation. Cows were fitted with a single jugular catheter on the day before the study. On the day of the study, cows were given treatments by subcutaneous injection of either sterile water or the designated insulin type and dose. Blood samples were taken hourly from the jugular catheter. Subcutaneous injection of both H and L resulted in linear decreases in plasma glucose concentrations, increased area under the curve, and decreased nadir for plasma glucose following administration of the insulin preparations. Plasma insulin concentration linearly increased with increasing dose of H. Though elevated concentrations of insulin were measurable in cows treated with H, they were not measurable in cows treated with L. Attempts to measure overall insulin concentrations and metabolites of L by a commercially available ELISA and a commercially available RIA kit were not successful and did not retrieve values that we felt truly represented the amount of insulin activity exhibited during this treatment. Both long-acting insulin preparations elicited insulin-like activity in lactating dairy cows, as evidenced by reduced plasma glucose concentrations. Given these results, the potential exists to use both H and L to study the effects of insulin in mid lactation dairy cows without the confounding

Insulin degludec versus insulin glargine in insulin-naive patients with type 2 diabetes

DEFF Research Database (Denmark)

Zinman, Bernard; Philis-Tsimikas, Athena; Cariou, Bertrand

2012-01-01

To compare ultra-long-acting insulin degludec with glargine for efficacy and safety in insulin-naive patients with type 2 diabetes inadequately controlled with oral antidiabetic drugs (OADs).......To compare ultra-long-acting insulin degludec with glargine for efficacy and safety in insulin-naive patients with type 2 diabetes inadequately controlled with oral antidiabetic drugs (OADs)....

Insulin appearance of subcutaneously infused insulin: influence of the basal rate pulse interval of the infusion pump.

Science.gov (United States)

Birch, K; Hildebrandt, P; Jensen, B M; Kühl, C; Brange, J

1985-05-01

To compare the metabolic control and the pharmacokinetics of infused insulin using an insulin pump (Auto-Syringe AS 6C) which provides the basal rate in pulses every 2-10 min with a pump (Medix Syringe Driver 209) providing the basal rate in pulses every 15-60 min, 6 C-peptide negative diabetic patients received, in random order, identical, but individual, insulin treatment during one 4-day period using the Auto-Syringe pump and another 4-day period using the Medix pump. On the fourth day of each period, blood glucose and plasma-free insulin were estimated every 30 min for 7 hr and every 5 min for the next hour. Plasma-free insulin was significantly higher on 3 time points out of the 26 possible when using the Medix pump, but this was not reflected in the blood glucose concentrations which were similar in the 2 periods. The results indicate that, from a metabolic and pharmacokinetic point of view, insulin pumps working with larger intervals between the basal rate pulses are just as good as the more technically advanced and hence often more expensive pumps which provide the basal rate in more and smaller pulses.

Glucagon-like peptide-1 receptor agonists compared with basal insulins for the treatment of type 2 diabetes mellitus: a systematic review and meta-analysis.

Science.gov (United States)

Singh, Sonal; Wright, Eugene E; Kwan, Anita Y M; Thompson, Juliette C; Syed, Iqra A; Korol, Ellen E; Waser, Nathalie A; Yu, Maria B; Juneja, Rattan

2017-02-01

Since 2005, several glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have been approved to treat people with type 2 diabetes. These agents are considered for use at the same point in the treatment paradigm as basal insulins. A comprehensive comparison of these drug classes, therefore, can help inform treatment decisions. This systematic review and meta-analysis assessed the clinical efficacy and safety of GLP-1 RAs compared with basal insulins. MEDLINE, EMBASE, CENTRAL and PubMed databases were searched. Randomized clinical trials (RCTs) of ≥16 weeks' duration comparing GLP-1 RAs vs basal insulins in adults with type 2 diabetes inadequately controlled with oral antihyperglycemic drugs were included. Data on the change from baseline to 26 weeks (±10 weeks) of treatment in hemoglobin A1c (HbA1c) and weight, as well as the proportion of patients experiencing hypoglycaemia, were extracted. Fixed-effect pairwise meta-analyses were conducted where data were available from ≥2 studies. Fifteen RCTs were identified and 11 were meta-analysed. The once-weekly GLP-1 RAs, exenatide long acting release (LAR) and dulaglutide, led to greater, statistically significant mean HbA1c reductions vs basal insulins (exenatide: -0.31% [95% confidence interval -0.42, -0.19], dulaglutide: -0.39% [-0.49, -0.29]) whilst once-daily liraglutide and twice-daily exenatide did not (liraglutide: 0.06% [-0.06, 0.18], exenatide: 0.01% [-0.11, 0.13]). Mean weight reduction was seen with all GLP-1 RAs while mean weight gain was seen with basal insulins. Interpretation of the analysis of hypoglycaemia was limited by inconsistent definitions and reporting. Because of the limited number of available studies sensitivity analyses to explore heterogeneity could not be conducted. Although weight reduction is seen with all GLP-1 RA's, only the once-weekly agents, exenatide LAR and dulaglutide, demonstrate significant HbA1c reductions when compared to basal insulins. © 2016 The Authors. Diabetes

INSULIN AND INSULIN RESISTANCE: NEW MOLECULE MARKERS AND TARGET MOLECULE FOR THE DIAGNOSIS AND THERAPY OF DISEASES OF THE CENTRAL NERVOUS SYSTEM

Directory of Open Access Journals (Sweden)

A. B. Salmina

2013-01-01

Full Text Available The review summarizes current data on the role of insulin in the regulation of t glucose metabolism in the central nervous system at physiologic and pathologic conditions. For many years, the brain has been considered as an insulin-independent organ which utilizes glucose without insulin activity. However, it is become clear now that insulin not only regulates glucose transport and metabolism, but also has modulatory efftects in impact on excitability, proliferation and differentiation of brain progenitor cells, synaptic plasticity and memory formation, secretion of neurotransmitters, apoptosis. We have critically reviewed literature information and our own data on the role of insulin and insulin resistance in neuron-glia metabolic coupling, regulation of NAD+ metabolism and action of NAdependent enzymes, neurogenesis, brain development in (pathophysiological conditions. The paper clarifies interrelations between alterations in glucose homeostasis, development of insulin resistance and development of neurodegeneration (Alzheimer's disease and Parkinson's disease, autism, stroke, and depression. We discuss the application of novel molecular markers of insulin resistance (adipokines, α-hydroxybutyrate, BDNF, insulin-regulated aminopeptidase, provasopressin and molecular targets for diagnostics and treatment of brain disorders associated with insulin resistance.

High power electron accelerators for flue gas treatment

Energy Technology Data Exchange (ETDEWEB)

Zimek, Z. [Institute of Nuclear Chemistry and Technology, Warsaw (Poland)

2011-07-01

Flue gas treatment process based on electron beam application for SO{sub 2} and NO{sub x} removal was successfully demonstrated in number of laboratories, pilot plants and industrial demonstration facilities. The industrial scale application of an electron beam process for flue gas treatment requires accelerators modules with a beam power 100-500 kW and electron energy range 0.8-1.5 MeV. The most important accelerator parameters for successful flue gas radiation technology implementation are related to accelerator reliability/availability, electrical efficiency and accelerator price. Experience gained in high power accelerators exploitation in flue gas treatment industrial demonstration facility was described and high power accelerator constructions have been reviewed. (author)

Drug-use patterns of initially prescribed insulin detemir and insulin glargine in the Netherlands; A comparative analysis using pharmacy data from IADB.nl

NARCIS (Netherlands)

Visser, S.T.; Vegter, S.; Boersma, C.; De Grooth, R.; Postma, M.J.

2010-01-01

OBJECTIVES: Newer long-acting insulin analogs have shown to result in several treatment improvements if compared with NPH insulins. Promising results from clinical trials require confirmation from observational settings reflecting potential “real-life” benefits. Therefore, the current study aimed to

Pancreatic Transdifferentiation and Glucose-Regulated Production of Human Insulin in the H4IIE Rat Liver Cell Line

Directory of Open Access Journals (Sweden)

Binhai Ren

2016-04-01

Full Text Available Due to the limitations of current treatment regimes, gene therapy is a promising strategy being explored to correct blood glucose concentrations in diabetic patients. In the current study, we used a retroviral vector to deliver either the human insulin gene alone, the rat NeuroD1 gene alone, or the human insulin gene and rat NeuroD1 genes together, to the rat liver cell line, H4IIE, to determine if storage of insulin and pancreatic transdifferentiation occurred. Stable clones were selected and expanded into cell lines: H4IIEins (insulin gene alone, H4IIE/ND (NeuroD1 gene alone, and H4IIEins/ND (insulin and NeuroD1 genes. The H4IIEins cells did not store insulin; however, H4IIE/ND and H4IIEins/ND cells stored 65.5 ± 5.6 and 1475.4 ± 171.8 pmol/insulin/5 × 106 cells, respectively. Additionally, several β cell transcription factors and pancreatic hormones were expressed in both H4IIE/ND and H4IIEins/ND cells. Electron microscopy revealed insulin storage vesicles in the H4IIE/ND and H4IIEins/ND cell lines. Regulated secretion of insulin to glucose (0–20 mmol/L was seen in the H4IIEins/ND cell line. The H4IIEins/ND cells were transplanted into diabetic immunoincompetent mice, resulting in normalization of blood glucose. This data shows that the expression of NeuroD1 and insulin in liver cells may be a useful strategy for inducing islet neogenesis and reversing diabetes.

The role of insulin C-peptide in the coevolution analyses of the insulin signaling pathway: a hint for its functions.

Directory of Open Access Journals (Sweden)

Shuai Wang

Full Text Available As the linker between the A chain and B chain of proinsulin, C-peptide displays high variability in length and amino acid composition, and has been considered as an inert byproduct of insulin synthesis and processing for many years. Recent studies have suggested that C-peptide can act as a bioactive hormone, exerting various biological effects on the pathophysiology and treatment of diabetes. In this study, we analyzed the coevolution of insulin molecules among vertebrates, aiming at exploring the evolutionary characteristics of insulin molecule, especially the C-peptide. We also calculated the correlations of evolutionary rates between the insulin and the insulin receptor (IR sequences as well as the domain-domain pairs of the ligand and receptor by the mirrortree method. The results revealed distinctive features of C-peptide in insulin intramolecular coevolution and correlated residue substitutions, which partly supported the idea that C-peptide can act as a bioactive hormone, with significant sequence features, as well as a linker assisting the formation of mature insulin during synthesis. Interestingly, the evolution of C-peptide exerted the highest correlation with that of the insulin receptor and its ligand binding domain (LBD, implying a potential relationship with the insulin signaling pathway.

The Role of Insulin, Insulin Growth Factor, and Insulin-Degrading Enzyme in Brain Aging and Alzheimer's Disease

OpenAIRE

Messier, Claude; Teutenberg, Kevin

2005-01-01

Most brain insulin comes from the pancreas and is taken up by the brain by what appears to be a receptor-based carrier. Type 2 diabetes animal models associated with insulin resistance show reduced insulin brain uptake and content. Recent data point to changes in the insulin receptor cascade in obesity-related insulin resistance, suggesting that brain insulin receptors also become less sensitive to insulin, which could reduce synaptic plasticity. Insulin transport to the brain is reduced in a...

Bilirubin Increases Insulin Sensitivity by Regulating Cholesterol Metabolism, Adipokines and PPARγ Levels

Science.gov (United States)

Liu, Jinfeng; Dong, Huansheng; Zhang, Yong; Cao, Mingjun; Song, Lili; Pan, Qingjie; Bulmer, Andrew; Adams, David B.; Dong, Xiao; Wang, Hongjun

2015-01-01

Obesity can cause insulin resistance and type 2 diabetes. Moderate elevations in bilirubin levels have anti-diabetic effects. This study is aimed at determining the mechanisms by which bilirubin treatment reduces obesity and insulin resistance in a diet-induced obesity (DIO) mouse model. DIO mice were treated with bilirubin or vehicle for 14 days. Body weights, plasma glucose, and insulin tolerance tests were performed prior to, immediately, and 7 weeks post-treatment. Serum lipid, leptin, adiponectin, insulin, total and direct bilirubin levels were measured. Expression of factors involved in adipose metabolism including sterol regulatory element-binding protein (SREBP-1), insulin receptor (IR), and PPARγ in liver were measured by RT-PCR and Western blot. Compared to controls, bilirubin-treated mice exhibited reductions in body weight, blood glucose levels, total cholesterol (TC), leptin, total and direct bilirubin, and increases in adiponectin and expression of SREBP-1, IR, and PPARγ mRNA. The improved metabolic control achieved by bilirubin-treated mice was persistent: at two months after treatment termination, bilirubin-treated DIO mice remained insulin sensitive with lower leptin and higher adiponectin levels, together with increased PPARγ expression. These results indicate that bilirubin regulates cholesterol metabolism, adipokines and PPARγ levels, which likely contribute to increased insulin sensitivity and glucose tolerance in DIO mice. PMID:26017184

Combination Treatment of Deep Sea Water and Fucoidan Attenuates High Glucose-Induced Insulin-Resistance in HepG2 Hepatocytes

Science.gov (United States)

He, Shan; Peng, Wei-Bing; Zhou, Hong-Lei

2018-01-01

Insulin resistance (IR) plays a central role in the development of several metabolic diseases, which leads to increased morbidity and mortality rates, in addition to soaring health-care costs. Deep sea water (DSW) and fucoidans (FPS) have drawn much attention in recent years because of their potential medical and pharmaceutical applications. This study investigated the effects and mechanisms of combination treatment of DSW and FPS in improving IR in HepG2 hepatocytes induced by a high glucose concentration. The results elucidated that co-treatment with DSW and FPS could synergistically repress hepatic glucose production and increase the glycogen level in IR-HepG2 cells. In addition, they stimulated the phosphorylation levels of the components of the insulin signaling pathway, including tyrosine phosphorylation of IRS-1, and serine phosphorylation of Akt and GSK-3β. Furthermore, they increased the phosphorylation of AMPK and ACC, which in turn decreased the intracellular triglyceride level. Taken together, these results suggested that co-treatment with DSW and FPS had a greater improving effect than DSW or FPS alone on IR. They might attenuate IR by targeting Akt/GSK-3β and AMPK pathways. These results may have some implications in the treatment of metabolic diseases. PMID:29393871

Treatment of autistic spectrum disorder with insulin-like growth factors.

Science.gov (United States)

Riikonen, Raili

2016-11-01

There are no treatments for the core symptoms of autistic spectrum disorder (ASD), but there is now more knowledge on emerging mechanisms and on mechanism-based therapies. In autism there are altered synapses: genes affected are commonly related to synaptic and immune function. Dysregulation of activity-dependent signaling networks may have a key role the etiology of autism. There is an over-activation of IGF-AKT-mTor in autism spectrum disorders. Morphological and electro-physiological defects of the cerebellum are linked to system-wide ASD-like behavior defects. The molecular basis for a cerebellar contribution has been demonstrated in a mouse model. These have led to a potential mechanism-based use of drug targets and mouse models. Neurotrophic factors are potential candidates for the treatment. Insulin-like growth factor-1 (IGF-1) is altered in autism. It reduces neuro-inflammation: by causing changes of cytokines such as IL-6 and microglial function. IGF-1 reduces the defects in the synapse. It alleviates NMDA-induced neurotoxicity via the IGF-AKT-mTor pathway in microglia. IGF-1 may rescue function in Rett syndrome and ASD caused by changes of the SCHANK3 gene. There are recently pilot studies of the treatment of Rett syndrome and of SCHANK3 gene deficiency syndromes. The FDA has granted Orphan drug designations for Fragile X syndrome, SCHANK3 gene deficiency syndrome and Rett syndrome. Copyright © 2016 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

pH-sensitive thiolated nanoparticles facilitate the oral delivery of insulin in vitro and in vivo

Science.gov (United States)

Zhang, Yan; Lin, Xia; Du, Xuli; Geng, Sicong; Li, Hongren; Sun, Hong; Tang, Xing; Xiao, Wei

2015-02-01

In this work, we designed and developed a delivery system composed of enteric Eudragit L100-cysteine/reduced glutathione nanoparticles (Eul-cys/GSH NPs) for oral delivery of insulin. First, interactions between Eul-cys and mucin glycoproteins, which are believed to be the result of disulfide bonds, were confirmed using rheology experiments. Subsequently, the insulin-loaded Eul-cys/GSH NPs were prepared by the diffusion method using the rich gel network multipore structure at the surface of the Eul-cys when the pH was higher than the p Ka of Eul-cys polymer. The Eul-cys/GSH NPs obtained were characterized by dynamic light scattering, transmission electron microscopy, and atomic force microscopy. The results obtained showed that the average particle size ranged from 240 to 280 nm, and the particles were almost spherical in shape. The in vitro drug release results showed that the Eul-cys/GSH NPs retained a large amount of insulin in simulated gastric fluid, while a significant insulin release was found in simulated intestinal fluid. The in situ release study suggested that NPs released a greater amount of FITC-insulin (49.2 %) into the intestinal mucus layer compared with that of FITC-insulin solution (16.4 %), which facilitating insulin delivery through the intestinal mucosa. Eul-cys/GSH NPs exhibited promising mucoadhesive properties demonstrated using an in vitro cell model. Consequently, NPs were introduced into the ileum loop of healthy rats, thus enhancing the intestinal absorption of insulin and providing a prolonged reduction in blood glucose levels. These results suggest that Eul-cys/GSH NPs may be a promising delivery system for the treatment of diabetes.

pH-sensitive thiolated nanoparticles facilitate the oral delivery of insulin in vitro and in vivo

Energy Technology Data Exchange (ETDEWEB)

Zhang, Yan [Shenyang University, Normal College (China); Lin, Xia; Du, Xuli; Geng, Sicong [Shenyang Pharmaceutical University, Department of Pharmaceutics (China); Li, Hongren; Sun, Hong [Shenyang University, Normal College (China); Tang, Xing, E-mail: tanglab@126.com [Shenyang Pharmaceutical University, Department of Pharmaceutics (China); Xiao, Wei, E-mail: wzhzh-nj@tom.com [Jiangsu Kanion Pharmaceutical Co., Ltd (China)

2015-02-15

In this work, we designed and developed a delivery system composed of enteric Eudragit L100-cysteine/reduced glutathione nanoparticles (Eul-cys/GSH NPs) for oral delivery of insulin. First, interactions between Eul-cys and mucin glycoproteins, which are believed to be the result of disulfide bonds, were confirmed using rheology experiments. Subsequently, the insulin-loaded Eul-cys/GSH NPs were prepared by the diffusion method using the rich gel network multipore structure at the surface of the Eul-cys when the pH was higher than the pKa of Eul-cys polymer. The Eul-cys/GSH NPs obtained were characterized by dynamic light scattering, transmission electron microscopy, and atomic force microscopy. The results obtained showed that the average particle size ranged from 240 to 280 nm, and the particles were almost spherical in shape. The in vitro drug release results showed that the Eul-cys/GSH NPs retained a large amount of insulin in simulated gastric fluid, while a significant insulin release was found in simulated intestinal fluid. The in situ release study suggested that NPs released a greater amount of FITC-insulin (49.2 %) into the intestinal mucus layer compared with that of FITC-insulin solution (16.4 %), which facilitating insulin delivery through the intestinal mucosa. Eul-cys/GSH NPs exhibited promising mucoadhesive properties demonstrated using an in vitro cell model. Consequently, NPs were introduced into the ileum loop of healthy rats, thus enhancing the intestinal absorption of insulin and providing a prolonged reduction in blood glucose levels. These results suggest that Eul-cys/GSH NPs may be a promising delivery system for the treatment of diabetes.

pH-sensitive thiolated nanoparticles facilitate the oral delivery of insulin in vitro and in vivo

International Nuclear Information System (INIS)

Zhang, Yan; Lin, Xia; Du, Xuli; Geng, Sicong; Li, Hongren; Sun, Hong; Tang, Xing; Xiao, Wei

2015-01-01

In this work, we designed and developed a delivery system composed of enteric Eudragit L100-cysteine/reduced glutathione nanoparticles (Eul-cys/GSH NPs) for oral delivery of insulin. First, interactions between Eul-cys and mucin glycoproteins, which are believed to be the result of disulfide bonds, were confirmed using rheology experiments. Subsequently, the insulin-loaded Eul-cys/GSH NPs were prepared by the diffusion method using the rich gel network multipore structure at the surface of the Eul-cys when the pH was higher than the pKa of Eul-cys polymer. The Eul-cys/GSH NPs obtained were characterized by dynamic light scattering, transmission electron microscopy, and atomic force microscopy. The results obtained showed that the average particle size ranged from 240 to 280 nm, and the particles were almost spherical in shape. The in vitro drug release results showed that the Eul-cys/GSH NPs retained a large amount of insulin in simulated gastric fluid, while a significant insulin release was found in simulated intestinal fluid. The in situ release study suggested that NPs released a greater amount of FITC-insulin (49.2 %) into the intestinal mucus layer compared with that of FITC-insulin solution (16.4 %), which facilitating insulin delivery through the intestinal mucosa. Eul-cys/GSH NPs exhibited promising mucoadhesive properties demonstrated using an in vitro cell model. Consequently, NPs were introduced into the ileum loop of healthy rats, thus enhancing the intestinal absorption of insulin and providing a prolonged reduction in blood glucose levels. These results suggest that Eul-cys/GSH NPs may be a promising delivery system for the treatment of diabetes

Insulin Use in Pregnancy: An Update

OpenAIRE

Blum, Alyson K.

2016-01-01

IN BRIEF Insulin remains the standard of care for the treatment of type 1 diabetes, type 2 diabetes, and uncontrolled gestational diabetes. Tight control maintained in the first trimester and throughout pregnancy plays a vital role in decreasing poor fetal outcomes, including structural anomalies, macrosomia, hypoglycemia of the newborn, adolescent and adult obesity, and diabetes. Understanding new insulin formulations and strengths is important in assessing risks, since no data on their use ...

Jinlida reduces insulin resistance and ameliorates liver oxidative stress in high-fat fed rats.

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Liu, Yixuan; Song, An; Zang, Shasha; Wang, Chao; Song, Guangyao; Li, Xiaoling; Zhu, Yajun; Yu, Xian; Li, Ling; Wang, Yun; Duan, Liyuan

2015-03-13

Jinlida (JLD) is a compound preparation formulated on the basis of traditional Chinese medicine and is officially approved for the treatment of type 2 diabetes (T2DM) in China. We aimed to elucidate the mechanism of JLD treatment, in comparison to metformin treatment, on ameliorating insulin sensitivity in insulin resistant rats and to reveal its anti-oxidant properties. Rats were fed with standard or high-fat diet for 6 weeks. After 6 weeks, the high-fat fed rats were subdivided into five groups and orally fed with JLD or metformin for 8 weeks. Fasting blood glucose (FBG), fasting blood insulin, blood lipid and antioxidant enzymes were measured. Intraperitoneal glucose tolerance test (IPGTT) and hyperinsulinemic euglycemic clamp technique were carried out to measure insulin sensitivity. Gene expression of the major signaling pathway molecules that regulate glucose uptake, including insulin receptor (INSR), insulin receptor substrate-1 (IRS-1), phosphoinositide-3-kinase (PI3K), protein kinase beta (AKT), and glucose transporter type 2 (GLUT2), were assessed by quantitative RT-PCR. The totle and phosphorylation expression of IRS-1, AKT, JNK and p38MAPK were determined by Western blot. Treatment with JLD effectively ameliorated the high-fat induced hyperglycemia, hyperinsulinemia and hyperlipidemia. Similar to metformin, the high insulin resistance in high-fat fed rats was significantly decreased by JLD treatment. JLD displayed anti-oxidant effects, coupled with up-regulation of the insulin signaling pathway. The attenuation of hepatic oxidative stress by JLD treatment was associated with reduced phosphorylation protein levels of JNK and p38MAPK. Treatment with JLD could moderate glucose and lipid metabolism as well as reduce hepatic oxidative stress, most likely through the JNK and p38MAPK pathways. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Metoprolol compared to carvedilol deteriorates insulin-stimulated endothelial function in patients with type 2 diabetes - a randomized study

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Raunsø Jakob

2010-05-01

Full Text Available Abstract Aim Studies of beta blockade in patients with type 2 diabetes have shown inferiority of metoprolol treatment compared to carvedilol on indices of insulin resistance. The aim of this study was to examine the effect of metoprolol versus carvedilol on endothelial function and insulin-stimulated endothelial function in patients with type 2 diabetes. Method 24 patients with type 2 diabetes were randomized to receive either 200 mg metoprolol succinate or 50 mg carvedilol daily. Endothelium-dependent vasodilation was assessed by using venous occlusion plethysmography with increasing doses of intra-arterial infusions of the agonist serotonin. Insulin-stimulated endothelial function was assessed after co-infusion of insulin for sixty minutes. Vaso-reactivity studies were done before and after the two-month treatment period. Results Insulin-stimulated endothelial function was deteriorated after treatment with metoprolol, the percentage change in forearm blood-flow was 60.19% ± 17.89 (at the highest serotonin dosages before treatment and -33.80% ± 23.38 after treatment (p = 0.007. Treatment with carvedilol did not change insulin-stimulated endothelial function. Endothelium-dependent vasodilation without insulin was not changed in either of the two treatment groups. Conclusion This study shows that vascular insulin sensitivity was preserved during treatment with carvedilol while blunted during treatment with metoprolol in patients with type 2 diabetes. Trial registration Current Controlled Trials NCT00497003

Long-term efficacy and safety of vildagliptin add-on therapy in type 2 diabetes mellitus with insulin treatment.

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Kanazawa, Ippei; Tanaka, Ken-Ichiro; Notsu, Masakazu; Tanaka, Sayuri; Kiyohara, Nobuaki; Koike, Sayo; Yamane, Yuko; Tada, Yuko; Sasaki, Motofumi; Yamauchi, Mika; Sugimoto, Toshitsugu

2017-01-01

The use of dipeptidyl peptidase (DPP)-4 inhibitors in patients with type 2 diabetes treated with insulin may be beneficial. However, the long-term efficacy and safety of vildagliptin add-on therapy in these patients remains unclear. A total of 73 patients with type 2 diabetes treated with insulin were randomly assigned to receive either add-on therapy of vildagliptin (n=37) or conventional therapy without DPP-4 inhibitors (n=36) for glucose control. Hemoglobin A1c (HbA1c) levels, dose and number of insulin injections, number of hypoglycemia episodes, and liver and renal function were monitored for 2years. The baseline characteristics of subjects, including age, dose of insulin injections, or HbA1c levels, did not differ between the two groups. In the vildagliptin group, HbA1c levels significantly decreased and the significance of HbA1c reduction was maintained for 24months (from 8.0±1.2% to 7.4±1.0%, pinsulin injections significantly reduced (-5.6units, p1, and -0.9 times, p1). However, these parameters were unchanged in the control group. The number of patients who experienced three or more episodes of hypoglycemia per year was significantly lower in the vildagliptin group (n=4) than in the control group (n=11) (odds ratio, 0.28; 95% confidence interval, 0.08-0.97; pinsulin treatment for 24months was well tolerated and led to sustained reductions in HbA1c, the dose and number of insulin injections, and the risk of hypoglycemia. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Insulin glargine 300 U/ml in the management of diabetes: clinical utility and patient perspectives

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de Galan BE

2016-10-01

Full Text Available Bastiaan E de Galan Department of Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands Abstract: There is ongoing interest in optimizing basal insulin treatment by developing insulins with a flat pharmacological profile, a long duration of action (typically beyond 24 hours and minimum day-to-day variation. Glargine-300 is a modified form of the long-acting insulin analog glargine in that it has been concentrated at 300 units/mL rather than the conventional 100 units/mL. Glargine-300 has a longer duration of action and a flatter pharmacological profile than original glargine-100. This property allows for more flexibility around the timing of administration, when injected once per day. Open-label studies in patients with diabetes have shown that treatment with glargine-300 achieves comparable glycemic control compared to treatment with glargine-100, albeit with consistently higher insulin requirements. These studies also showed that treatment with glargine-300 was associated with lower risks of nocturnal hypoglycemia in patients with type 2 diabetes, particularly those already on insulin, whereas data are mixed in insulin-naïve patients with type 2 diabetes or in patients with type 1 diabetes. Treatment with glargine-300 did not appear to affect the risk of overall hypoglycemia, whereas studies lacked sufficient power to investigate the effect on the risk of severe hypoglycemia. Future studies need to establish the role of glargine-300 in the treatment of diabetes alongside the other new long-acting insulin analog, insulin degludec, which was recently introduced to the market. Keywords: insulin glargine-300, type 1 diabetes, type 2 diabetes, hypoglycemia, HbA1c, patient-reported outcomes

Insulin-induced enhancement of MCF-7 breast cancer cell response to 5-fluorouracil and cyclophosphamide.

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Agrawal, Siddarth; Łuc, Mateusz; Ziółkowski, Piotr; Agrawal, Anil Kumar; Pielka, Ewa; Walaszek, Kinga; Zduniak, Krzysztof; Woźniak, Marta

2017-06-01

The study was designed to evaluate the potential use of insulin for cancer-specific treatment. Insulin-induced sensitivity of MCF-7 breast cancer cells to chemotherapeutic agents 5-fluorouracil and cyclophosphamide was evaluated. To investigate and establish the possible mechanisms of this phenomenon, we assessed cell proliferation, induction of apoptosis, activation of apoptotic and autophagic pathways, expression of glucose transporters 1 and 3, formation of reactive oxygen species, and wound-healing assay. Additionally, we reviewed the literature regarding theuse of insulin in cancer-specific treatment. We found that insulin increases the cytotoxic effect of 5-fluorouracil and cyclophosphamide in vitro up to two-fold. The effect was linked to enhancement of apoptosis, activation of apoptotic and autophagic pathways, and overexpression of glucose transporters 1 and 3 as well as inhibition of cell proliferation and motility. We propose a model for insulin-induced sensitization process. Insulin acts as a sensitizer of cancer cells to cytotoxic therapy through various mechanisms opening a possibility for metronomic insulin-based treatments.

InsuOnline, an Electronic Game for Medical Education on Insulin Therapy: A Randomized Controlled Trial With Primary Care Physicians.

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Diehl, Leandro Arthur; Souza, Rodrigo Martins; Gordan, Pedro Alejandro; Esteves, Roberto Zonato; Coelho, Izabel Cristina Meister

2017-03-09

Most patients with diabetes mellitus (DM) are followed by primary care physicians, who often lack knowledge or confidence to prescribe insulin properly. This contributes to clinical inertia and poor glycemic control. Effectiveness of traditional continuing medical education (CME) to solve that is limited, so new approaches are required. Electronic games are a good option, as they can be very effective and easily disseminated. The objective of our study was to assess applicability, user acceptance, and educational effectiveness of InsuOnline, an electronic serious game for medical education on insulin therapy for DM, compared with a traditional CME activity. Primary care physicians (PCPs) from South of Brazil were invited by phone or email to participate in an unblinded randomized controlled trial and randomly allocated to play the game InsuOnline, installed as an app in their own computers, at the time of their choice, with minimal or no external guidance, or to participate in a traditional CME session, composed by onsite lectures and cases discussion. Both interventions had the same content and duration (~4 h). Applicability was assessed by the number of subjects who completed the assigned intervention in each group. Insulin-prescribing competence (factual knowledge, problem-solving skills, and attitudes) was self-assessed through a questionnaire applied before, immediately after, and 3 months after the interventions. Acceptance of the intervention (satisfaction and perceived importance for clinical practice) was also assessed immediately after and 3 months after the interventions, respectively. Subjects' characteristics were similar between groups (mean age 38, 51.4% [69/134] male). In the game group, 69 of 88 (78%) completed the intervention, compared with 65 of 73 (89%) in the control group, with no difference in applicability. Percentage of right answers in the competence subscale, which was 52% at the baseline in both groups, significantly improved

Tartary buckwheat flavonoids ameliorate high fructose-induced insulin resistance and oxidative stress associated with the insulin signaling and Nrf2/HO-1 pathways in mice.

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Hu, Yuanyuan; Hou, Zuoxu; Yi, Ruokun; Wang, Zhongming; Sun, Peng; Li, Guijie; Zhao, Xin; Wang, Qiang

2017-08-01

The present study was conducted to explore the effects of a purified tartary buckwheat flavonoid fraction (TBF) on insulin resistance and hepatic oxidative stress in mice fed high fructose in drinking water (20%) for 8 weeks. The results indicated that continuous administration of TBF dose-dependently improved the insulin sensitivity and glucose intolerance in high fructose-fed mice. TBF treatment also reversed the reduced level of insulin action on the phosphorylation of insulin receptor substrate-1 (IRS-1), protein kinase B (Akt) and phosphatidylinositol 3-kinase (PI3K), as well as the translocation of glucose transporter type 4 (GLUT4) in the insulin-resistant liver. Furthermore, TBF was found to exert high antioxidant capacity as it acts as a shield against oxidative stress induced by high fructose by restoring the antioxidant status, and modulating nuclear factor E2 related factor 2 (Nrf2) translocation to the nucleus with subsequently up-regulated antioxidative enzyme protein expression. Histopathological examinations revealed that impaired pancreatic/hepatic tissues were effectively restored in high fructose-fed mice following TBF treatment. Our results show that TBF intake is effective in preventing the conversion of high fructose-induced insulin resistance and hepatic oxidative stress in mice by improving the insulin signaling molecules and the Nrf2 signal pathway in the liver.

[Attitudes toward insulin prescription in type 2 diabetic patients non-compliant with diet therapy].

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Mordenti, F; D'Angiolini, G; Murgia, F

2000-01-01

Investigate the compliance of type 2 diabetic patients with the prescription of insulin according to pre-existing ideas on insulin, and to personality traits. Twenty insulin-treated type 2 diabetic patients were selected on the basis of previous scarce compliance with diet and exercise and BMI > 28 kg/m2. The patients' attitudes toward insulin prescription were evaluated with a semi-structured interview and personality traits were evaluated with the ACL test(Adjective Check List). When insulin was first prescribed to these patients, 65% accepted immediately. However, 45% answered that their acquiescence to insulin treatment was accompanied by doubts or apprehension. The fear of insulin dependence was shared by 50%, with a much greater prevalence among those who resisted to insulin treatment (86% vs 31%) and those who recalled doubts and fears about insulin (73% vs 22%). Patients with a fear of dependence differed significantly from the others in five personality scales: greater opposition and ambiguity, less self-confidence, more inflexible, less demanding of others and more inclined to bargain. The irrational fear of dependence may, therefore, play a role in both the manifest acceptance/rejection of insulin and non-expressed doubts, and may in turn be influenced by personality traits. Specific patient education on insulin treatment in type 2 diabetes is necessary, and should be planned according to the personality factors that may influence the perception of facts and the patients' motivation.

Insulin like growth factor-1/insulin bypasses Pref-1/FA1-mediated inhibition of adipocyte differentiation

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Zhang, Hongbin; Nøhr, Jane; Jensen, Charlotte Harken

2003-01-01

that forced expression of the soluble form, FA1, or full-length Pref-1 did not inhibit adipocyte differentiation of 3T3-L1 cells when differentiation was induced by standard treatment with methylisobutylxanthine, dexamethasone, and high concentrations of insulin. However, forced expression of either form...... of Pref-1/FA1 in 3T3-L1 or 3T3-F442A cells inhibited adipocyte differentiation when insulin or insulin-like growth factor-1 (IGF-1) was omitted from the differentiation mixture. We demonstrate that the level of the mature form of the IGF-1 receptor is reduced and that IGF-1-dependent activation of p42/p44...... mitogen-activated protein kinases (MAPKs) is compromised in preadipocytes with forced expression of Pref-1. This is accompanied by suppression of clonal expansion and terminal differentiation. Accordingly, supplementation with insulin or IGF-1 rescued p42/p44 MAPK activation, clonal expansion...

Interaction of dipalmitoyl phosphatidylcholine (DPPC) liposomes and insulin

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Mady, Mohsen M.; Elshemey, Wael M.

2011-06-01

Insulin, a peptide that has been used for decades in the treatment of diabetes, has well-defined properties and delivery requirements. Liposomes, which are lipid bilayer vesicles, have gained increasing attention as drug carriers which reduce the toxicity and increase the pharmacological activity of various drugs. The molecular interaction between (uncharged lipid) dipalmitoyl phosphatidylcholine (DPPC) liposomes and insulin has been characterized by using Fourier transform infrared spectroscopy (FTIR) and X-ray diffraction. The characteristic protein absorption band peaks, Amide I (at about 1660 cm-1) and Amide II band (at about 1546 cm-1) are potentially reduced in the liposome insulin complex. Wide-angle x-ray scattering measurements showed that the association of insulin with DPPC lipid of liposomes still maintains the characteristic DPPC diffraction peaks with almost no change in relative intensities or change in peak positions. The absence of any shift in protein peak positions after insulin being associated with DPPC liposomes indicates that insulin is successfully forming complex with DPPC liposomes with possibly no pronounced alterations in the structure of insulin molecule.

Increased prevalence of insulin-treated diabetes mellitus in Funen County, Denmark

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Eshøj, O; Green, A; Borch-Johnsen, K

1994-01-01

: There was a significant increase in the prevalence of insulin-treated diabetes mellitus in Funen County, Denmark from 1973 to 1987. Analysis of the data shows that an important factor for this increase is a liability to start insulin treatment of type 2 (non-insulin-dependent) diabetes mellitus at an earlier stage than...

Insulin and vanadium protect against osteoarthritis development secondary to diabetes mellitus in rats.

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El Karib, Abbas O; Al-Ani, Bahjat; Al-Hashem, Fahaid; Dallak, Mohammad; Bin-Jaliah, Ismaeel; El-Gamal, Basiouny; Bashir, Salah O; Eid, Refaat A; Haidara, Mohamed A

2016-07-01

Diabetic complications such as cardiovascular disease and osteoarthritis (OA) are among the common public health problems. The effect of insulin on OA secondary to diabetes has not been investigated before in animal models. Therefore, we sought to determine whether insulin and the insulin-mimicking agent, vanadium can protect from developing OA in diabetic rats. Type 1 diabetes mellitus (T1DM) was induced in Sprague-Dawley rats and treated with insulin and/or vanadium. Tissues harvested from the articular cartilage of the knee joint were examined by scanning electron microscopy, and blood samples were assayed for oxidative stress and inflammatory biomarkers. Eight weeks following the induction of diabetes, a profound damage to the knee joint compared to the control non-diabetic group was observed. Treatment of diabetic rats with insulin and/or vanadium differentially protected from diabetes-induced cartilage damage and deteriorated fibrils of collagen fibers. The relative biological potencies were insulin + vanadium > insulin > vanadium. Furthermore, there was about 2- to 5-fold increase in TNF-α (from 31.02 ± 1.92 to 60.5 ± 1.18 pg/ml, p 1) and IL-6 (from 64.67 ± 8.16 to 338.0 ± 38.9 pg/ml, p 1) cytokines and free radicals measured as TBARS (from 3.21 ± 0.37 to 11.48 ± 1.5 µM, p 1) in the diabetic group, which was significantly reduced with insulin and or vanadium. Meanwhile, SOD decreased (from 17.79 ± 8.9 to 8.250.29, p 1) and was increased with insulin and vanadium. The relative potencies of the treating agents on inflammatory and oxidative stress biomarkers were insulin + vanadium > insulin > vanadium. The present study demonstrates that co-administration of insulin and vanadium to T1DM rats protect against diabetes-induced OA possibly by lowering biomarkers of inflammation and oxidative stress.

Efficacy and safety comparison between liraglutide as add-on therapy to insulin and insulin dose-increase in Chinese subjects with poorly controlled type 2 diabetes and abdominal obesity

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Li Chun-jun

2012-11-01

Full Text Available Abstract Objective To assess the efficacy and safety of adding liraglutide to established insulin therapy in poorly controlled Chinese subjects with type 2 diabetes and abdominal obesity compared with increasing insulin dose. Methods A 12-week, randomized, parallel-group study was carried out. A total of 84 patients completed the trial who had been randomly assigned to either the liraglutide-added group or the insulin-increasing group while continuing current insulin based treatment. Insulin dose was reduced by 0-30% upon the initiation of liraglutide. Insulin doses were subsequently adjusted to optimized glycemic control. Glycosylated hemoglobin (HbA1c values, blood glucose, total daily insulin dose, body weight, waist circumference, and the number of hypoglycemic events and adverse events were evaluated. Results At the end of study, the mean reduction in HbA1c between the liraglutide-added group and the insulin-increasing group was not significantly different (1.9% vs. 1.77%, p>0.05. However, the percentage of subjects reaching the composite endpoint of HbA1c ≤ 7.0% with no weight gain and no hypoglycemia, was significantly higher in the liraglutide-added group than in the insulin-increasing group (67% vs. 19%, p2, p Conclusions Addition of liraglutide to abdominally obese, insulin-treated patients led to improvement in glycemic control similar to that achieved by increasing insulin dosage, but with a lower daily dose of insulin and fewer hypoglycemic events. Adding liraglutide to insulin also induced a significant reduction in body weight and waist circumference. Liraglutide combined with insulin may be the best treatment option for poorly controlled type 2 diabetes and abdominal obesity.

SGLT2 inhibitors – an insulin-independent therapeutic approach for treatment of type 2 diabetes: focus on canagliflozin

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Seufert J

2015-11-01

Full Text Available Jochen SeufertDepartment of Endocrinology and Diabetology, Clinic for Internal Medicine II, Freiburg University Hospital, Freiburg, GermanyAbstract: Despite the availability of a great variety of medications, a significant proportion of people with type 2 diabetes mellitus (T2DM are not able to achieve or maintain adequate glycemic control. Beyond improved glucose control, novel treatments would ideally provide a reduction of cardiovascular risk, with a favorable impact on excess weight, and a low intrinsic hypoglycemia risk, as well as a synergistic mechanism of action for broad combination therapy. With the development of sodium glucose cotransporter 2 (SGLT2 inhibitors, an antidiabetic pharmacologic option has recently become available that comes close to meeting these requirements. For the first time, SGLT2 inhibitors offer a therapeutic approach acting directly on the kidneys without requiring insulin secretion or action. Canagliflozin, dapagliflozin, and empagliflozin are the SGLT2 inhibitors approved to date. Taken once a day, these medications can be combined with all other antidiabetic medications including insulin, due to their insulin-independent mechanism of action, with only a minimal risk of hypoglycemia. SGLT2 inhibitors provide additional reductions in body weight and blood pressure due to the therapeutically induced excretion of glucose and sodium through the kidneys. These "concomitant effects" are particularly interesting with regard to the increased cardiovascular risk in T2DM. In many cases, T2DM treatment requires a multidimensional approach where the treatment goals have to be adapted to the individual patient. While there is a consensus on the use of metformin as a first-line drug therapy, various antidiabetics are used for treatment intensification. New mechanisms of action like that of SGLT2 inhibitors such as canagliflozin, which can be used both in early and late stages of diabetes, are a welcome addition to expand

Detection of transketolase in bone marrow-derived insulin-producing cells: benfotiamine enhances insulin synthesis and glucose metabolism.

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Oh, Seh-Hoon; Witek, Rafal P; Bae, Si-Hyun; Darwiche, Houda; Jung, Youngmi; Pi, Liya; Brown, Alicia; Petersen, Bryon E

2009-01-01

Adult bone marrow (BM)-derived insulin-producing cells (IPCs) are capable of regulating blood glucose levels in chemically induced hyperglycemic mice. Using cell transplantation therapy, fully functional BM-derived IPCs help to mediate treatment of diabetes mellitus. Here, we demonstrate the detection of the pentose phosphate pathway enzyme, transketolase (TK), in BM-derived IPCs cultured under high-glucose conditions. Benfotiamine, a known activator of TK, was not shown to affect the proliferation of insulinoma cell line, INS-1; however, when INS-1 cells were cultured with oxythiamine, an inhibitor of TK, cell proliferation was suppressed. Treatment with benfotiamine activated glucose metabolism in INS-1 cells in high-glucose culture conditions, and appeared to maximize the BM-derived IPCs ability to synthesize insulin. Benfotiamine was not shown to induce the glucose receptor Glut-2, however it was shown to activate glucokinase, the enzyme responsible for conversion of glucose to glucose-6-phosphate. Furthermore, benfotiamine-treated groups showed upregulation of the downstream glycolytic enzyme, glyceraldehyde phosphate dehydrogenase (GAPDH). However, in cells where the pentose phosphate pathway was blocked by oxythiamine treatment, there was a clear downregulation of Glut-2, glucokinase, insulin, and GAPDH. When benfotiamine was used to treat mice transplanted with BM-derived IPCs transplanted, their glucose level was brought to a normal range. The glucose challenge of normal mice treated with benfotiamine lead to rapidly normalized blood glucose levels. These results indicate that benfotiamine activates glucose metabolism and insulin synthesis to prevent glucose toxicity caused by high concentrations of blood glucose in diabetes mellitus.

Detection of Transketolase in Bone Marrow—Derived Insulin-Producing Cells: Benfotiamine Enhances Insulin Synthesis and Glucose Metabolism

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Witek, Rafal P.; Bae, Si-Hyun; Darwiche, Houda; Jung, Youngmi; Pi, Liya; Brown, Alicia; Petersen, Bryon E.

2009-01-01

Adult bone marrow (BM)-derived insulin-producing cells (IPCs) are capable of regulating blood glucose levels in chemically induced hyperglycemic mice. Using cell transplantation therapy, fully functional BM-derived IPCs help to mediate treatment of diabetes mellitus. Here, we demonstrate the detection of the pentose phosphate pathway enzyme, transketolase (TK), in BM-derived IPCs cultured under high-glucose conditions. Benfotiamine, a known activator of TK, was not shown to affect the proliferation of insulinoma cell line, INS-1; however, when INS-1 cells were cultured with oxythiamine, an inhibitor of TK, cell proliferation was suppressed. Treatment with benfotiamine activated glucose metabolism in INS-1 cells in high-glucose culture conditions, and appeared to maximize the BM-derived IPCs ability to synthesize insulin. Benfotiamine was not shown to induce the glucose receptor Glut-2, however it was shown to activate glucokinase, the enzyme responsible for conversion of glucose to glucose-6-phosphate. Furthermore, benfotiamine-treated groups showed upregulation of the downstream glycolytic enzyme, glyceraldehyde phosphate dehydrogenase (GAPDH). However, in cells where the pentose phosphate pathway was blocked by oxythiamine treatment, there was a clear downregulation of Glut-2, glucokinase, insulin, and GAPDH. When benfotiamine was used to treat mice transplanted with BM-derived IPCs transplanted, their glucose level was brought to a normal range. The glucose challenge of normal mice treated with benfotiamine lead to rapidly normalized blood glucose levels. These results indicate that benfotiamine activates glucose metabolism and insulin synthesis to prevent glucose toxicity caused by high concentrations of blood glucose in diabetes mellitus. PMID:18393672

Glucose and insulin dynamics associated with continuous rate infusion of dextrose solution or dextrose solution and insulin in healthy and endotoxin-exposed horses.

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Han, Janet H; McKenzie, Harold C; McCutcheon, L Jill; Geor, Raymond J

2011-04-01

To investigate the effects of a continuous rate infusion (CRI) of dextrose solution or dextrose solution and insulin on glucose and insulin concentrations in healthy and endotoxin-exposed horses. 9 adult mares. During phase 1, treatments consisted of saline (0.9% NaCl) solution (control group; n = 4) or 20% dextrose solution (group 1; 4) administered IV as a 360-minute CRI. During phase 2, treatments consisted of 360-minute CRIs of 20% dextrose solution and insulin administered simultaneously at 367.6 mg/kg/h (30 kcal/kg/d) and 0.07 U/kg/h, respectively, in healthy horses (group 2; n = 4) or horses administered 35 ng of lipopolysaccharide/kg, IV, 24 hours before starting the dextrose solution and insulin CRIs (group 3; 4). A balanced crossover study design was used in both phases. Blood samples were collected for measurement of plasma glucose and insulin concentrations. Infusion of dextrose solution alone resulted in hyperglycemia for most of the 360-minute CRI. Insulin concentration increased significantly in group 1, compared with that in the control group. Mean insulin concentration of group 2 was significantly higher throughout most of the infusion period, compared with concentrations of the control group and group 1. Mean glucose concentration did not differ significantly between groups 2 and 3. Insulin infusion at a rate of 0.07 U/kg/h was found to be effective for the prevention of hyperglycemia when administered concurrently with dextrose solution. This rate was considered to be safe because horses did not become hypoglycemic during infusions of dextrose solution.

Insulin sensitizers prevent fine particulate matter-induced vascular insulin resistance and changes in endothelial progenitor cell homeostasis.

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Haberzettl, Petra; McCracken, James P; Bhatnagar, Aruni; Conklin, Daniel J

2016-06-01

Exposure to fine particular matter (PM2.5) increases the risk of developing cardiovascular disease and Type 2 diabetes. Because blood vessels are sensitive targets of air pollutant exposure, we examined the effects of concentrated ambient PM2.5 (CAP) on vascular insulin sensitivity and circulating levels of endothelial progenitor cells (EPCs), which reflect cardiovascular health. We found that CAP exposure for 9 days decreased insulin-stimulated Akt phosphorylation in the aorta of mice maintained on control diet. This change was accompanied by the induction of IL-1β and increases in the abundance of cleaved IL-18 and p10 subunit of Casp-1, consistent with the activation of the inflammasome pathway. CAP exposure also suppressed circulating levels of EPCs (Flk-1(+)/Sca-1(+) cells), while enhancing the bone marrow abundance of these cells. Although similar changes in vascular insulin signaling and EPC levels were observed in mice fed high-fat diet, CAP exposure did not exacerbate diet-induced changes in vascular insulin resistance or EPC homeostasis. Treatment with an insulin sensitizer, metformin or rosiglitazone, prevented CAP-induced vascular insulin resistance and NF-κB and inflammasome activation and restored peripheral blood and bone marrow EPC levels. These findings suggest that PM2.5 exposure induces diet-independent vascular insulin resistance and inflammation and prevents EPC mobilization, and that this EPC mobilization defect could be mediated by vascular insulin resistance. Impaired vascular insulin sensitivity may be an important mechanism underlying PM2.5-induced vascular injury, and pharmacological sensitization to insulin action could potentially prevent deficits in vascular repair and mitigate vascular inflammation due to exposure to elevated levels of ambient air pollution. Copyright © 2016 the American Physiological Society.

Treatment outcomes after initiation of exenatide twice daily or insulin in clinical practice: 12-month results from CHOICE in six European countries

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Ostenson CG

2013-04-01

Full Text Available Claes-Göran Östenson,1 Stephan Matthaei,2 Matthew Reaney,3 Thure Krarup,4 Bruno Guerci,5 Jacek Kiljanski,6 Carole Salaun-Martin,7 Hélène Sapin,7 David Bruhn,8 Chantal Mathieu,9 Michael Theodorakis10 1Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden; 2Diabetes-Center Quakenbrück, Quakenbrück, Germany; 3Eli Lilly, Windlesham, Surrey, UK; 4Department of Endocrinology I, Bispebjerg Hospital, Copenhagen, Denmark; 5Diabetology, Metabolic Diseases and Nutrition, Brabois Hospital, CHU Nancy, and INSERM CIC, ILCV, Vandoeuvre Lès Nancy, France; 6Eli Lilly, Warsaw, Poland; 7Eli Lilly, Neuilly Cedex, France; 8Eli Lilly, San Diego, California, USA; 9Department of Endocrinology, UZ Gasthuisberg, Leuven, Belgium; 10Department of Clinical Therapeutics, University of Athens School of Medicine, Athens, Greece* *Michael Theodorakis was affiliated with the institution shown at the time of the study, but has since left this institution Objective: The CHanges to treatment and Outcomes in patients with type 2 diabetes initiating InjeCtablE therapy (CHOICE study assessed time to, and reasons for, significant treatment change after patients with type 2 diabetes (T2DM initiated their first injectable glucose-lowering therapy (exenatide twice daily [BID] or insulin in routine clinical practice, and these patients’ clinical outcomes, in six European countries. This paper reports interim data from the first 12 months of the study. Research design and methods: CHOICE (NCT00635492 is a prospective, noninterventional, observational study. Clinical data were collected at initiation of first injectable therapy and after approximately 3, 6, and 12 months. Results: Of 2497 patients enrolled in CHOICE, 1096 in the exenatide BID and 1239 in the insulin cohorts had ≥1 post-baseline assessment and were included in this analysis. Overall, 32.2% of the exenatide BID cohort and 29.1% of the insulin cohort (Kaplan–Meier estimates had

Effects of Steaming Time and Frequency for Manufactured Red Liriope platyphylla on the Insulin Secretion Ability and Insulin Receptor Signaling Pathway.

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Choi, Sun Il; Lee, Hye Ryun; Goo, Jun Seo; Kim, Ji Eun; Nam, So Hee; Hwang, In Sik; Lee, Young Ju; Prak, So Hae; Lee, Hee Seob; Lee, Jong Sup; Jang, In Surk; Son, Hong Ju; Hwang, Dae Youn

2011-06-01

In oriental medicine, Liriope platyphylla (LP) has long been regarded as a curative herb useful for the treatment of diabetes, asthma, and neurodegenerative disorders. The principal objective of this study was to assess the effects of steaming time and frequency for manufactured Red LP (RLP) on insulin secretion ability and insulin receptor signaling pathway. To achieve our goal, several types of LPs manufactured under different conditions were applied to INS cells and streptozotocin (STZ)-induced diabetic ICR mice, after which alterations in insulin concentrations were detected in the culture supernatants and sera. The optimal concentration for the investigation of insulin secretion ability was found to be 50 ug/mL of LP. At this concentration, maximum insulin secretion was observed in the INS cells treated with LP extract steamed for 3 h (3-SLP) with two repeated steps (3 h steaming and 24 h air-dried) carried out 9 times (9-SALP); no significant changes in viability were detected in any of the treated cells. Additionally, the expression and phosphorylation levels of most components in the insulin receptor signaling pathway were increased significantly in the majority of cells treated with steaming-processed LP as compared to the cells treated with LP prepared without steaming. With regard to glucose transporter (GLUT) expression, alterations of steaming time induced similar responses on the expression levels of GLUT-2 and GLUT-3. However, differences in steaming frequency were also shown to induce dose-dependent responses in the expression level of GLUT-2 only; no significant differences in GLUT-3 expression were detected under these conditions. Furthermore, these responses observed in vitro were similarly detected in STZ-induced diabetic mice. 24-SLP and 9-SALP treatment applied for 14 days induced the down-regulation of glucose concentration and upregulation of insulin concentration. Therefore, these results indicated that the steaming processed LP may

Non-insulin drugs to treat hyperglycaemia in type 1 diabetes mellitus

DEFF Research Database (Denmark)

Frandsen, Christian Seerup; Dejgaard, Thomas Fremming; Madsbad, Sten

2016-01-01

Insulin treatment of individuals with type 1 diabetes has shortcomings and many patients do not achieve glycaemic and metabolic targets. Consequently, the focus is on novel non-insulin therapeutic approaches that reduce hyperglycaemia and improve metabolic variables without increasing the risk...... with few participants; evidence for the efficacy of concomitant treatments is scarce and largely clinically insignificant. A subgroup of patients with type 1 diabetes for whom non-insulin antidiabetic drugs could significantly benefit glycaemic control cannot yet be defined, but we suggest that obese...... of hypoglycaemia or other adverse events. Several therapies given in conjunction with insulin have been investigated in clinical trials, including pramlintide, glucagon-like peptide-1 receptor agonists, dipeptidyl peptidase-4 inhibitors, sodium-glucose co-transporter inhibitors, metformin, sulfonylureas...

Association of an APOC3 promoter variant with type 2 diabetes risk and need for insulin treatment in lean persons

NARCIS (Netherlands)

M. van Hoek (Mandy); T.W. van Herpt (Thijs); A. Dehghan (Abbas); A. Hofman (Albert); A. Lieverse (Aloysius); C.M. van Duijn (Cornelia); J.C.M. Witteman (Jacqueline); E.J.G. Sijbrands (Eric)

2011-01-01

textabstractAims/hypothesis: An APOC3 promoter haplotype has been previously associated with type 1 diabetes. In this population-based study, we investigated whether APOC3 polymorphisms increase type 2 diabetes risk and need for insulin treatment in lean participants. Methods: In the Rotterdam

Cold exposure potentiates the effect of insulin on in vivo glucose uptake

International Nuclear Information System (INIS)

Vallerand, A.L.; Perusse, F.; Bukowiecki, L.J.

1987-01-01

The effects of cold exposure and insulin injection on the rates of net 2-[ 3 H]deoxyglucose uptake (K i ) in peripheral tissues were investigated in warm-acclimated rats. Cold exposure and insulin treatment independently increased K i values in skeletal muscles, heart, white adipose tissue, and brown adipose tissue. The effects of cold exposure were particularly evident in brown adipose tissue where the K i increased >100 times. When the two treatments were combined, it was found that cold exposure synergistically enhanced the maximal insulin responses for glucose uptake in brown adipose tissue, all white adipose tissue depots, and skeletal muscles investigated. The results indicate that cold exposure induces an insulin-like effect on K i that does not appear to be specifically associated with shivering thermogenesis in skeletal muscles, because that effect was observed in all insulin-sensitive tissues. The data also demonstrate that cold exposure significantly potentiates the maximal insulin responses for glucose uptake in the same tissues. This potentialization may result from (1) an enhanced responsiveness of peripheral tissues to insulin, possibly occurring at metabolic steps lying beyond the insulin receptor and (2) an increased tissue blood flow augmenting glucose and insulin availability and thereby amplifying glucose uptake

Insulin receptors

International Nuclear Information System (INIS)

Kahn, C.R.; Harrison, L.C.

1988-01-01

This book contains the proceedings on insulin receptors. Part A: Methods for the study of structure and function. Topics covered include: Method for purification and labeling of insulin receptors, the insulin receptor kinase, and insulin receptors on special tissues

Add-on treatment with intermediate-acting insulin versus sliding-scale insulin for patients with type 2 diabetes or insulin resistance during cyclic glucocorticoid-containing antineoplastic chemotherapy: a randomized crossover study

NARCIS (Netherlands)

Gerards, M. C.; de Maar, J. S.; Steenbruggen, T. G.; Hoekstra, J. B. L.; Vriesendorp, T. M.; Gerdes, V. E. A.

2016-01-01

The aim of this study was to compare the effectiveness and safety of intermediate-acting insulin (IMI) titrated on body weight and glucocorticoid dose with that of short-acting sliding-scale insulin (SSI) in patients on recurrent high-dose glucocorticoid-containing chemotherapy. We enrolled 26

Electron beam application in gas waste treatment in China

International Nuclear Information System (INIS)

Wu Haifeng

2003-01-01

In the most recent decade, electron beam waste treatment technology attracted serious attention from environment policymaker and industrial leaders in power industry in China. Starting in middle of 1980's, Chinese research institute began experiment of electron beam treatment on flue gas. By the end of 2000, two 10,000 cubic meters per hour small scale electron beam gas purifying station were established in Sichuang province and Beijing. Several electron beam gas purifying demonstration projects are under construction. With robust economy and strong energy demand, needless to say, in near future, electron beam gas purifying technology will have a bright prospect in China. (author)

Hematopoietic-Derived Galectin-3 Causes Cellular and Systemic Insulin Resistance.

Science.gov (United States)

Li, Pingping; Liu, Shuainan; Lu, Min; Bandyopadhyay, Gautum; Oh, Dayoung; Imamura, Takeshi; Johnson, Andrew M F; Sears, Dorothy; Shen, Zhufang; Cui, Bing; Kong, Lijuan; Hou, Shaocong; Liang, Xiao; Iovino, Salvatore; Watkins, Steven M; Ying, Wei; Osborn, Olivia; Wollam, Joshua; Brenner, Martin; Olefsky, Jerrold M

2016-11-03

In obesity, macrophages and other immune cells accumulate in insulin target tissues, promoting a chronic inflammatory state and insulin resistance. Galectin-3 (Gal3), a lectin mainly secreted by macrophages, is elevated in both obese subjects and mice. Administration of Gal3 to mice causes insulin resistance and glucose intolerance, whereas inhibition of Gal3, through either genetic or pharmacologic loss of function, improved insulin sensitivity in obese mice. In vitro treatment with Gal3 directly enhanced macrophage chemotaxis, reduced insulin-stimulated glucose uptake in myocytes and 3T3-L1 adipocytes and impaired insulin-mediated suppression of glucose output in primary mouse hepatocytes. Importantly, we found that Gal3 can bind directly to the insulin receptor (IR) and inhibit downstream IR signaling. These observations elucidate a novel role for Gal3 in hepatocyte, adipocyte, and myocyte insulin resistance, suggesting that Gal3 can link inflammation to decreased insulin sensitivity. Inhibition of Gal3 could be a new approach to treat insulin resistance. Copyright © 2016 Elsevier Inc. All rights reserved.

Internalization and localization of basal insulin peglispro in cells.

Science.gov (United States)

Moyers, Julie S; Volk, Catherine B; Cao, Julia X C; Zhang, Chen; Ding, Liyun; Kiselyov, Vladislav V; Michael, M Dodson

2017-10-15

Basal insulin peglispro (BIL) is a novel, PEGylated insulin lispro that has a large hydrodynamic size compared with insulin lispro. It has a prolonged duration of action, which is related to a delay in insulin absorption and a reduction in clearance. Given the different physical properties of BIL compared with native insulin and insulin lispro, it is important to assess the cellular internalization characteristics of the molecule. Using immunofluorescent confocal imaging, we compared the cellular internalization and localization patterns of BIL, biosynthetic human insulin, and insulin lispro. We assessed the effects of BIL on internalization of the insulin receptor (IR) and studied cellular clearance of BIL. Co-localization studies using antibodies to either insulin or PEG, and the early endosomal marker EEA1 showed that the overall internalization and subcellular localization pattern of BIL was similar to that of human insulin and insulin lispro; all were rapidly internalized and co-localized with EEA1. During ligand washout for 4 h, concomitant loss of insulin, PEG methoxy group, and PEG backbone immunostaining was observed for BIL, similar to the loss of insulin immunostaining observed for insulin lispro and human insulin. Co-localization studies using an antibody to the lysosomal marker LAMP1 did not reveal evidence of lysosomal localization for insulin lispro, human insulin, BIL, or PEG using either insulin or PEG immunostaining reagents. BIL and human insulin both induced rapid phosphorylation and internalization of human IR. Our findings show that treatment of cells with BIL stimulates internalization and localization of IR to early endosomes. Both the insulin and PEG moieties of BIL undergo a dynamic cellular process of rapid internalization and transport to early endosomes followed by loss of cellular immunostaining in a manner similar to that of insulin lispro and human insulin. The rate of clearance for the insulin lispro portion of BIL was slower than

Comparison of the therapeutic effect between sodium bicarbonate and insulin on acute propafenone toxicity.

Science.gov (United States)

Yi, Hwa Yeon; Lee, Jang Young; Lee, Won Suk; Sung, Won Young; Seo, Sang Won

2014-10-01

Unlike other sodium-channel-blocking antiarrhythmic agents, propafenone has β-blocking effects and calcium-channel-blocking effects. Yi et al recently studied insulin's treatment effect on acute propafenone toxicity in rats. However, because the degree of effectiveness of insulin compared to the previously known antidote sodium bicarbonate (NaHCO3) was not studied, the 2 treatment methods were compared for propafenone intoxication in rats. Rats received intravenous propafenone (36 mg/[kg h]) for 12 minutes. After the induction of toxicity, rats (n = 10 per group) received normal saline solution (NSS), NaHCO3, or insulin with glucose as treatment. Animals in the NSS, NaHCO3, and Insulin groups received an intravenous infusion of 36 mg/(kg h) propafenone until death occurred. For each animal, the mean arterial pressure (MAP, heart rate, PR interval, QRS duration, total hemoglobin, sodium, potassium, potential of hydrogen, bicarbonate, glucose, lactate, and central venous oxygen saturation (Scvo2) were measured and compared among the groups. Survival of the Insulin group was greater than that of the NSS group by log-rank test (P = .021). Sodium bicarbonate prevented the decline of MAP for 55 minutes. In comparison, insulin prevented the decline of MAP and heart rate, and the elongation of the PR interval and QRS duration for 55 minutes (P < .05). Propafenone toxicity led to decreased Ca(2+), potential of hydrogen, and Scvo2 and increased lactate levels. Insulin prevented the decrease of Ca(2+) and Scvo2, whereas NaHCO3 prevented the increase in lactate. Insulin treatment was more effective than NaHCO3 on acute propafenone toxicity in rat. Therefore, when propafenone-induced cardiotoxicity occurs, which is unresponsive to current treatment methods, glucose-insulin infusion may be considered. Copyright © 2014 Elsevier Inc. All rights reserved.

Short-and long-term glucocorticoid treatment enhances insulin signalling in human subcutaneous adipose tissue

OpenAIRE

Gathercole, LL; Morgan, SA; Bujalska, IJ; Stewart, PM; Tomlinson, JW

2011-01-01

Background: Endogenous or exogenous glucocorticoid (GC) excess (Cushing's syndrome) is characterized by increased adiposity and insulin resistance. Although GCs cause global insulin resistance in vivo, we have previously shown that GCs are able to augment insulin action in human adipose tissue, contrasting with their action in skeletal muscle. Cushing's syndrome develops following chronic GC exposure and, in addition, is a state of hyperinsulinemia. Objectives: We have therefore compared the ...

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....

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

Gestational diabetes mellitus (GDM) is associated with an increased prevalence of fetal and maternal complications primarily caused by maternal hyperglycemia, which results in abnormal fetal growth. Diet modification is a common first step in the treatment of GDM, followed by antidiabetic pharmacotherapy if this approach fails. Insulin therapy is generally accepted; however, oral hypoglycemic agents have been used in this population. In this prospective, randomised study, we compared maternal metabolic status after treatment with insulin or metformin. Pregnant women (gestational age: ≥ 20 weeks) with GDM requiring medical hypoglycemic treatment were randomly allocated to the Metformin (n = 35) or Insulin (n = 43) Groups. Maternal metabolic status - assessed by glycated hemoglobin (HBA1c) level, glycemic profile, insulin concentration, Homeostatic Model Assessment - Insulin Resistance index, and lipids - was recorded at booking and throughout pregnancy. The characteristics of the study group were: maternal age 33.5 ± 5.9 years, gestational age at baseline 28.5 ± 3.5 weeks, prepregnancy body mass index (BMI) 32.2 ± 3.5 kg/m(2), HbA1c at baseline 5.6 ± 0.6%, and average daily glycemia 5.9 ± 0.6 mmol/dl. Fasting glycemia at term was significantly lower in the Insulin Group but there were no significant differences in mean daily glycemia, HbA1c and BMI at term between the groups. Longitudinally, there was a small but significant increase in BMI and a significant increase in high-density lipoprotein-cholesterol in the Insulin Group and a significant increase in the atherogenic index of plasma (AIP) and a trend towards higher triglycerides in the Metformin Group. Both fasting and average daily glycemia were significantly reduced following treatment in both groups. No such change was evident for HbA1c. In a relative risk analysis, metformin treatment was associated with an insignificant elevated risk of HbA1c, triglycerides and lipid indices falling within the

Acute insulin resistance mediated by advanced glycation endproducts in severely burned rats.

Science.gov (United States)

Zhang, Xing; Xu, Jie; Cai, Xiaoqing; Ji, Lele; Li, Jia; Cao, Bing; Li, Jun; Hu, Dahai; Li, Yan; Wang, Haichang; Xiong, Lize; Xiao, Ruiping; Gao, Feng

2014-06-01

Hyperglycemia often occurs in severe burns; however, the underlying mechanisms and importance of managing postburn hyperglycemia are not well recognized. This study was designed to investigate the dynamic changes of postburn hyperglycemia and the underlying mechanisms and to evaluate whether early glycemic control is beneficial in severe burns. Prospective, randomized experimental study. Animal research laboratory. Sprague-Dawley rats. Anesthetized rats were subjected to a full-thickness burn injury comprising 40% of the total body surface area and were randomized to receive vehicle, insulin, and a soluble form of receptor for advanced glycation endproducts treatments. An in vitro study was performed on cultured H9C2 cells subjected to vehicle or carboxymethyllysine treatment. We found that blood glucose change presented a distinct pattern with two occurrences of hyperglycemia at 0.5- and 3-hour postburn, respectively. Acute insulin resistance evidenced by impaired insulin signaling and glucose uptake occurred at 3-hour postburn, which was associated with the second hyperglycemia and positively correlated with mortality. Mechanistically, we found that serum carboxymethyllysine, a dominant species of advanced glycation endproducts, increased within 1-hour postburn, preceding the occurrence of insulin resistance. More importantly, treatment of animals with soluble form of receptor for advanced glycation endproducts, blockade of advanced glycation endproducts signaling, alleviated severe burn-induced insulin resistance. In addition, early hyperglycemic control with insulin not only reduced serum carboxymethyllysine but also blunted postburn insulin resistance and reduced mortality. These findings suggest that severe burn-induced insulin resistance is partly at least mediated by serum advanced glycation endproducts and positively correlated with mortality. Early glycemic control with insulin or inhibition of advanced glycation endproducts with soluble form of receptor

Microvascular Recruitment in Insulin Resistance

DEFF Research Database (Denmark)

Sjøberg, Kim Anker

the resonating sound from the microbubbles in the systemic circulation were recorded for determination of microvascular recruitment in designated muscle segments. Results showed that microvascular recruitment increased with insulin stimulation by ~30% in rats and ~40% in humans (study I). Furthermore......, it was observed that muscle contractions increased muscle perfusion rapidly by 3-4 fold and by 1-2 fold compared to basal and insulin, respectively, in both rat and human skeletal muscle (study I). The real-time contrast-enhanced ultrasound method was applied to investigate the vaso-active effect of the incretin...... hormone glucagon-like-peptide-1 (GLP-1) in the microcirculation. Glucagon-like-peptide-1 analogs are drugs used for treatments of insulin resistance and type 2 diabetes but the vascular effects of GLP-1 in vivo are elusive. Here it was shown that GLP-1 rapidly increased the microvascular recruitment...

Improved insulin sensitivity after exercise: focus on insulin signaling

DEFF Research Database (Denmark)

Frøsig, Christian; Richter, Erik

2009-01-01

After a single bout of exercise, the ability of insulin to stimulate glucose uptake is markedly improved locally in the previously active muscles. This makes exercise a potent stimulus counteracting insulin resistance characterizing type 2 diabetes (T2D). It is believed that at least part...... of the mechanism relates to an improved ability of insulin to stimulate translocation of glucose transporters (GLUT4) to the muscle membrane after exercise. How this is accomplished is still unclear; however, an obvious possibility is that exercise interacts with the insulin signaling pathway to GLUT4...... translocation allowing for a more potent insulin response. Parallel to unraveling of the insulin signaling cascade, this has been investigated within the past 25 years. Reviewing existing studies clearly indicates that improved insulin action can occur independent of interactions with proximal insulin signaling...

Treatment with constitutive androstane receptor ligand during pregnancy prevents insulin resistance in offspring from high-fat diet-induced obese pregnant mice.

Science.gov (United States)

Masuyama, Hisashi; Hiramatsu, Yuji

2012-07-15

The constitutive androstane receptor (CAR) has been reported to decrease insulin resistance even during pregnancy, while exposure to a high-fat diet (HFD) in utero in mice can induce a type 2 diabetes phenotype that can be transmitted to the progeny. Therefore, we examined whether treatment with a CAR ligand during pregnancy could prevent hypertension, insulin resistance, and hyperlipidemia in the offspring from HFD-induced obese pregnant mice (OH mice). We employed four groups of offspring from HFD-fed and control diet-fed pregnant mice with or without treatment with a CAR ligand. Treatment with a CAR ligand during pregnancy improved glucose tolerance and the levels of triglyceride and adipocytokine and restored the changes induced by HFD with amelioration of hypertension in the adult OH mice. This treatment also increased adiponectin mRNA expression, suppressed leptin expression in adipose tissues of OH mice, and abolished the effect of HFD on the epigenetic modifications of the genes encoding adiponectin and leptin in the offspring during immaturity and adulthood. Our data suggest that CAR might be a potential therapeutic target to prevent metabolic syndrome in adulthood of offspring exposed to an HFD in utero.

Exenatide with Metformin Ameliorated Visceral Adiposity and Insulin Resistance

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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.

Self-assembled lecithin/chitosan nanoparticles for oral insulin delivery: preparation and functional evaluation

Directory of Open Access Journals (Sweden)

Liu LY

2016-02-01

Full Text Available Liyao Liu, Cuiping Zhou, Xuejun Xia, Yuling Liu State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing Key Laboratory of Drug Delivery Technology and Novel Formulations, Department of Pharmaceutics, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People’s Republic of China Purpose: Here, we investigated the formation and functional properties of self-assembled lecithin/chitosan nanoparticles (L/C NPs loaded with insulin following insulin–phospholipid complex preparation, with the aim of developing a method for oral insulin delivery.Methods: Using a modified solvent-injection method, insulin-loaded L/C NPs were obtained by combining insulin–phospholipid complexes with L/C NPs. The nanoparticle size distribution was determined by dynamic light scattering, and morphologies were analyzed by cryogenic transmission electron microscopy. Fourier transform infrared spectroscopy analysis was used to disclose the molecular mechanism of prepared insulin-loaded L/C NPs. Fast ultrafiltration and a reversed-phase high-performance liquid chromatography assay were used to separate free insulin from insulin entrapped in the L/C NPs, as well as to measure the insulin-entrapment and drug-loading efficiencies. The in vitro release profile was obtained, and in vivo hypoglycemic effects were evaluated in streptozotocin-induced diabetic rats.Results: Our results indicated that insulin-containing L/C NPs had a mean size of 180 nm, an insulin-entrapment efficiency of 94%, and an insulin-loading efficiency of 4.5%. Cryogenic transmission electron microscopy observations of insulin-loaded L/C NPs revealed multilamellar structures with a hollow core, encircled by several bilayers. In vitro analysis revealed that insulin release from L/C NPs depended on the L/C ratio. Insulin-loaded L/C NPs orally administered to streptozotocin-induced diabetic rats exerted a significant

Insulin glargine 300 U/mL for basal insulin therapy in type 1 and type 2 diabetes mellitus

Directory of Open Access Journals (Sweden)

Lau IT

2017-06-01

Full Text Available Ip Tim Lau,1 Ka Fai Lee,2 Wing Yee So,3 Kathryn Tan,4 Vincent Tok Fai Yeung5 1Department of Medicine, Tseung Kwan O Hospital, 2Department of Medicine and Geriatrics, Kwong Wah Hospital, 3Department of Medicine and Therapeutics, Chinese University of Hong Kong, Prince of Wales Hospital, 4Department of Medicine, Queen Mary Hospital, University of Hong Kong, 5Department of Medicine and Geriatrics, Our Lady of Maryknoll Hospital, Hong Kong, China Objective: To review published clinical studies on the efficacy and safety of new insulin glargine 300 units/mL (Gla-300, a new long-acting insulin analog, for the treatment of type 1 and type 2 diabetes mellitus (T1DM, T2DMMaterials and methods: Data sources comprised primary research articles on Gla-300, including pharmacodynamic, pharmacokinetic, and clinical studies.Results: In pharmacodynamic and pharmacokinetic studies, Gla-300 showed a flatter time–action profile and longer duration of action than Gla-100. Noninferiority of Gla-300 versus Gla-100 for lowering of glycated hemoglobin was demonstrated in Phase III clinical studies covering a range of T1DM and T2DM patient populations. Over 6–12 months of follow-up, Gla-300 consistently showed comparable glycemic efficacy with less hypoglycemia vs Gla-100, even during the first 8 weeks of treatment. Although titrated insulin doses were 11%–17% higher with Gla-300 vs Gla-100, changes in body weight were similar or favored Gla-300.Conclusion: Clinical studies provide evidence that the pharmacodynamic and pharmacokinetic properties of Gla-300 may translate into clinical benefits in both T1DM and T2DM. Gla-300 may provide a new option for people initiating basal insulin, those requiring higher basal insulin doses, those with T1DM, and those who may be at increased risk for hypoglycemia, such as people with chronic kidney disease, the elderly, and those with cardiovascular comorbidities. Keywords: diabetes mellitus, long-acting insulin, insulin glargine

Insulin regimens and insulin adjustments in diabetic children, adolescents and young adults: personal experience.

Science.gov (United States)

Dorchy, H

2000-12-01

Because recent multicenter studies, even those performed in developed countries without financial restriction, show that treatment of childhood diabetes is inadequate in general and that levels of glycated hemoglobin (HbA1c) are very different, diabetes treatment teams should individually explore the reasons for failure, without any prejudice or bias. The "good" treatment is signed by good HbA1c associated with good quality of life, and is not necessarily exportable without adjustment to the local way of life. HbA1c must be under 7%, if the upper normal limit is about 6%, which is possible, in our experience, even in diabetic children and adolescents. Our "recipes" are summarized. The number of daily insulin injections, 2 or 4, by itself does not necessarily give better results, but the 4-injection regimen allows greater freedom, taking into account that the proper insulin adjustment is difficult before adolescence. Successful glycemic control in young patients depends mainly on the quality and intensity of diabetes education. Any dogmatism must be avoided; only the objective result is important.

Reduction of insulinotropic properties of GLP-1 and GIP after glucocorticoid-induced insulin resistance

DEFF Research Database (Denmark)

Eriksen, Marie; Jensen, David H; Tribler, Siri

2015-01-01

. In addition, first-phase insulin responses were determined at 7 mmol/l and 15 mmol/l and second-phase insulin responses at 7 mmol/l. RESULTS: After dexamethasone treatment, all 19 participants had increased insulin resistance (HOMA-IR and insulin sensitivity index [M/I] values) and 2 h plasma glucose...

Combination therapy in type 2 diabetes mellitus: adding empagliflozin to basal insulin

Directory of Open Access Journals (Sweden)

Andrew Ahmann

2015-11-01

Full Text Available Type 2 diabetes mellitus (T2DM management is complex, with few patients successfully achieving recommended glycemic targets with monotherapy, most progressing to combination therapy, and many eventually requiring insulin. Sodium glucose cotransporter 2 (SGLT2 inhibitors are an emerging class of antidiabetes agents with an insulin-independent mechanism of action, making them suitable for use in combination with any other class of antidiabetes agents, including insulin. This review evaluates a 78-week, randomized, double-blind, placebo-controlled trial investigating the impact of empagliflozin, an SGLT2 inhibitor, as add-on to basal insulin in patients with inadequate glycemic control on basal insulin, with or without metformin and/or a sulfonylurea. Empagliflozin added on to basal insulin resulted in significant and sustained reductions in glycated hemoglobin (HbA1c levels compared with placebo. Empagliflozin has previously been shown to induce weight loss, and was associated with sustained weight loss in this study. This combination therapy was well tolerated, with similar levels of hypoglycemic adverse events in the empagliflozin and placebo groups over the 78-week treatment period. Urinary tract infections and genital infections, side effects associated with SGLT2 inhibitors, were reported more commonly in the empagliflozin group; however, such events led to treatment discontinuation in very few patients. These findings suggest that, with their complementary mechanisms of action, empagliflozin added on to basal insulin may be a useful treatment option in patients on basal insulin who need additional glycemic control without weight gain.

A novel insulin resistance index to monitor changes in insulin sensitivity and glucose tolerance: the ACT NOW study.

Science.gov (United States)

Tripathy, Devjit; Cobb, Jeff E; Gall, Walter; Adam, Klaus-Peter; George, Tabitha; Schwenke, Dawn C; Banerji, MaryAnn; Bray, George A; Buchanan, Thomas A; Clement, Stephen C; Henry, Robert R; Kitabchi, Abbas E; Mudaliar, Sunder; Ratner, Robert E; Stentz, Frankie B; Reaven, Peter D; Musi, Nicolas; Ferrannini, Ele; DeFronzo, Ralph A

2015-05-01

The objective was to test the clinical utility of Quantose M(Q) to monitor changes in insulin sensitivity after pioglitazone therapy in prediabetic subjects. Quantose M(Q) is derived from fasting measurements of insulin, α-hydroxybutyrate, linoleoyl-glycerophosphocholine, and oleate, three nonglucose metabolites shown to correlate with insulin-stimulated glucose disposal. Participants were 428 of the total of 602 ACT NOW impaired glucose tolerance (IGT) subjects randomized to pioglitazone (45 mg/d) or placebo and followed for 2.4 years. At baseline and study end, fasting plasma metabolites required for determination of Quantose, glycated hemoglobin, and oral glucose tolerance test with frequent plasma insulin and glucose measurements to calculate the Matsuda index of insulin sensitivity were obtained. Pioglitazone treatment lowered IGT conversion to diabetes (hazard ratio = 0.25; 95% confidence interval = 0.13-0.50; P < .0001). Although glycated hemoglobin did not track with insulin sensitivity, Quantose M(Q) increased in pioglitazone-treated subjects (by 1.45 [3.45] mg·min(-1)·kgwbm(-1)) (median [interquartile range]) (P < .001 vs placebo), as did the Matsuda index (by 3.05 [4.77] units; P < .0001). Quantose M(Q) correlated with the Matsuda index at baseline and change in the Matsuda index from baseline (rho, 0.85 and 0.79, respectively; P < .0001) and was progressively higher across closeout glucose tolerance status (diabetes, IGT, normal glucose tolerance). In logistic models including only anthropometric and fasting measurements, Quantose M(Q) outperformed both Matsuda and fasting insulin in predicting incident diabetes. In IGT subjects, Quantose M(Q) parallels changes in insulin sensitivity and glucose tolerance with pioglitazone therapy. Due to its strong correlation with improved insulin sensitivity and its ease of use, Quantose M(Q) may serve as a useful clinical test to identify and monitor therapy in insulin-resistant patients.

Electron-beam and microwave treatment of some microbial strains

International Nuclear Information System (INIS)