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.

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.

Is the sex hormone binding globulin related to preeclampsia independent of insulin resistance

International Nuclear Information System (INIS)

Rahmanian, M.; Salari, Z.; Mirmohammadkhani, M.; Ghorbani, R.

2014-01-01

Objective: To evaluate the association between Sex Hormone Binding Globulin and preeclampsia in Iranian women considering the probable confounding effect of insulin resistance. Methods: The case-control study was conducted at the Semnan University of Medical Sciences, Iran, and comprised pregnant women who received prenatal care at Amiralmomenin Hospital in 2011. Cases represented patients admitted because of preeclampsia, while controls were randomly selected eligible pregnant women without hypertension and/or proteinuria. Fasting blood sugar and insulin were assessed for all participants as well as their blood concentration of Sex Hormone Binding Globulin. The Homeostasis Model Assessment of Insulin Resistance Score was used. The correlation between dependant and independent variables was reported by crude and adjusted odds ratio applying logistic regression models. SPSS 16.0 was used for statistical analysis. Results: Of the 100 pregnant women in the study, 45(45%) were cases. Insulin resistance was found to be significantly more frequent in the cases compared to the controls (adjusted odds ratio=2.78; 95% Confidence Interval: 1.11, 6.90; p<0.01). There was a significant reverse correlation between level of Sex Hormone Binding Globulin in blood and being a case of preeclampsia (adjusted odds ratio=0.99; 95% Confidence Interval: 0.98, 1.00; p=0.04). Conclusion: Independent of insulin resistance, every 1nmol/l increase in Sex Hormone Binding Globulin, decreases the odds of preeclampsia by 1%, notifying Sex Hormone Binding Globulin as an important biomarker about its etiology and prediction. (author)

Independent Benefits of Meeting the 2008 Physical Activity Guidelines to Insulin Resistance in Obese Latino Children

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Nazrat Mirza

2012-01-01

Full Text Available We examined the independent association between moderate-to-vigorous physical activity (MVPA and insulin resistance (IR among obese Latino children (N=113; 7–15 years who were enrolled in a community-based obesity intervention. Baseline information on physical activity was gathered by self-report. Clinical assessments of body composition, resting energy expenditure (REE, as well as glucose and insulin responses to an oral glucose tolerance test (OGTT were performed after an overnight fast. Insulin resistance was defined as a 2 h insulin concentration >57 μU·mL-1. We observed that those obese children who met the 2008 Guidelines for MVPA (≥60 min/day experienced a significantly lower odds of IR compared with those not meeting the Guidelines (OR=0.29; 95% CI: (0.10–0.92 and these findings were independent of age, sex, pubertal stage, acculturation, fasting insulin, and 2 h glucose concentrations. Efforts to promote 60 min or more of daily MVPA among children from ethnic minority and high-risk communities should assume primary public health importance.

Liraglutide, but not vildagliptin, restores normoglycaemia and insulin content in the animal model of type 2 diabetes, Psammomys obesus

DEFF Research Database (Denmark)

Vedtofte, Louise; Bodvarsdottir, Thóra B; Gotfredsen, Carsten F

2010-01-01

In order to investigate the effect and mechanism of liraglutide and vildagliptin in diabetic Psammomys obesus, we examined proliferation and apoptosis of beta-cells, beta-cell mass (BCM), and pancreatic insulin content after zero, six and fourteen days of treatment compared to control groups. One......, compared to the vehicle-treated animals pancreatic insulin content was normalized in animals treated for six and fourteen days with liraglutide. In contrast, vildagliptin, in doses causing full inhibition of plasma DPP-IV activity, neither reduced blood glucose nor altered HED-induced increases in BCM...... or pancreatic insulin content. These results suggest that liraglutide restores normoglycaemia and improves glycaemic control in P. obesus by increasing their insulin content and improving the function of the beta-cells. In contrast, vildagliptin does not improve glycaemic control in P. obesus nor affect beta...

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.

Obstructive sleep apnoea is independently associated with the metabolic syndrome but not insulin resistance state

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Sithole J

2006-11-01

Full Text Available Abstract Obstructive sleep apnoea (OSA is a cardio-metabolic disorder. Whether metabolic syndrome (MS, insulin resistance (IR and albuminuria are independently associated with OSA is unclear, but defining the interactions between OSA and various cardiovascular (CV risk factors independent of obesity facilitates the development of therapeutic strategies to mitigate their increased CV risks. We prospectively recruited 38 subjects with OSA and 41 controls. Anthropometric measurements, glucose, lipids, insulin and blood pressure (BP were measured after an overnight fast. IR state was defined as homeostasis model assessment (HOMA value >3.99 and MS diagnosed according to the International Diabetes Federation (IDF criteria. Subjects with OSA were more obese, more insulin resistant, more hyperglycaemic, had higher Epworth score (measure of day time somnolence and systolic blood pressure levels. The prevalence of MS was higher in OSA compared with non-OSA subjects (74% vs 24%, p 103 cm would predict MS in patients with OSA at 75–78% sensitivity and 61–64% specificity. The agreement between MS and IR state in this cohort is poor. Thus, OSA is associated with MS independent of obesity predominantly due to increased triglyceride, glucose and Epworth score values but not IR or microalbuminuria status. This observation suggests an alternative pathogenic factor mediating the increased cardiovascular risk in patients with OSA and MS, other than that due to IR. The independent link between Epworth score and MS in patients with OSA implicates the role of daytime sleepiness and chronic hypoxia as a potential mediator. Given the discordant between MS and IR state, measurement of waist is useful for predicting mainly MS but not insulin resistance status in patients with OSA. Appropriate pharmacological intervention targeting these independent factors is important in reducing the increased CV risks among patients with OSA.

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.

Insulin replacement restores the vesicular secretory apparatus in the diabetic rat lacrimal gland

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Ana Carolina Dias

2015-06-01

Full Text Available ABSTRACT Purpose: In the lacrimal gland (LG acinar cells, signaling regulates the release of secretory vesicles through specific Rab and SNARE exocytotic proteins. In diabetes mellitus (DM, the LGs are dysfunctional. The aim of this work was to determine if secretory apparatus changes were associated with any effects on the secretory vesicles (SV in diabetic rats as well as the expression levels of constituent Rab and members of the SNARE family, and if insulin supplementation reversed those changes. Methods: DM was induced in male Wistar rats with an intravenous dose of streptozotocin (60 mg/kg. One of the two diabetic groups was then treated every other day with insulin (1 IU. A third control group was injected with vehicle. After 10 weeks, Western blotting and RT-PCR were used to compared the Rab and SNARE secretory factor levels in the LGs. Transmission electron microscopy evaluated acinar cell SV density and integrity. Results: In the diabetes mellitus group, there were fewer and enlarged SV. The Rab 27b, Rab 3d, and syntaxin-1 protein expression declined in the rats with diabetes mellitus. Insulin treatment restored the SV density and the Rab 27b and syntaxin expression to their control protein levels, whereas the Vamp 2 mRNA expression increased above the control levels. Conclusions: Diabetes mellitus LG changes were associated with the declines in protein expression levels that were involved in supporting exocytosis and vesicular formation. They were partially reversed by insulin replacement therapy. These findings may help to improve therapeutic management of dry eye in diabetes mellitus.

Restoration of muscle mitochondrial function and metabolic flexibility in type 2 diabetes by exercise training is paralleled by increased myocellular fat storage and improved insulin sensitivity.

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Meex, Ruth C R; Schrauwen-Hinderling, Vera B; Moonen-Kornips, Esther; Schaart, Gert; Mensink, Marco; Phielix, Esther; van de Weijer, Tineke; Sels, Jean-Pierre; Schrauwen, Patrick; Hesselink, Matthijs K C

2010-03-01

Mitochondrial dysfunction and fat accumulation in skeletal muscle (increased intramyocellular lipid [IMCL]) have been linked to development of type 2 diabetes. We examined whether exercise training could restore mitochondrial function and insulin sensitivity in patients with type 2 diabetes. Eighteen male type 2 diabetic and 20 healthy male control subjects of comparable body weight, BMI, age, and VO2max participated in a 12-week combined progressive training program (three times per week and 45 min per session). In vivo mitochondrial function (assessed via magnetic resonance spectroscopy), insulin sensitivity (clamp), metabolic flexibility (indirect calorimetry), and IMCL content (histochemically) were measured before and after training. Mitochondrial function was lower in type 2 diabetic compared with control subjects (P = 0.03), improved by training in control subjects (28% increase; P = 0.02), and restored to control values in type 2 diabetic subjects (48% increase; P type 2 diabetic subjects (delta Rd 63% increase; P type 2 diabetic subjects was restored (delta respiratory exchange ratio 63% increase; P = 0.01) but was unchanged in control subjects (delta respiratory exchange ratio 7% increase; P = 0.22). Starting with comparable pretraining IMCL levels, training tended to increase IMCL content in type 2 diabetic subjects (27% increase; P = 0.10), especially in type 2 muscle fibers. Exercise training restored in vivo mitochondrial function in type 2 diabetic subjects. Insulin-mediated glucose disposal and metabolic flexibility improved in type 2 diabetic subjects in the face of near-significantly increased IMCL content. This indicates that increased capacity to store IMCL and restoration of improved mitochondrial function contribute to improved muscle insulin sensitivity.

Insulin resistance in Chinese patients with type 2 diabetes is associated with C-reactive protein independent of abdominal obesity

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Feng Xiaocheng

2010-12-01

Full Text Available Abstract Background There is debate as to whether the association between C-reactive protein (CRP and insulin resistance is independent of body fatness, particularly central obesity. Therefore, the association among CRP, insulin resistance and obesity was analyzed in Chinese patients with type 2 diabetes. Methods The study included 520 Chinese patients diagnosed with type 2 diabetes with CRP levels not exceeding 10 mg/L. The degree of insulin resistance was determined with the homeostasis model assessment of insulin resistance (HOMA-IR. The CRP levels were categorized into quartiles from the lowest to the highest concentrations (Q1-Q4. Results Body mass index (BMI and waist circumference (WC were both higher in Q4, Q3 and Q2 than those in Q1. HOMA-IR was higher in Q2, Q3 and Q4 than that in Q1 (Q1 vs Q4, P Conclusion These findings showed that insulin resistance was associated with CRP levels independent of abdominal obesity in Chinese patients with type 2 diabetes, suggesting that abdominal obesity could only partly explain the link between subclinical inflammation and insulin resistance.

Islet oxygen consumption rate (OCR) dose predicts insulin independence for first clinical islet allotransplants

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Kitzmann, JP; O’Gorman, D; Kin, T; Gruessner, AC; Senior, P; Imes, S; Gruessner, RW; Shapiro, AMJ; Papas, KK

2014-01-01

Human islet allotransplant (ITx) for the treatment of type 1 diabetes is in phase III clinical registration trials in the US and standard of care in several other countries. Current islet product release criteria include viability based on cell membrane integrity stains, glucose stimulated insulin release (GSIR), and islet equivalent (IE) dose based on counts. However, only a fraction of patients transplanted with islets that meet or exceed these release criteria become insulin independent following one transplant. Measurements of islet oxygen consumption rate (OCR) have been reported as highly predictive of transplant outcome in many models. In this paper we report on the assessment of clinical islet allograft preparations using islet oxygen consumption rate (OCR) dose (or viable IE dose) and current product release assays in a series of 13 first transplant recipients. The predictive capability of each assay was examined and successful graft function was defined as 100% insulin independence within 45 days post-transplant. Results showed that OCR dose was most predictive of CTO. IE dose was also highly predictive, while GSIR and membrane integrity stains were not. In conclusion, OCR dose can predict CTO with high specificity and sensitivity and is a useful tool for evaluating islet preparations prior to clinical ITx. PMID:25131089

Turmeric improves post-prandial working memory in pre-diabetes independent of insulin.

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Lee, Meei-Shyuan; Wahlqvist, Mark L; Chou, Yu-Ching; Fang, Wen-Hui; Lee, Jiunn-Tay; Kuan, Jen-Chun; Liu, Hsiao-Yu; Lu, Ting-Mei; Xiu, Lili; Hsu, Chih-Cheng; Andrews, Zane B; Pan, Wen-Harn

2014-01-01

Cognitive impairment develops with pre-diabetes and dementia is a complication of diabetes. Natural products like turmeric and cinnamon may ameliorate the underlying pathogenesis. People ≥ 60 years (n=48) with newly-recognised untreated pre-diabetes were randomised to a double-blind metabolic study of placebo, turmeric (1 g), cinnamon (2 g) or both (1 g & 2 g respectively), ingested at a white bread (119 g) breakfast. Observations were made over 6 hours for pre- and post-working memory (WM), glycaemic and insulin responses and biomarkers of Alzheimer's disease (AD)(0, 2, 4 and 6 hours): amyloid precursor protein (APP), γ-secretase subunits presenilin-1 (PS1), presenilin-2 (PS2), and glycogen synthase kinase (GSK-3β). Differences between natural product users and non-users were determined by Students t and chi square tests; and between pre-test and post-test WM by Wilcoxon signed rank tests. Interaction between turmeric and cinnamon was tested by 2-way ANOVA. Multivariable linear regression (MLR) took account of BMI, glycaemia, insulin and AD biomarkers in the WM responses to turmeric and cinnamon. No interaction between turmeric and cinnamon was detected. WM increased from 2.6 to 2.9 out of 3.0 (p=0.05) with turmeric, but was unchanged with cinnamon. WM improvement was inversely associated with insulin resistance (r=-0.418, pturmeric were best predicted with an R2 of 34.5%; and with significant turmeric, BMI and insulin/glucose AUC beta-coefficients. Co-ingestion of turmeric with white bread increases working memory independent of body fatness, glycaemia, insulin, or AD biomarkers.

N-stearoylethanolamine restores pancreas lipid composition in obesity-induced insulin resistant rats.

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Onopchenko, Oleksandra V; Kosiakova, Galina V; Oz, Murat; Klimashevsky, Vitaliy M; Gula, Nadiya M

2015-01-01

This study investigates the protective effect of N-stearoylethanolamine (NSE), a bioactive N-acylethanolamine , on the lipid profile distribution in the pancreas of obesity-induced insulin resistant (IR) rats fed with prolonged high fat diet (58% of fat for 6 months). The phospholipid composition was determined using 2D thin-layer chromatography. The level of individual phospholipids was estimated by measuring inorganic phosphorus content. The fatty acid (FA) composition and cholesterol level were investigated by gas-liquid chromatography. Compared to controls, plasma levels of triglycerides and insulin were significantly increased in IR rats. The pancreas lipid composition indicated a significant reduction of the free cholesterol level and some phospholipids such as phosphatidylcholine (PtdCho), phosphatidylethanolamine (PtdEtn), phosphatidylinositol (PtdIns), phosphatidylserine (PtdSer) compared to controls. Moreover, the FA composition of pancreas showed a significant redistribution of the main FA (18:1n-9, 18:2n-6, 18:3n-6 and 20:4n-6) levels between phospholipid, free FA, triglyceride fractions under IR conditions that was accompanied by a change in the estimated activities of Δ9-, Δ6-, Δ5-desaturase. Administration of N-stearoylethanolamine (NSE, 50 mg/kg daily per os for 2 weeks) IR rats triggered an increase in the content of free cholesterol, PtdCho and normalization of PtdEtn, PtdSer level. Furthermore, the NSE modulated the activity of desaturases, thus influenced FA composition and restored the FA ratios in the lipid fractions. These NSE-induced changes were associated with a normalization of plasma triglyceride content, considerable decrease of insulin and index HOMA-IR level in rats under IR conditions.

Vitamin D insufficiency is associated with insulin resistance independently of obesity in primary schoolchildren. The healthy growth study.

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Moschonis, George; Androutsos, Odysseas; Hulshof, Toine; Dracopoulou, Maria; Chrousos, George P; Manios, Yannis

2018-04-02

To explore the associations of vitamin D status and obesity with insulin resistance (IR) in children. A sample of 2282 schoolchildren (9-13 years old) in Greece was examined. Sociodemographic, anthropometric (weight, height), biochemical (fasting plasma glucose, serum insulin and 25(OH)D), pubertal status and physical activity data were collected, using standard methods. The "Vitamin D Standardization Program" protocol was applied to standardize serum 25(OH)D values. The prevalence of vitamin D insufficiency (serum 25(OH)D < 50 nmol/L) was higher in obese children compared to their over- and normal-weight counterparts (60.5% vs 51.6% and 51%, P = .017). Furthermore, children with IR (both obese and non-obese) had higher prevalence of vitamin D insufficiency compared to non-obese, non-insulin resistant children (66% and 59.2% vs 49.8%, P < .05), possibly indicating that IR is associated with vitamin D insufficiency, independently of obesity. In line with the above, the results from logistic regression analyses controlled for several potential confounders, showed a 1.48 (95% C.I: 1.2-1.84) higher likelihood for vitamin D insufficiency for insulin resistant children compared to the non-insulin resistant ones, while no significant association was observed with obesity. The present study revealed a high prevalence of vitamin D insufficiency among schoolchildren in Greece, particularly among obese and insulin resistant ones. In addition, it highlighted that the significant association of vitamin D insufficiency with IR is possibly independent of obesity. Further clinical trials are needed to confirm this possible independent association but also explore the potential beneficial effect of vitamin D supplementation on IR and possibly on weight management too. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

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.

Stimulation of muscle protein synthesis by somatotropin in pigs is independent of the somatotropin-induced increase in circulating insulin.

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Wilson, Fiona A; Orellana, Renán A; Suryawan, Agus; Nguyen, Hanh V; Jeyapalan, Asumthia S; Frank, Jason; Davis, Teresa A

2008-07-01

Chronic treatment of growing pigs with porcine somatotropin (pST) promotes protein synthesis and doubles postprandial levels of insulin, a hormone that stimulates translation initiation. This study aimed to determine whether the pST-induced increase in skeletal muscle protein synthesis was mediated through an insulin-induced stimulation of translation initiation. After 7-10 days of pST (150 microg x kg(-1) x day(-1)) or control saline treatment, pancreatic glucose-amino acid clamps were performed in overnight-fasted pigs to reproduce 1) fasted (5 microU/ml), 2) fed control (25 microU/ml), and 3) fed pST-treated (50 microU/ml) insulin levels while glucose and amino acids were maintained at baseline fasting levels. Fractional protein synthesis rates and indexes of translation initiation were examined in skeletal muscle. Effectiveness of pST treatment was confirmed by reduced urea nitrogen and elevated insulin-like growth factor I levels in plasma. Skeletal muscle protein synthesis was independently increased by both insulin and pST. Insulin increased the phosphorylation of protein kinase B and the downstream effectors of the mammalian target of rapamycin, ribosomal protein S6 kinase, and eukaryotic initiation factor (eIF)4E-binding protein-1 (4E-BP1). Furthermore, insulin reduced inactive 4E-BP1.eIF4E complex association and increased active eIF4E.eIF4G complex formation, indicating enhanced eIF4F complex assembly. However, pST treatment did not alter translation initiation factor activation. We conclude that the pST-induced stimulation of skeletal muscle protein synthesis in growing pigs is independent of the insulin-associated activation of translation initiation.

Benefits of combination of insulin degludec and liraglutide are independent of baseline glycated haemoglobin level and duration of type 2 diabetes

DEFF Research Database (Denmark)

Rodbard, Helena W; Buse, John B; Woo, Vincent C

2016-01-01

liraglutide, irrespective of baseline HbA1c. In DUAL II, insulin dose and hypoglycaemia rate were similar with IDegLira and IDeg (maximum dose limited to 50 U) independent of baseline HbA1c. The reduction in HbA1c with IDegLira was independent of disease duration and previous insulin dose but varied depending...... of disease progression stage including baseline glycated haemoglobin (HbA1c), disease duration and previous insulin dose. RESULTS: Across four categories of baseline HbA1c (≤7.5-9.0%), HbA1c reductions were significantly greater with IDegLira (1.1-2.5%) compared with IDeg or liraglutide alone in DUAL I...

Objectively measured sedentary time may predict insulin resistance independent of moderate- and vigorous-intensity physical activity

NARCIS (Netherlands)

Helmerhorst, Hendrik J. F.; Wijndaele, Katrien; Brage, Søren; Wareham, Nicholas J.; Ekelund, Ulf

2009-01-01

To examine the prospective association between objectively measured time spent sedentary and insulin resistance and whether this association is independent of moderate- and vigorous-intensity physical activity (MVPA) and other relevant confounders. This was a population-based study (Medical Research

Use of radioimmunoassay to study secretory potentialities of β-cells in patients with insulin-independent diabetes mellitus

International Nuclear Information System (INIS)

Balabolkin, M.I.; Sharapov, A.N.

1984-01-01

The nature of insulin and C-peptides secretion in 21 patient with insulin-independent diabetes mellitus (IIDM) with different acetilating phenotype in the course of intravenous glucose loadin is studied by means of the radioimmunoassay. In all patients a different nature of insulin secretion during the first stage is revealed. In the group of fast acetilators an increase in the immuno-reactive insulin (IRI) concentration in the blood serum has been observed, more strongly pronounced in patients with accompanying obesity, whereas in the group of slow acetilators a regular decrease in the IRI level is revealed during this period. The nature of C-peptides secretion in patients with the second type of diabetes mellitus with different acetilator phenotype repeats in the main the IRI dynamics characteristic of fast and slow acetilators. In patients with IIDM with obesity belonging to fast acetilators, the nature of C-peptide secretion has dynamics with differing from IRI

Impact of anti-insulin antibodies on islet transplantation outcome: data from the GRAGIL Network.

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Lablanche, Sandrine; Borot, Sophie; Thaunat, Olivier; Bayle, Francois; Badet, Lionel; Morelon, Emmanuel; Thivolet, Charles; Wojtusciszyn, Anne; Frimat, Luc; Kessler, Laurence; Penfornis, Alfred; Brault, Coralie; Colin, Cyrille; Bosco, Domenico; Berney, Thierry; Benhamou, Pierre Y

2014-08-27

In patients with type 1 diabetes, insulin antibodies (IA), altering the pharmacokinetics of circulating insulin, might be associated with high glucose concentration, prolonged hypoglycemia, and higher insulin requirement. The impact of IA on islet transplantation has never been explored. Our aim was to evaluate islet transplantation results at 1 year according to the presence of IA. Our work is a retrospective, case-control study, comparing IA-negative and IA-positive patients among the cohort of patients with type 1 diabetes transplanted within the Swiss-French GRAGIL network between 2003 and 2010. Data about IA were available for 17 patients. Before islet transplantation, 10 patients (59%) were screened positive for IA. At 12 months after transplantation, IA-positive patients reached insulin independence less frequently than IA-negative patients (cumulative incidence of insulin independence, 22.2% vs. 71.4%; P=0.02); β score was ≥7 in 43% of IA-negative patients versus 0% in IA-positive patients (P=0.022). When comparing IA-positive patients with IA-negative patients, insulin dose was 0.15 U/kg (0.10-0.18 U/kg) versus 0.01 U/kg (0-0.09 U/kg) (P=0.2); HbA1c was 6.1% (5.8%-6.3%) versus 6.1% (5.9%-6.8%) (P=0.16); basal C-peptide level was 460 ρmol/L (350-510 ρmol/L) versus 265 ρmol/L (177-405 ρmol/L) (P=0.28); occurrence of hypoglycemia was 12.5% versus 16.5% (P=0.9); and homeostatic model assessment insulin resistance was 1.25 (1-2.4) versus 0.7 (0.52-0.92) (P=0.01). After islet transplantation, IA-positive patients achieved insulin independence less frequently, exhibiting lower β score and higher homeostatic model assessment insulin resistance compared with IA-negative patients. However, in both groups, islet transplantation restored good glycemic control and drastically reduced hypoglycemia and insulin requirements.

Antidiabetic activity of Kalanchoe pinnata in streptozotocin-induced diabetic rats by glucose independent insulin secretagogue action.

Science.gov (United States)

Patil, Swapnil B; Dongare, Vandana R; Kulkarni, Chaitanya R; Joglekar, Madhav M; Arvindekar, Akalpita U

2013-11-01

Kalanchoe pinnata Lam. (Crassulaceae) is used as a traditional medicine worldwide to treat several ailments, including diabetes. However, the mechanism for the antihyperglycemic action is unknown. The present study evaluates the antihyperglycemic and insulin secretagogue potential of Kalanchoe pinnata and assessment of the probable mechanism of action. Steam distillate of Kalanchoe pinnata leaves was subjected to solvent fractionation and antidiabetic activity was detected in dichloromethane (DCM) fraction. In the in vivo studies, rats were treated with 5 and 10 mg/kg body weight of DCM fraction for 45 days orally. Lipid profile and other biochemical parameters were estimated. The probable mechanism for insulin secretagogue action was evaluated through studies using diazoxide and nifedipine. The bioactive component from DCM fraction was studied using HPTLC, GCMS and IR. Fasting blood glucose values were reduced to 116 mg/dl from 228 mg/dl on treatment with 10 mg/kg body weight of DCM fraction, while glycated hemoglobin improved to 8.4% compared with 12.9% in diabetic controls. The insulin level and lipid profile values were close to normal values. In vitro studies demonstrated a dose-dependent insulin secretagogue action. Insulin secretion was 3.29-fold higher at 10 µg/ml as compared to the positive control. The insulin secretagogue activity was glucose independent and K(+)-ATP channel dependent. The bioactive component of the DCM fraction was identified to be a phenyl alkyl ether derivative. The DCM fraction of Kalanchoe pinnata demonstrates excellent insulin secretagogue action and can be useful in treatment of diabetes mellitus.

Restoration of Muscle Mitochondrial Function and Metabolic Flexibility in Type 2 Diabetes by Exercise Training Is Paralleled by Increased Myocellular Fat Storage and Improved Insulin Sensitivity

NARCIS (Netherlands)

Meex, R.C.R.; Schrauwen-Hinderling, V.B.; Moonen-Kornips, E.; Schaart, G.; Mensink, M.R.; Phielix, E.; Weijer, van de T.; Sels, J.P.; Schrauwen, P.; Hesselink, M.K.C.

2010-01-01

OBJECTIVE-Mitochondrial dysfunction and fat accumulation in skeletal muscle (increased intramyocellular lipid [IMCL]) have been linked to development of type 2 diabetes. We examined whether exercise training could restore mitochondrial function and insulin sensitivity in patients with type 2

Normocaloric Diet Restores Weight Gain and Insulin Sensitivity in Obese Mice

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Giovanni Enrico Lombardo

2016-05-01

Full Text Available An increased incidence of obesity is registered worldwide, and its association with insulin resistance and type 2 diabetes is closely related with increased morbidity and mortality for cardiovascular diseases. A major clinical problem in the management of obesity is the non-adherence or low adherence of patients to a hypo-caloric dietetic restriction. In this study we evaluated in obese mice the effects on insulin sensitivity of shifting from high-calorie foods to normal diet. Male C57BL/6JolaHsd mice (n=20 were fed with high fat diet for a 24 weeks period. Afterwards, body weight, energy and food intake were measured in all animals, together with parameters of insulin sensitivity by homeostatic model assessment of insulin resistance and plasma glucose levels in response to insulin administration. Moreover, in half of these mice, Glut4 mRNA levels were measured in muscle at the end of the high fat treatment, whereas the rest of the animals (n=10 were shifted to normocaloric diet for 10 weeks, after which the same analyses were carried out. A significant reduction of body weight was found after the transition from high to normal fat diet, and this decrease correlated well with an improvement in insulin sensitivity. In fact, we found a reduction in serum insulin levels and the recovery of insulin responsiveness in terms of glucose disposal measured by insulin tolerance test and Glut4 mRNA and protein expression. These results indicate that obesity related insulin resistance may be rescued by shifting from high fat diet to normocaloric diet.

Dysregulation of glycogen synthase COOH- and NH2-terminal phosphorylation by insulin in obesity and type 2 diabetes mellitus

DEFF Research Database (Denmark)

Højlund, Kurt; Birk, Jesper Bratz; Klein, Ditte Kjærsgaard

2009-01-01

Context: Insulin-stimulated glucose disposal is impaired in obesity and type 2 diabetes mellitus (T2DM) and is tightly linked to impaired skeletal muscle glucose uptake and storage. Impaired activation of glycogen synthase (GS) by insulin is a well-established defect in both obesity and T2DM....... The exaggerated insulin resistance in T2DM compared with obese subjects was not reflected by differences in site 3 phosphorylation but was accompanied by a significantly higher site 1b phosphorylation during insulin stimulation. Hyperphosphorylation of another Ca(2+)/calmodulin-dependent kinase-II target......, phospholamban-Thr17, was also evident in T2DM. Dephosphorylation of GS by phosphatase treatment fully restored GS activity in all groups. Conclusions: Dysregulation of GS phosphorylation plays a major role in impaired insulin regulation of GS in obesity and T2DM. In obesity, independent of T2DM...

Partial deletion of eNOS gene causes hyperinsulinemic state, unbalance of cardiac insulin signaling pathways and coronary dysfunction independently of high fat diet.

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Cecilia Vecoli

Full Text Available Abnormalities in eNOS gene, possibly interacting with high fat diet (HFD, affect peripheral vascular function and glucose metabolism. The relative role of eNOS gene, HFD and metabolic derangement on coronary function has not been fully elucidated. We test whether eNOS gene deficiency per se or in association with HFD modulates coronary function through mechanisms involving molecular pathways related to insulin signaling. Wild type (WT, eNOS-/- and eNOS+/- mice were studied. WT and eNOS+/- mice were fed with either standard or HF diet for 16 weeks and compared with standard diet fed eNOS-/-. Glucose and insulin tolerance tests were performed during the last week of diet. Coronary resistance (CR was measured at baseline and during infusions of acetylcholine (Ach or sodium-nitroprusside (SNP to evaluate endothelium-dependent or independent vasodilation, in the Langendorff isolated hearts. Cardiac expression of Akt and ERK genes as evaluation of two major insulin-regulated signaling pathways involved in the control of vascular tone were assessed by western blot. HFD-fed mice developed an overt diabetic state. Conversely, chow-fed genetically modified mice (in particular eNOS-/- showed a metabolic pattern characterized by normoglycemia and hyperinsulinemia with a limited degree of insulin resistance. CR was significantly higher in animals with eNOS gene deletions than in WT, independently of diet. Percent decrease in CR, during Ach infusion, was significantly lower in both eNOS-/- and eNOS+/- mice than in WT, independently of diet. SNP reduced CR in all groups except eNOS-/-. The cardiac ERK1-2/Akt ratio, increased in animals with eNOS gene deletions compared with WT, independently of diet. These results suggest that the eNOS genetic deficiency, associated or not with HFD, has a relevant effect on coronary vascular function, possibly mediated by increase in blood insulin levels and unbalance in insulin-dependent signaling in coronary vessels

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...

Skeletal muscle insulin resistance associated with cholesterol-induced activation of macrophages is prevented by high density lipoprotein.

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Andrew L Carey

Full Text Available BACKGROUND: Emerging evidence suggests that high density lipoprotein (HDL may modulate glucose metabolism through multiple mechanisms including pancreatic insulin secretion as well as insulin-independent glucose uptake into muscle. We hypothesized that HDL may also increase skeletal muscle insulin sensitivity via cholesterol removal and anti-inflammatory actions in macrophages associated with excess adiposity and ectopic lipid deposition. METHODS: Human primary and THP-1 macrophages were treated with vehicle (PBS or acetylated low density lipoprotein (acLDL with or without HDL for 18 hours. Treatments were then removed, and macrophages were incubated with fresh media for 4 hours. This conditioned media was then applied to primary human skeletal myotubes derived from vastus lateralis biopsies taken from patients with type 2 diabetes to examine insulin-stimulated glucose uptake. RESULTS: Conditioned media from acLDL-treated primary and THP-1 macrophages reduced insulin-stimulated glucose uptake in primary human skeletal myotubes compared with vehicle (primary macrophages, 168±21% of basal uptake to 104±19%; THP-1 macrophages, 142±8% of basal uptake to 108±6%; P<0.05. This was restored by co-treatment of macrophages with HDL. While acLDL increased total intracellular cholesterol content, phosphorylation of c-jun N-terminal kinase and secretion of pro- and anti-inflammatory cytokines from macrophages, none were altered by co-incubation with HDL. Insulin-stimulated Akt phosphorylation in human skeletal myotubes exposed to conditioned media was unaltered by either treatment condition. CONCLUSION: Inhibition of insulin-stimulated glucose uptake in primary human skeletal myotubes by conditioned media from macrophages pre-incubated with acLDL was restored by co-treatment with HDL. However, these actions were not linked to modulation of common pro- or anti-inflammatory mediators or insulin signaling via Akt.

Glucagon-Like Peptide 1 Recruits Muscle Microvasculature and Improves Insulin’s Metabolic Action in the Presence of Insulin Resistance

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Chai, Weidong; Zhang, Xingxing; Barrett, Eugene J.

2014-01-01

Glucagon-like peptide 1 (GLP-1) acutely recruits muscle microvasculature, increases muscle delivery of insulin, and enhances muscle use of glucose, independent of its effect on insulin secretion. To examine whether GLP-1 modulates muscle microvascular and metabolic insulin responses in the setting of insulin resistance, we assessed muscle microvascular blood volume (MBV), flow velocity, and blood flow in control insulin-sensitive rats and rats made insulin-resistant acutely (systemic lipid infusion) or chronically (high-fat diet [HFD]) before and after a euglycemic-hyperinsulinemic clamp (3 mU/kg/min) with or without superimposed systemic GLP-1 infusion. Insulin significantly recruited muscle microvasculature and addition of GLP-1 further expanded muscle MBV and increased insulin-mediated glucose disposal. GLP-1 infusion potently recruited muscle microvasculature in the presence of either acute or chronic insulin resistance by increasing muscle MBV. This was associated with an increased muscle delivery of insulin and muscle interstitial oxygen saturation. Muscle insulin sensitivity was completely restored in the presence of systemic lipid infusion and significantly improved in rats fed an HFD. We conclude that GLP-1 infusion potently expands muscle microvascular surface area and improves insulin’s metabolic action in the insulin-resistant states. This may contribute to improved glycemic control seen in diabetic patients receiving incretin-based therapy. PMID:24658303

Insulin resistance is associated with larger thyroid volume in adults with type 1 diabetes independently from presence of thyroid autoimmunity.

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Rogowicz-Frontczak, Anita; Pilacinski, Stanislaw; Chwialkowska, Anna Teresa; Naskret, Dariusz; Zozulinska-Ziolkiewicz, Dorota

2018-04-19

To investigate the effect of insulin resistance (IR) on thyroid function, thyroid autoimmunity (AIT) and thyroid volume in type 1 diabetes (T1DM). 100 consecutive patients with T1DM aged 29 (±6) years with diabetes duration 13 (±6) years were included. Exclusion criteria were: history of thyroid disease, current treatment with L-thyroxin or anti-thyroid drugs. Evaluation of thyroid stimulating hormone (TSH), free thyroid hormones and anti-thyroid antibodies was performed. Thyroid volume was measured by ultrasonography. IR was assessed using the estimated glucose disposal rate (eGDR) formula. In the study group 22% of subjects had insulin resistance defined as eGDR lower or equal to 7.5 mg/kg/min. The prevalence of thyroid autoimmunity (positivity for ATPO or ATg or TRAb) in the study group was 37%. There were no significant differences in the concentration of TSH, FT3, FT4, the prevalence of AIT and hypothyroidism between IR and insulin sensitive (IS) group. Mean (±SD) thyroid volume was 15.6 (±6.2) mL in patients with IR and 11.7 (±4.7) mL in IS subjects (p = .002). Thyroid volume correlated inversely with eGDR (r = -0.35, p < .001). In a multivariate linear regression model the association between thyroid volume and eGDR was independent of sex, age, duration of diabetes, daily insulin dose, BMI, cigarette smoking, TSH value and presence of thyroid autoimmunity (beta: -0.29, p = .012). Insulin resisance is associated with larger thyroid volume in patients with type 1 diabetes independently of sex, body mass index, TSH value and presence of autoimmune thyroid disease.

Excessive Refined Carbohydrates and Scarce Micronutrients Intakes Increase Inflammatory Mediators and Insulin Resistance in Prepubertal and Pubertal Obese Children Independently of Obesity

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Mardia López-Alarcón

2014-01-01

Full Text Available Background. Low-grade inflammation is the link between obesity and insulin resistance. Because physiologic insulin resistance occurs at puberty, obese pubertal children are at higher risk for insulin resistance. Excessive diets in refined carbohydrates and saturated fats are risk factors for insulin resistance, but calcium, magnesium, vitamin-D, and the omega-3 fatty acids likely protect against inflammation and insulin resistance. Objective. To analyze interactions among dietary saturated fat, refined carbohydrates, calcium, magnesium, vitamin D, and omega-3 fatty acids on the risk of inflammation and insulin resistance in a sample of prepubertal and pubertal children. Methods. A sample of 229 children from Mexico City was analyzed in a cross-sectional design. Anthropometric measurements, 24 h recall questionnaires, and blood samples were obtained. Serum insulin, glucose, calcium, magnesium, 25-OHD3, C-reactive protein, leptin, adiponectin, and erythrocytes fatty acids were measured. Parametric and nonparametric statistics were used for analysis. Results. While mean macronutrients intake was excessive, micronutrients intake was deficient (P<0.01. Inflammation determinants were central obesity and magnesium-deficient diets. Determinants of insulin resistance were carbohydrates intake and circulating magnesium and adiponectin. Conclusions. Magnesium-deficient diets are determinants of inflammation, while high intake of refined carbohydrates is a risk factor for insulin resistance, independently of central adiposity.

Body fat and insulin resistance independently predict increased serum C-reactive protein in hyperandrogenic women with polycystic ovary syndrome.

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Tosi, Flavia; Dorizzi, Romolo; Castello, Roberto; Maffeis, Claudio; Spiazzi, Giovanna; Zoppini, Giacomo; Muggeo, Michele; Moghetti, Paolo

2009-11-01

Increased serum C-reactive protein (CRP), an independent predictor of coronary heart disease, was reported in women with polycystic ovary syndrome (PCOS). It remains unclear whether this finding is due to the association between PCOS and either insulin resistance, obesity, or androgen excess, which are all common features of this condition. The aims of this study were to assess whether increased serum CRP is a specific feature of PCOS and to investigate the mechanisms underlying this association. Serum high-sensitivity CRP (hs-CRP) was measured in 86 hyperandrogenic women (age 21.6+/-4.2 years, body mass index (BMI) 23.6+/-3.5 kg/m2), 50 with PCOS and 36 with idiopathic hyperandrogenism (HA). Thirty-five BMI-matched healthy women were also studied as controls. In these subjects, endocrine and metabolic profiles were assessed. In all hyperandrogenic subjects and 14 controls, insulin sensitivity was measured by the glucose clamp technique. Body fat was measured by bioelectrical impedance. Hs-CRP concentrations were higher in PCOS women (3.43+/-2.01 mg/l) than in HA subjects and healthy women (2.43+/-1.04, PPCOS). In multiple regression analyses, increased serum hs-CRP was independently predicted by higher body fat and lower insulin sensitivity. However, in lean women, serum-free testosterone was an additional, negative, predictive variable. PCOS is accompanied by a low-grade chronic inflammation. Body fat appears the main determining factor of this finding, which is only partly explained by insulin resistance. At least in lean women, androgen excess per se seems to play an additional, possibly protective, role in this association.

Central leptin action on euglycemia restoration in type 1 diabetes: Restraining responses normally induced by fasting?

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Xu, Yuanzhong; Tong, Qingchun

2017-07-01

Leptin monotherapy is sufficient to restore euglycemia in insulinopenic type 1 diabetes (T1D), yet the underlying mechanism remains poorly understood. Accumulating evidence demonstrates that the brain mediates the leptin action on euglycemia restoration. Here, we first review evidence supporting that symptoms in T1D resemble an uncontrolled response to fasting. Then, we discuss recent research progress on brain neurons and their neurotransmitters that potentially mediate the leptin action. Finally, peripheral effective pathways, which are normally involved in fasting responses and associated with leptin action on euglycemia restoration in T1D, will also be discussed. This summary complements several previous excellent reviews on this topic (Meek and Morton, 2016; Perry et al., 2016; Fujikawa and Coppari, 2015). A deep understanding of neurocircuitry and the peripheral effective pathways that mediate the leptin action on euglycemia restoration will likely lead to novel targets for an insulin-independent therapeutics against T1D. Copyright © 2016 Elsevier Ltd. All rights reserved.

Insulin and the Lung

DEFF Research Database (Denmark)

Singh, Suchita; Prakash, Y S; Linneberg, Allan

2013-01-01

, molecular understanding is necessary. Insulin resistance is a strong, independent risk factor for asthma development, but it is unknown whether a direct effect of insulin on the lung is involved. This review summarizes current knowledge regarding the effect of insulin on cellular components of the lung...... and highlights the molecular consequences of insulin-related metabolic signaling cascades that could adversely affect lung structure and function. Examples include airway smooth muscle proliferation and contractility and regulatory signaling networks that are associated with asthma. These aspects of insulin...

β1-adrenergic receptor stimulation by agonist Compound 49b restores insulin receptor signal transduction in vivo

Science.gov (United States)

Jiang, Youde; Zhang, Qiuhua; Ye, Eun-Ah

2014-01-01

Purpose Determine whether Compound 49b treatment ameliorates retinal changes due to the lack of β2-adrenergic receptor signaling. Methods Using retinas from 3-month-old β2-adrenergic receptor-deficient mice, we treated mice with our novel β1-/β2-adrenergic receptor agonist, Compound 49b, to assess the effects of adrenergic agonists acting only on β1-adrenergic receptors due to the absence of β2-adrenergic receptors. Western blotting or enzyme-linked immunosorbent assay (ELISA) analyses were performed for β1- and β2-adrenergic receptors, as well as key insulin resistance proteins, including TNF-α, SOCS3, IRS-1Ser307, and IRTyr960. Analyses were also performed on key anti- and proapoptotic proteins: Akt, Bcl-xL, Bax, and caspase 3. Electroretinogram analyses were conducted to assess functional changes, while histological assessment was conducted for changes in retinal thickness. Results A 2-month treatment of β2-adrenergic receptor-deficient mice with daily eye drops of 1 mM Compound 49b, a novel β1- and β2-adrenergic receptor agonist, reversed the changes in insulin resistance markers (TNF-α and SOCS3) observed in untreated β2-adrenergic receptor-deficient mice, and concomitantly increased morphological integrity (retinal thickness) and functional responses (electroretinogram amplitude). These results suggest that stimulating β1-adrenergic receptors on retinal endothelial cells or Müller cells can compensate for the loss of β2-adrenergic receptor signaling on Müller cells, restore insulin signal transduction, reduce retinal apoptosis, and enhance retinal function. Conclusions Since our previous studies with β1-adrenergic receptor knockout mice confirmed that the reverse also occurs (β2-adrenergic receptor stimulation can compensate for the loss of β1-adrenergic receptor activity), it appears that increased activity in either of these pathways alone is sufficient to block insulin resistance–based retinal cell apoptosis. PMID:24966659

Serum 25-Hydroxyvitamin D Concentration Is Independently Inversely Associated with Insulin Resistance in the Healthy, Non-Obese Korean Population

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So Young Ock

2016-07-01

Full Text Available BackgroundWe evaluated the associations between 25-hydroxyvitamin D (25(OHD concentrations in serum and insulin resistance in the healthy Korean population.MethodsWe conducted this cross-sectional analysis in 1,807 healthy Korean people (628 men and 1,179 women aged 30 to 64 years in the Cardiovascular and Metabolic Disease Etiologic Research Center study. All participants were assessed for 25(OHD, fasting glucose, and insulin levels, and completed a health examination and lifestyle questionnaire according to standard procedures. Insulin resistance was defined as the homeostasis model assessment insulin resistance higher than the 75 percentile.ResultsCompared to those in the highest tertile (≥14.3 ng/mL, the odds ratio (OR for insulin resistance was 1.37 (95% confidence interval [CI], 1.01 to 1.86 for the 1st tertile (<9.7 ng/mL and 1.19 (95% CI, 0.08 to 1.62 for the 2nd tertile (9.7 to 14.3 ng/mL after adjusting for age, gender, waist circumference, alcohol consumption, smoking status, physical exercise, season, and cohort. After stratification of the subjects by adiposity, these associations remained only in non-obese subjects (lowest tertile vs. highest tertile, multivariable OR, 1.64; 95% CI, 1.05 to 2.56.ConclusionSerum 25(OHD has an independent inverse association with insulin resistance in the healthy, non-obese Korean population, even among people with vitamin D insufficiency.

Chelation of intracellular calcium blocks insulin action in the adipocyte

International Nuclear Information System (INIS)

Pershadsingh, H.A.; Shade, D.L.; Delfert, D.M.; McDonald, J.M.

1987-01-01

The hypothesis that intracellular Ca 2+ is an essential component of the intracellular mechanism of insulin action in the adipocyte was evaluated. Cells were loaded with the Ca 2+ chelator quin-2, by preincubating them with quin-2 AM, the tetrakis(acetoxymethyl) ester of quin-2. Quin-2 loading inhibited insulin-stimulated glucose transport without affecting basal activity. The ability of insulin to stimulate glucose uptake in quin-2-loaded cells could be partially restored by preincubating cells with buffer supplemented with 1.2 mM CaCl 2 and the Ca 2+ ionophore A23187. These conditions had no effect on basal activity and omission of CaCl 2 from the buffer prevented the restoration of insulin-stimulated glucose uptake by A23187. Quin-2 loading also inhibited insulin-stimulated glucose oxidation and the ability of insulin to inhibit cAMP-stimulated lipolysis without affecting their basal activities. Incubation of cells with 100 μM quin-2 or quin-2 AM had no effect on intracellular ATP concentration or the specific binding of 125 I=labeled insulin to adipocytes. These findings suggest that intracellular Ca 2+ is an essential component in the coupling of the insulin-activated receptor complex to cellular physiological/metabolic machinery. Furthermore, differing quin-2 AM dose-response profiles suggest the presence of dual Ca 2+ -dependent pathways in the adipocyte. One involves insulin stimulation of glucose transport and oxidation, whereas the other involves the antilipolytic action of insulin

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.

Assessment of the fatty liver index as an indicator of hepatic steatosis for predicting incident diabetes independently of insulin resistance in a Korean population.

Science.gov (United States)

Jung, C H; Lee, W J; Hwang, J Y; Yu, J H; Shin, M S; Lee, M J; Jang, J E; Leem, J; Park, J-Y; Kim, H-K

2013-04-01

Fatty liver disease, especially non-alcoholic fatty liver disease, is considered to be the hepatic manifestation of the metabolic syndrome, both closely associated with insulin resistance. Furthermore, fatty liver disease assessed by ultrasonography is known to be a predictor of the development of Type 2 diabetes mellitus. However, it remains unclear whether fatty liver disease plays a role in the pathogenesis of Type 2 diabetes independently of insulin resistance. In this study, we investigated whether fatty liver disease assessed by the fatty liver index can predict the development of Type 2 diabetes independently of systemic insulin resistance. We examined the clinical and laboratory data of 7860 subjects without diabetes who underwent general routine health evaluations at the Asan Medical Center in 2007 and had returned for follow-up examinations in 2011. Fatty liver index was calculated using an equation that considers serum triglyceride levels, γ-glutamyltransferase, waist circumference and BMI. During a 4-year period, 457 incident diabetes cases (5.8%) were identified. The odds ratios for the development of Type 2 diabetes were significantly higher in the group with a fatty liver index ≥ 60 (fatty liver index-positive) than in the group with a fatty liver index hepatic steatosis is valuable in identifying subjects at high risk for Type 2 diabetes. In addition, fatty liver disease itself contributes to the development of Type 2 diabetes independently of systemic insulin resistance. © 2012 The Authors. Diabetic Medicine © 2012 Diabetes UK.

Determination of 24-hour insulin infusion pattern by an artificial endocrine pancreas for intravenous insulin infusion with a miniature pump

DEFF Research Database (Denmark)

Kølendorf, K; Christiansen, J S; Bojsen, J

1981-01-01

UNLABELLED: Intravenous insulin infusion with a glucose controlled insulin infusion system (GCIIS) is known to restore glucose homeostasis. A simpler approach to improve blood glucose regulation is preprogrammed intravenous insulin infusion with portable pumps without sensor-mediated feedback. We...... report a study designed to evaluate whether the preprogrammed insulin infusion pattern to be used in the miniature insulin infusion pump (MIIP) could be optimized by concomitant employment of the GCIIS for blood glucose control. Six juvenile-onset insulin-dependent diabetics (mean age 31 yrs) were...... studied. Mean blood glucose (MBG) was 6.2 mmol/l +/- 0.5 (SD) during glucose controlled infusion and 5.3 +/- 0.6 during the combined MIIP + GCIIS-day. The insulin requirements calculated from the s.c. regimen (56 U +/- 10 SD) were identical to the GCIIS-measured (51 U +/- 14) and to the amounts delivered...

Blood Glucose and Insulin Concentrations after Octreotide Administration in Horses With Insulin Dysregulation.

Science.gov (United States)

Frank, N; Hermida, P; Sanchez-Londoño, A; Singh, R; Gradil, C M; Uricchio, C K

2017-07-01

Octreotide is a somatostatin analog that suppresses insulin secretion. We hypothesized that octreotide would suppress insulin concentrations in horses and that normal (N) horses and those with insulin dysregulation (ID) would differ significantly in their plasma glucose and insulin responses to administration of octreotide. Twelve horses, N = 5, ID = 7. Prospective study. An oral sugar test was performed to assign horses to N and ID groups. Octreotide (1.0 μg/kg IV) was then administered, and blood was collected at 0, 5, 10, 15, 20, 25, 30, 45, 60, 75, and 90 minute, and 2, 3, 4, 6, 8, 12, and 24 hour for measurement of glucose and insulin concentrations. Area under the curve (AUC) values were calculated. Mean AUC values for glucose and insulin did not differ between normal (n = 5) and ID (n = 7) groups after octreotide injection. Significant time (P glucose and insulin concentrations. A group × time interaction (P = .091) was detected for insulin concentrations after administration of octreotide, but the group (P = .33) effect was not significant. Octreotide suppresses insulin secretion, resulting in hyperglycemia, and then concentrations increase above baseline as glycemic control is restored. Our hypothesis that octreotide causes insulin concentrations to decrease in horses was supported, but differences between N and ID groups did not reach statistical significance when blood glucose and insulin responses were compared. The utility of an octreotide response test remains to be determined. Copyright © 2017 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.

Intracellular serotonin modulates insulin secretion from pancreatic beta-cells by protein serotonylation.

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Nils Paulmann

2009-10-01

Full Text Available While serotonin (5-HT co-localization with insulin in granules of pancreatic beta-cells was demonstrated more than three decades ago, its physiological role in the etiology of diabetes is still unclear. We combined biochemical and electrophysiological analyses of mice selectively deficient in peripheral tryptophan hydroxylase (Tph1-/- and 5-HT to show that intracellular 5-HT regulates insulin secretion. We found that these mice are diabetic and have an impaired insulin secretion due to the lack of 5-HT in the pancreas. The pharmacological restoration of peripheral 5-HT levels rescued the impaired insulin secretion in vivo. These findings were further evidenced by patch clamp experiments with isolated Tph1-/- beta-cells, which clearly showed that the secretory defect is downstream of Ca(2+-signaling and can be rescued by direct intracellular application of 5-HT via the clamp pipette. In elucidating the underlying mechanism further, we demonstrate the covalent coupling of 5-HT by transglutaminases during insulin exocytosis to two key players in insulin secretion, the small GTPases Rab3a and Rab27a. This renders them constitutively active in a receptor-independent signaling mechanism we have recently termed serotonylation. Concordantly, an inhibition of such activating serotonylation in beta-cells abates insulin secretion. We also observed inactivation of serotonylated Rab3a by enhanced proteasomal degradation, which is in line with the inactivation of other serotonylated GTPases. Our results demonstrate that 5-HT regulates insulin secretion by serotonylation of GTPases within pancreatic beta-cells and suggest that intracellular 5-HT functions in various microenvironments via this mechanism in concert with the known receptor-mediated signaling.

Independent technical review of the Sandia National Laboratories Environmental Restoration Project

International Nuclear Information System (INIS)

1994-11-01

An Independent Technical Review was conducted of the Environmental Restoration Project. The objective of the review was recommendations, from a commercial perspective, on a systems level path forward to safe, minimum cost and schedule project completion. The work presented represents the consensus analysis and recommendations of thirteen individuals with varied backgrounds, expertise, and experience. The ITR team recommends that the barriers to the opportunity described in the diagnosis be eliminated using an integrated DOE-Sandia system approach. Piecemeal changes will not result in the desired commercial efficiency. DOE needs to operate as the contracting agency for a Major System Acquisition. If it does not, commercial performance will not be achieved regardless of the contractor. Likewise, Sandia needs to establish and implement the necessary project structure and management systems to operate with commercial contractor like efficiency

Consumption of a High-Fat Diet Induces Central Insulin Resistance Independent of Adiposity

Science.gov (United States)

Clegg, Deborah J.; Gotoh, Koro; Kemp, Christopher; Wortman, Matthew D.; Benoit, Stephen C.; Brown, Lynda M.; D’Alessio, David; Tso, Patrick; Seeley, Randy J.; Woods, Stephen C.

2011-01-01

Plasma insulin enters the CNS where it interacts with insulin receptors in areas that are related to energy homeostasis and elicits a decrease of food intake and body weight. Here, we demonstrate that consumption of a high-fat (HF) diet impairs the central actions of insulin. Male Long-Evans rats were given chronic (70-day) or acute (3-day) ad libitum access to HF, low-fat (LF), or chow diets. Insulin administered into the 3rd-cerebral ventricle (i3vt) decreased food intake and body weight of LF and chow rats but had no effect on HF rats in either the chronic or the acute experiment. Rats chronically pair-fed the HF diet to match the caloric intake of LF rats, and with body weights and adiposity levels comparable to those of LF rats, were also unresponsive to i3vt insulin when returned to ad lib food whereas rats pair-fed the LF diet had reduced food intake and body weight when administered i3vt insulin. Insulin’s inability to reduce food intake in the presence of the high-fat diet was associated with a reduced ability of insulin to activate its signaling cascade, as measured by pAKT. Finally, i3vt administration of insulin increased hypothalamic expression of POMC mRNA in the LF-but not the HF-fed rats. We conclude that consumption of a HF diet leads to central insulin resistance following short exposure to the diet, and as demonstrated by reductions in insulin signaling and insulin-induced hypothalamic expression of POMC mRNA. PMID:21241723

Adipose tissue CIDEA is associated, independently of weight variation, to change in insulin resistance during a longitudinal weight control dietary program in obese individuals.

Science.gov (United States)

Montastier, Emilie; Déjean, Sébastien; Le Gall, Caroline; Saris, Wim H M; Langin, Dominique; Viguerie, Nathalie

2014-01-01

Weight loss reduces risk factors associated with obesity. However, long-term metabolic improvement remains a challenge. We investigated quantitative gene expression of subcutaneous adipose tissue in obese individuals and its relationship with low calorie diet and long term weight maintenance induced changes in insulin resistance. Three hundred eleven overweight and obese individuals followed a dietary protocol consisting of an 8-week low calorie diet followed by a 6-month ad libitum weight-maintenance diet. Individuals were clustered according to insulin resistance trajectories assessed using homeostasis model assessment of insulin resistance (HOMA-IR) index. Adipose tissue mRNA levels of 267 genes selected for regulation according to obesity, metabolic status and response to dieting was assessed using high throughput RT-qPCR. A combination of discriminant analyses was used to identify genes with regulation according to insulin resistance trajectories. Partial correlation was used to control for change in body mass index. Three different HOMA-IR profile groups were determined. HOMA-IR improved during low calorie diet in the 3 groups. At the end of the 6-month follow-up, groups A and B had reduced HOMA-IR by 50%. In group C, HOMA-IR had returned to baseline values. Genes were differentially expressed in the adipose tissue of individuals according to groups but a single gene, CIDEA, was common to all phases of the dietary intervention. Changes in adipose tissue CIDEA mRNA levels paralleled variations in insulin sensitivity independently of change in body mass index. Overall, CIDEA was up-regulated in adipose tissue of individuals with successful long term insulin resistance relapse and not in adipose tissue of unsuccessful individuals. The concomitant change in adipose tissue CIDEA mRNA levels and insulin sensitivity suggests a beneficial role of adipose tissue CIDEA in long term glucose homeostasis, independently of weight variation. ClinicalTrials.gov NCT00390637.

Central and peripheral effects of chronic food restriction and weight restoration in the rat.

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Kinzig, Kimberly P; Hargrave, Sara L; Tao, Erin E

2009-02-01

Previous studies have demonstrated that some endocrine consequences of long-term caloric restriction persist after weight restoration in human subjects. Here we evaluate effects of chronic food restriction in rats that were restricted to 70% of control kcal for 4 wk and subsequently weight restored. Measures were taken from rats at 80% (chronically restricted; CR), 90% (partially weight restored; PR), 100% (fully weight restored; FR), and after 4 wk at 100% body weight of controls (extended weight restored; ER). Plasma insulin and leptin were decreased, and ghrelin was increased in CR compared with controls. Leptin and ghrelin normalized with weight restoration at PR, FR, and ER; however, baseline insulin was not normalized until the ER state. Hypothalamic mRNA expression levels for proopiomelanocortin (POMC), agouti-related protein (AgRP), and neuropeptide Y (NPY) revealed significantly less POMC mRNA expression in CR and PR rats, and significantly less arcuate NPY mRNA in PR and FR. In the dorsomedial hypothalamus, CR, PR, and FR rats had significantly increased NPY expression that was not normalized until the ER state. In response to a test meal, insulin and ghrelin release patterns were altered through the FR stage, and ghrelin remained affected at ER. Collectively, these data demonstrate that mere weight restoration is not sufficient to normalize hypothalamic gene expression levels and endocrine responses to a meal, and that meal-related ghrelin responses persist despite weight restoration for up to 4 wk.

Reversal of dexamethasone induced insulin resistance in 3T3L1 adipocytes by 3β-taraxerol of Mangifera indica.

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Sangeetha, K N; Shilpa, K; Jyothi Kumari, P; Lakshmi, B S

2013-02-15

The present study investigates the efficacy of Mangifera indica ethyl acetate extract (MIEE) and its bioactive compound, 3β-taraxerol in the reversal of dexamethasone (DEX) induced insulin resistance in 3T3L1 adipocytes. MIEE and 3β-taraxerol were evaluated for their ability to restore impaired glucose uptake and, expression of molecular markers in the insulin signaling pathway induced by DEX in 3T3L1 adipocytes using 2-deoxy-D-[1-(3)H] glucose uptake assay and ELISA. An insulin resistant model has been developed using a glucocorticoid, DEX on 3T3L1 adipocytes. Insulin resistant condition was observed at 24h of DEX induction wherein a maximum degree of resistance of about 50% was measured based on inhibition of glucose uptake, which was confirmed using cytotoxicity analysis. The developed model of insulin resistance was studied in comparison to positive control rosiglitazone. DEX induced inhibition of glucose uptake and the expression of insulin signaling markers GLUT4 and PI3K were found to be restored by 3β-taraxerol and MIEE, thus delineating its mechanism of action in the reversal of insulin resistance. 3β-Taraxerol effectively restored DEX induced desensitization via restoration of PI3K and GLUT4 expression. To conclude, since 3β-taraxerol exhibits significant effect in reversing insulin resistance it can be further investigated as an insulin resistance reversal agent. Copyright © 2012 Elsevier GmbH. All rights reserved.

Acute inhibition of central c-Jun N-terminal kinase restores hypothalamic insulin signalling and alleviates glucose intolerance in diabetic mice.

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Benzler, J; Ganjam, G K; Legler, K; Stöhr, S; Krüger, M; Steger, J; Tups, A

2013-05-01

The hypothalamus has been identified as a main insulin target tissue for regulating normal body weight and glucose metabolism. Recent observations suggest that c-Jun-N-terminal kinase (JNK)-signalling plays a crucial role in the development of obesity and insulin resistance because neuronal JNK-1 ablation in the mouse prevented high-fat diet-induced obesity (DIO) and increased energy expenditure, as well as insulin sensitivity. In the present study, we investigated whether central JNK inhibition is associated with sensitisation of hypothalamic insulin signalling in mice fed a high-fat diet for 3 weeks and in leptin-deficient mice. We determined whether i.c.v. injection of a pharmacological JNK-inhibitor (SP600125) improved impaired glucose homeostasis. By immunohistochemistry, we first observed that JNK activity was increased in the arcuate nucleus (ARC) and the ventromedial hypothalamus (VMH) in both mouse models, relative to normoglycaemic controls. This suggests that up-regulation of JNK in these regions is associated with glucose intolerance and obesity, independent of leptin levels. Acute i.c.v. injection of SP600125 ameliorated glucose tolerance within 30 min in both leptin-deficient and DIO mice. Given the acute nature of i.c.v. injections, these effects cannot be attributed to changes in food intake or energy balance. In a hypothalamic cell line, and in the ARC and VMH of leptin-deficient mice, JNK inhibition by SP600125 consistently improved impaired insulin signalling. This was determined by a reduction of phospho-insulin receptor substrate-1 [IRS-1(Ser612)] protein in a hypothalamic cell line and a decline in the number of pIRS-1(Ser612) immunoreactive cells in the ARC and VMH. Serine 612 phosphorylation of IRS-1 is assumed to negatively regulate insulin signalling. In leptin-deficient mice, in both nuclei, central inhibition of JNK increased the number of cells immunoreactive for phospho-Akt (Ser473) and phospho-GSK-3β (Ser9), which are important

Insulin resistance, insulin sensitization and inflammation in polycystic ovarian syndrome

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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.

Reduced Insulin/IGF-1 Signaling Restores the Dynamic Properties of Key Stress Granule Proteins during Aging

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Marie C. Lechler

2017-01-01

Full Text Available Summary: Low-complexity “prion-like” domains in key RNA-binding proteins (RBPs mediate the reversible assembly of RNA granules. Individual RBPs harboring these domains have been linked to specific neurodegenerative diseases. Although their aggregation in neurodegeneration has been extensively characterized, it remains unknown how the process of aging disturbs RBP dynamics. We show that a wide variety of RNA granule components, including stress granule proteins, become highly insoluble with age in C. elegans and that reduced insulin/insulin-like growth factor 1 (IGF-1 daf-2 receptor signaling efficiently prevents their aggregation. Importantly, stress-granule-related RBP aggregates are associated with reduced fitness. We show that heat shock transcription factor 1 (HSF-1 is a main regulator of stress-granule-related RBP aggregation in both young and aged animals. During aging, increasing DAF-16 activity restores dynamic stress-granule-related RBPs, partly by decreasing the buildup of other misfolded proteins that seed RBP aggregation. Longevity-associated mechanisms found to maintain dynamic RBPs during aging could be relevant for neurodegenerative diseases. : Lechler et al. show that RNA-binding proteins (RBPs including stress granule proteins are prone to aggregate with age in C. elegans. Aggregation of stress granule RBPs with “prion-like” domains is associated with reduced fitness. Their aggregation is prevented by longevity pathways and promoted by the aggregation of other misfolded proteins. Keywords: neurodegenerative diseases, Caenorhabditis elegans, protein aggregation, aging, RNA-binding proteins, stress granules, HSF-1, DAF-2, longevity

Bariatric surgery in morbidly obese insulin resistant humans normalises insulin signalling but not insulin-stimulated glucose disposal.

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Mimi Z Chen

Full Text Available Weight-loss after bariatric surgery improves insulin sensitivity, but the underlying molecular mechanism is not clear. To ascertain the effect of bariatric surgery on insulin signalling, we examined glucose disposal and Akt activation in morbidly obese volunteers before and after Roux-en-Y gastric bypass surgery (RYGB, and compared this to lean volunteers.The hyperinsulinaemic euglycaemic clamp, at five infusion rates, was used to determine glucose disposal rates (GDR in eight morbidly obese (body mass index, BMI=47.3 ± 2.2 kg/m(2 patients, before and after RYGB, and in eight lean volunteers (BMI=20.7 ± 0.7 kg/m2. Biopsies of brachioradialis muscle, taken at fasting and insulin concentrations that induced half-maximal (GDR50 and maximal (GDR100 GDR in each subject, were used to examine the phosphorylation of Akt-Thr308, Akt-473, and pras40, in vivo biomarkers for Akt activity.Pre-operatively, insulin-stimulated GDR was lower in the obese compared to the lean individuals (P<0.001. Weight-loss of 29.9 ± 4 kg after surgery significantly improved GDR50 (P=0.004 but not GDR100 (P=0.3. These subjects still remained significantly more insulin resistant than the lean individuals (p<0.001. Weight loss increased insulin-stimulated skeletal muscle Akt-Thr308 and Akt-Ser473 phosphorylation, P=0.02 and P=0.03 respectively (MANCOVA, and Akt activity towards the substrate PRAS40 (P=0.003, MANCOVA, and in contrast to GDR, were fully normalised after the surgery (obese vs lean, P=0.6, P=0.35, P=0.46, respectively.Our data show that although Akt activity substantially improved after surgery, it did not lead to a full restoration of insulin-stimulated glucose disposal. This suggests that a major defect downstream of, or parallel to, Akt signalling remains after significant weight-loss.

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

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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.

Normocaloric Diet Restores Weight Gain and Insulin Sensitivity in Obese Mice

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Lombardo, Giovanni Enrico; Arcidiacono, Biagio; De Rose, Roberta Francesca; Lepore, Saverio Massimo; Costa, Nicola; Montalcini, Tiziana; Brunetti, Antonio; Russo, Diego; De Sarro, Giovambattista; Celano, Marilena

2016-01-01

An increased incidence of obesity is registered worldwide, and its association with insulin resistance and type 2 diabetes is closely related with increased morbidity and mortality for cardiovascular diseases. A major clinical problem in the management of obesity is the non-adherence or low adherence of patients to a hypo-caloric dietetic restriction. In this study we evaluated in obese mice the effects on insulin sensitivity of shifting from high-calorie foods to normal diet. Male C57BL/6Jol...

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.

Plasma levels of lysine, tyrosine, and valine during pregnancy are independent risk factors of insulin resistance and gestational diabetes.

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Park, Sunmin; Park, Jin Young; Lee, Ju Hong; Kim, Sung-Hoon

2015-03-01

This study compared plasma concentrations of amino acids in pregnant women with and without gestational diabetes mellitus (GDM) and identified the association between plasma amino acid levels and GDM, insulin resistance, and insulin secretion at 24-28 weeks of pregnancy. Circulating amino acid levels were evaluated using high-performance liquid chromatography at 24-28 weeks of pregnancy in 25 non-GDM and 64 GDM women after adjusting for covariates such as maternal age, body mass index (BMI) before pregnancy, BMI and gestational age at screening GDM, and daily caloric intake. Backward stepwise logistic regression analysis was used to identify the predictors of developing GDM, and homeostatic model assessments for insulin resistance (HOMA-IR) and β-cell function (HOMA-B). Circulating levels of amino acids except threonine and tyrosine were significantly higher in GDM women than non-GDM women. Along with the intakes of energy, protein, and fat from animal sources, the intakes of each amino acid were significantly higher in the GDM group without a direct correlation to plasma amino acid levels. The variation in GDM development was explained by maternal age, diastolic blood pressure, and plasma lysine levels (R(2)=0.691). Height, BMI before pregnancy, systolic blood pressure, and plasma tyrosine and valine levels accounted for the variation in HOMA-IR (R(2)=0.589). The 53.3% variation of HOMA-B was explained by maternal age, BMI at GDM screening, plasma insulin level at 1 h during the oral glucose tolerance test (OGTT), and plasma valine level. Circulating concentrations of lysine, tyrosine, and valine were independently and positively associated with GDM through modifying insulin resistance and secretion.

Independent associations of insulin resistance with high whole-body intermuscular and low leg subcutaneous adipose tissue distribution in obese HIV-infected women123

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Albu, Jeanine B; Kenya, Sonjia; He, Qing; Wainwright, Marsha; Berk, Evan S; Heshka, Stanley; Kotler, Donald P; Engelson, Ellen S

2009-01-01

Background Obesity and insulin resistance are growing problems in HIV-positive (HIV+) women receiving highly active antiretroviral therapy (HAART). Objective The objective was to determine the contribution of adipose tissue (AT) enlargement and distribution to the presence of insulin resistance in obese HIV+ women. Design Whole-body intermuscular AT (IMAT), visceral AT (VAT), subcutaneous AT (SAT), and SAT distribution (leg versus upper body) were measured by whole-body magnetic resonance imaging. Insulin sensitivity (SI) was measured with an intravenous glucose tolerance test in obese HIV+ women recruited because of their desire to lose weight (n = 17) and in obese healthy controls (n = 32). Results The HIV+ women had relatively less whole-body SAT and more VAT and IMAT than did the controls (P < 0.05 for all). A significant interaction by HIV status was observed for the relation of total SAT with SI (P < 0.001 for the regression’s slope interactions after adjustment for age, height, and weight). However, relations of IMAT, VAT, and SAT distribution (leg SAT as a percentage of total SAT; leg SAT%) with SI did not differ significantly between groups. For both groups combined, the best model predicting a low SI included significant contributions by both high IMAT and low leg SAT%, independent of age, height, and weight, and no interaction between groups was observed (overall r2 = 0.44, P = 0.0003). Conclusion In obese HIV+ women, high whole-body IMAT and low leg SAT% distribution are independently associated with insulin resistance. PMID:17616768

Insulin resistance and improvements in signal transduction.

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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.

Insulin promotes Rip11 accumulation at the plasma membrane by inhibiting a dynamin- and PI3-kinase-dependent, but Akt-independent, internalisation event.

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Boal, Frédéric; Hodgson, Lorna R; Reed, Sam E; Yarwood, Sophie E; Just, Victoria J; Stephens, David J; McCaffrey, Mary W; Tavaré, Jeremy M

2016-01-01

Rip11 is a Rab11 effector protein that has been shown to be important in controlling the trafficking of several intracellular cargoes, including the fatty acid transporter FAT/CD36, V-ATPase and the glucose transporter GLUT4. We have previously demonstrated that Rip11 translocates to the plasma membrane in response to insulin and here we examine the basis of this regulated phenomenon in more detail. We show that Rip11 rapidly recycles between the cell interior and surface, and that the ability of insulin to increase the appearance of Rip11 at the cell surface involves an inhibition of Rip11 internalisation from the plasma membrane. By contrast the hormone has no effect on the rate of Rip11 translocation towards the plasma membrane. The ability of insulin to inhibit Rip11 internalisation requires dynamin and class I PI3-kinases, but is independent of the activation of the protein kinase Akt; characteristics which are very similar to the mechanism by which insulin inhibits GLUT4 endocytosis. Copyright © 2015. Published by Elsevier Inc.

En route to Background Independence: Broken split-symmetry, and how to restore it with bi-metric average actions

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Becker, D.; Reuter, M.

2014-01-01

The most momentous requirement a quantum theory of gravity must satisfy is Background Independence, necessitating in particular an ab initio derivation of the arena all non-gravitational physics takes place in, namely spacetime. Using the background field technique, this requirement translates into the condition of an unbroken split-symmetry connecting the (quantized) metric fluctuations to the (classical) background metric. If the regularization scheme used violates split-symmetry during the quantization process it is mandatory to restore it in the end at the level of observable physics. In this paper we present a detailed investigation of split-symmetry breaking and restoration within the Effective Average Action (EAA) approach to Quantum Einstein Gravity (QEG) with a special emphasis on the Asymptotic Safety conjecture. In particular we demonstrate for the first time in a non-trivial setting that the two key requirements of Background Independence and Asymptotic Safety can be satisfied simultaneously. Carefully disentangling fluctuation and background fields, we employ a ‘bi-metric’ ansatz for the EAA and project the flow generated by its functional renormalization group equation on a truncated theory space spanned by two separate Einstein–Hilbert actions for the dynamical and the background metric, respectively. A new powerful method is used to derive the corresponding renormalization group (RG) equations for the Newton- and cosmological constant, both in the dynamical and the background sector. We classify and analyze their solutions in detail, determine their fixed point structure, and identify an attractor mechanism which turns out instrumental in the split-symmetry restoration. We show that there exists a subset of RG trajectories which are both asymptotically safe and split-symmetry restoring: In the ultraviolet they emanate from a non-Gaussian fixed point, and in the infrared they loose all symmetry violating contributions inflicted on them by the

Glucagon Decreases IGF-1 Bioactivity in Humans, Independently of Insulin, by Modulating Its Binding Proteins.

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Sarem, Zeinab; Bumke-Vogt, Christiane; Mahmoud, Ayman M; Assefa, Biruhalem; Weickert, Martin O; Adamidou, Aikatarini; Bähr, Volker; Frystyk, Jan; Möhlig, Matthias; Spranger, Joachim; Lieske, Stefanie; Birkenfeld, Andreas L; Pfeiffer, Andreas F H; Arafat, Ayman M

2017-09-01

Depending on its lipolytic activity, glucagon plays a promising role in obesity treatment. Glucagon-induced growth hormone (GH) release can promote its effect on lipid metabolism, although the underlying mechanisms have not been well-defined. The present study highlights the glucagon effect on the GH/insulinlike growth factor 1 (IGF-1)/IGF-binding protein (IGFBP) axis in vivo and in vitro, taking into consideration insulin as a confounding factor. In a double-blind, placebo-controlled study, we investigated changes in GH, IGFBP, and IGF-1 bioactivity after intramuscular glucagon administration in 13 lean controls, 11 obese participants, and 13 patients with type 1 diabetes mellitus (T1DM). The effect of glucagon on the transcription factor forkhead box protein O1 (FOXO1) translocation, the transcription of GH/IGF-1 system members, and phosphorylation of protein kinase B (Akt) was further investigated in vitro. Despite unchanged total IGF-1 and IGFBP-3 levels, glucagon decreased IGF-1 bioactivity in all study groups by increasing IGFBP-1 and IGFBP-2. The reduction in IGF-1 bioactivity occurred before the glucagon-induced surge in GH. In contrast to the transient increase in circulating insulin in obese and lean participants, no change was observed in those with T1DM. In vitro, glucagon dose dependently induced a substantial nuclear translocation of FOXO1 in human osteosarcoma cells and tended to increase IGFBP-1 and IGFBP-2 gene expression in mouse primary hepatocytes, despite absent Akt phosphorylation. Our data point to the glucagon-induced decrease in bioactive IGF-1 levels as a mechanism through which glucagon induces GH secretion. This insulin-independent reduction is related to increased IGFBP-1 and IGFBP-2 levels, which are most likely mediated via activation of the FOXO/mTOR (mechanistic target of rapamycin) pathway. Copyright © 2017 Endocrine Society

Insulin in the brain: there and back again.

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Banks, William A; Owen, Joshua B; Erickson, Michelle A

2012-10-01

Insulin performs unique functions within the CNS. Produced nearly exclusively by the pancreas, insulin crosses the blood-brain barrier (BBB) using a saturable transporter, affecting feeding and cognition through CNS mechanisms largely independent of glucose utilization. Whereas peripheral insulin acts primarily as a metabolic regulatory hormone, CNS insulin has an array of effects on brain that may more closely resemble the actions of the ancestral insulin molecule. Brain endothelial cells (BECs), the cells that form the vascular BBB and contain the transporter that translocates insulin from blood to brain, are themselves regulated by insulin. The insulin transporter is altered by physiological and pathological factors including hyperglycemia and the diabetic state. The latter can lead to BBB disruption. Pericytes, pluripotent cells in intimate contact with the BECs, protect the integrity of the BBB and its ability to transport insulin. Most of insulin's known actions within the CNS are mediated through two canonical pathways, the phosphoinositide-3 kinase (PI3)/Akt and Ras/mitogen activated kinase (MAPK) cascades. Resistance to insulin action within the CNS, sometimes referred to as diabetes mellitus type III, is associated with peripheral insulin resistance, but it is possible that variable hormonal resistance syndromes exist so that resistance at one tissue bed may be independent of that at others. CNS insulin resistance is associated with Alzheimer's disease, depression, and impaired baroreceptor gain in pregnancy. These aspects of CNS insulin action and the control of its entry by the BBB are likely only a small part of the story of insulin within the brain. Published by Elsevier Inc.

E4orf1 induction in adipose tissue promotes insulin-independent signaling in the adipocyte.

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Kusminski, Christine M; Gallardo-Montejano, Violeta I; Wang, Zhao V; Hegde, Vijay; Bickel, Perry E; Dhurandhar, Nikhil V; Scherer, Philipp E

2015-10-01

Type 2 diabetes remains a worldwide epidemic with major pathophysiological changes as a result of chronic insulin resistance. Insulin regulates numerous biochemical pathways related to carbohydrate and lipid metabolism. We have generated a novel mouse model that allows us to constitutively activate, in an inducible fashion, the distal branch of the insulin signaling transduction pathway specifically in adipocytes. Using the adenoviral 36 E4orf1 protein, we chronically stimulate locally the Ras-ERK-MAPK signaling pathway. At the whole body level, this leads to reduced body-weight gain under a high fat diet challenge. Despite overlapping glucose tolerance curves, there is a reduced requirement for insulin action under these conditions. The mice further exhibit reduced circulating adiponectin levels that ultimately lead to impaired lipid clearance, and inflamed and fibrotic white adipose tissues. Nevertheless, they are protected from diet-induced hepatic steatosis. As we observe constitutively elevated p-Akt levels in the adipocytes, even under conditions of low insulin levels, this pinpoints enhanced Ras-ERK-MAPK signaling in transgenic adipocytes as a potential alternative route to bypass proximal insulin signaling events. We conclude that E4orf1 expression in the adipocyte leads to enhanced baseline activation of the distal insulin signaling node, yet impaired insulin receptor stimulation in the presence of insulin, with important implications for the regulation of adiponectin secretion. The resulting systemic phenotype is complex, yet highlights the powerful nature of manipulating selective branches of the insulin signaling network within the adipocyte.

Roles of mitochondrial fragmentation and reactive oxygen species in mitochondrial dysfunction and myocardial insulin resistance

International Nuclear Information System (INIS)

Watanabe, Tomoyuki; Saotome, Masao; Nobuhara, Mamoru; Sakamoto, Atsushi; Urushida, Tsuyoshi; Katoh, Hideki; Satoh, Hiroshi; Funaki, Makoto; Hayashi, Hideharu

2014-01-01

Purpose: Evidence suggests an association between aberrant mitochondrial dynamics and cardiac diseases. Because myocardial metabolic deficiency caused by insulin resistance plays a crucial role in heart disease, we investigated the role of dynamin-related protein-1 (DRP1; a mitochondrial fission protein) in the pathogenesis of myocardial insulin resistance. Methods and Results: DRP1-expressing H9c2 myocytes, which had fragmented mitochondria with mitochondrial membrane potential (ΔΨ m ) depolarization, exhibited attenuated insulin signaling and 2-deoxy-D-glucose (2-DG) uptake, indicating insulin resistance. Treatment of the DRP1-expressing myocytes with Mn(III)tetrakis(1-methyl-4-pyridyl)porphyrin pentachloride (TMPyP) significantly improved insulin resistance and mitochondrial dysfunction. When myocytes were exposed to hydrogen peroxide (H 2 O 2 ), they increased DRP1 expression and mitochondrial fragmentation, resulting in ΔΨ m depolarization and insulin resistance. When DRP1 was suppressed by siRNA, H 2 O 2 -induced mitochondrial dysfunction and insulin resistance were restored. Our results suggest that a mutual enhancement between DRP1 and reactive oxygen species could induce mitochondrial dysfunction and myocardial insulin resistance. In palmitate-induced insulin-resistant myocytes, neither DRP1-suppression nor TMPyP restored the ΔΨ m depolarization and impaired 2-DG uptake, however they improved insulin signaling. Conclusions: A mutual enhancement between DRP1 and ROS could promote mitochondrial dysfunction and inhibition of insulin signal transduction. However, other mechanisms, including lipid metabolite-induced mitochondrial dysfunction, may be involved in palmitate-induced insulin resistance. - Highlights: • DRP1 promotes mitochondrial fragmentation and insulin-resistance. • A mutual enhancement between DRP1 and ROS ipromotes insulin-resistance. • Palmitate increases DRP1 expression and induces insulin-resistance. • Inhibition of DRP or ROS

Roles of mitochondrial fragmentation and reactive oxygen species in mitochondrial dysfunction and myocardial insulin resistance

Energy Technology Data Exchange (ETDEWEB)

Watanabe, Tomoyuki [Internal Medicine III, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu 431-3192 (Japan); Saotome, Masao, E-mail: msaotome@hama-med.ac.jp [Internal Medicine III, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu 431-3192 (Japan); Nobuhara, Mamoru; Sakamoto, Atsushi; Urushida, Tsuyoshi; Katoh, Hideki; Satoh, Hiroshi [Internal Medicine III, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu 431-3192 (Japan); Funaki, Makoto [Clinical Research Center for Diabetes, Tokushima University Hospital, 2-50-1 Kuramoto-cho, Tokushima 770-8503 (Japan); Hayashi, Hideharu [Internal Medicine III, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu 431-3192 (Japan)

2014-05-01

Purpose: Evidence suggests an association between aberrant mitochondrial dynamics and cardiac diseases. Because myocardial metabolic deficiency caused by insulin resistance plays a crucial role in heart disease, we investigated the role of dynamin-related protein-1 (DRP1; a mitochondrial fission protein) in the pathogenesis of myocardial insulin resistance. Methods and Results: DRP1-expressing H9c2 myocytes, which had fragmented mitochondria with mitochondrial membrane potential (ΔΨ{sub m}) depolarization, exhibited attenuated insulin signaling and 2-deoxy-D-glucose (2-DG) uptake, indicating insulin resistance. Treatment of the DRP1-expressing myocytes with Mn(III)tetrakis(1-methyl-4-pyridyl)porphyrin pentachloride (TMPyP) significantly improved insulin resistance and mitochondrial dysfunction. When myocytes were exposed to hydrogen peroxide (H{sub 2}O{sub 2}), they increased DRP1 expression and mitochondrial fragmentation, resulting in ΔΨ{sub m} depolarization and insulin resistance. When DRP1 was suppressed by siRNA, H{sub 2}O{sub 2}-induced mitochondrial dysfunction and insulin resistance were restored. Our results suggest that a mutual enhancement between DRP1 and reactive oxygen species could induce mitochondrial dysfunction and myocardial insulin resistance. In palmitate-induced insulin-resistant myocytes, neither DRP1-suppression nor TMPyP restored the ΔΨ{sub m} depolarization and impaired 2-DG uptake, however they improved insulin signaling. Conclusions: A mutual enhancement between DRP1 and ROS could promote mitochondrial dysfunction and inhibition of insulin signal transduction. However, other mechanisms, including lipid metabolite-induced mitochondrial dysfunction, may be involved in palmitate-induced insulin resistance. - Highlights: • DRP1 promotes mitochondrial fragmentation and insulin-resistance. • A mutual enhancement between DRP1 and ROS ipromotes insulin-resistance. • Palmitate increases DRP1 expression and induces insulin

Adenoviral gene transfer of PLD1-D4 enhances insulin sensitivity in mice by disrupting phospholipase D1 interaction with PED/PEA-15.

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Angela Cassese

Full Text Available Over-expression of phosphoprotein enriched in diabetes/phosphoprotein enriched in astrocytes (PED/PEA-15 causes insulin resistance by interacting with the D4 domain of phospholipase D1 (PLD1. Indeed, the disruption of this association restores insulin sensitivity in cultured cells over-expressing PED/PEA-15. Whether the displacement of PLD1 from PED/PEA-15 improves insulin sensitivity in vivo has not been explored yet. In this work we show that treatment with a recombinant adenoviral vector containing the human D4 cDNA (Ad-D4 restores normal glucose homeostasis in transgenic mice overexpressing PED/PEA-15 (Tg ped/pea-15 by improving both insulin sensitivity and secretion. In skeletal muscle of these mice, D4 over-expression inhibited PED/PEA-15-PLD1 interaction, decreased Protein Kinase C alpha activation and restored insulin induced Protein Kinase C zeta activation, leading to amelioration of insulin-dependent glucose uptake. Interestingly, Ad-D4 administration improved insulin sensitivity also in high-fat diet treated obese C57Bl/6 mice. We conclude that PED/PEA-15-PLD1 interaction may represent a novel target for interventions aiming at improving glucose tolerance.

Ovarian SAHA syndrome is associated with a more insulin-resistant profile and represents an independent risk factor for glucose abnormalities in women with polycystic ovary syndrome: a prospective controlled study.

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Dalamaga, Maria; Papadavid, Evangelia; Basios, Georgios; Vaggopoulos, Vassilios; Rigopoulos, Dimitrios; Kassanos, Dimitrios; Trakakis, Eftihios

2013-12-01

SAHA syndrome is characterized by the tetrad: seborrhea, acne, hirsutism, and androgenetic alopecia. No previous study has examined the prevalence of glucose abnormalities in ovarian SAHA and explored whether it may be an independent risk factor for glucose abnormalities. In a prospective controlled study, we investigated the spectrum of glucose abnormalities in ovarian SAHA and explored whether it is associated with a more insulin-resistant profile. In all, 316 patients with a diagnosis of polycystic ovary syndrome (PCOS) (56 with SAHA) and 102 age-matched healthy women were examined and underwent a 2-hour oral glucose tolerance test. Serum glucose homeostasis parameters, hormones, and adipokines were determined. SAHA prevalence was 17.7% in patients with PCOS and predominance of the severe PCOS phenotype. Ovarian SAHA was independently associated with a more insulin-resistant profile (higher homeostatic model assessment of insulin resistance score, lower quantitative insulin sensitivity check index [QUICKI] and MATSUDA indices, and relative hypoadiponectinemia), and represented an independent risk factor for glucose abnormalities regardless of anthropometric features, age, and PCOS phenotype. There was no performance of skin biopsies. The prompt recognition of SAHA syndrome in women with PCOS permits an earlier diagnosis and surveillance of metabolic abnormalities, especially in Mediterranean PCOS population exhibiting a lower prevalence of glucose abnormalities. Copyright © 2013 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.

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.

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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.

E4orf1 induction in adipose tissue promotes insulin-independent signaling in the adipocyte

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Christine M. Kusminski

2015-10-01

Conclusion: We conclude that E4orf1 expression in the adipocyte leads to enhanced baseline activation of the distal insulin signaling node, yet impaired insulin receptor stimulation in the presence of insulin, with important implications for the regulation of adiponectin secretion. The resulting systemic phenotype is complex, yet highlights the powerful nature of manipulating selective branches of the insulin signaling network within the adipocyte.

Insulin-Like Growth Factor (IGF Binding Protein-2, Independently of IGF-1, Induces GLUT-4 Translocation and Glucose Uptake in 3T3-L1 Adipocytes

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Biruhalem Assefa

2017-01-01

Full Text Available Insulin-like growth factor binding protein-2 (IGFBP-2 is the predominant IGF binding protein produced during adipogenesis and is known to increase the insulin-stimulated glucose uptake (GU in myotubes. We investigated the IGFBP-2-induced changes in basal and insulin-stimulated GU in adipocytes and the underlying mechanisms. We further determined the role of insulin and IGF-1 receptors in mediating the IGFBP-2 and the impact of IGFBP-2 on the IGF-1-induced GU. Fully differentiated 3T3-L1 adipocytes were treated with IGFBP-2 in the presence and absence of insulin and IGF-1. Insulin, IGF-1, and IGFBP-2 induced a dose-dependent increase in GU. IGFBP-2 increased the insulin-induced GU after long-term incubation. The IGFBP-2-induced impact on GU was neither affected by insulin or IGF-1 receptor blockage nor by insulin receptor knockdown. IGFBP-2 significantly increased the phosphorylation of PI3K, Akt, AMPK, TBC1D1, and PKCζ/λ and induced GLUT-4 translocation. Moreover, inhibition of PI3K and AMPK significantly reduced IGFBP-2-stimulated GU. In conclusion, IGFBP-2 stimulates GU in 3T3-L1 adipocytes through activation of PI3K/Akt, AMPK/TBC1D1, and PI3K/PKCζ/λ/GLUT-4 signaling. The stimulatory effect of IGFBP-2 on GU is independent of its binding to IGF-1 and is possibly not mediated through the insulin or IGF-1 receptor. This study highlights the potential role of IGFBP-2 in glucose metabolism.

Insulin-Independent GABAA Receptor-Mediated Response in the Barrel Cortex of Mice with Impaired Met Activity.

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Lo, Fu-Sun; Erzurumlu, Reha S; Powell, Elizabeth M

2016-03-30

Autism spectrum disorder (ASD) is a neurodevelopmental disorder caused by genetic variants, susceptibility alleles, and environmental perturbations. The autism associated geneMETtyrosine kinase has been implicated in many behavioral domains and endophenotypes of autism, including abnormal neural signaling in human sensory cortex. We investigated somatosensory thalamocortical synaptic communication in mice deficient in Met activity in cortical excitatory neurons to gain insights into aberrant somatosensation characteristic of ASD. The ratio of excitation to inhibition is dramatically increased due to decreased postsynaptic GABAAreceptor-mediated inhibition in the trigeminal thalamocortical pathway of mice lacking active Met in the cerebral cortex. Furthermore, in contrast to wild-type mice, insulin failed to increase GABAAreceptor-mediated response in the barrel cortex of mice with compromised Met signaling. Thus, lacking insulin effects may be a risk factor in ASD pathogenesis. A proposed common cause of neurodevelopmental disorders is an imbalance in excitatory neural transmission, provided by the glutamatergic neurons, and the inhibitory signals from the GABAergic interneurons. Many genes associated with autism spectrum disorders impair synaptic transmission in the expected cell type. Previously, inactivation of the autism-associated Met tyrosine kinase receptor in GABAergic interneurons led to decreased inhibition. In thus report, decreased Met signaling in glutamatergic neurons had no effect on excitation, but decimated inhibition. Further experiments indicate that loss of Met activity downregulates GABAAreceptors on glutamatergic neurons in an insulin independent manner. These data provide a new mechanism for the loss of inhibition and subsequent abnormal excitation/inhibition balance and potential molecular candidates for treatment or prevention. Copyright © 2016 the authors 0270-6474/16/363691-07$15.00/0.

β cell membrane remodelling and procoagulant events occur in inflammation-driven insulin impairment: a GLP-1 receptor dependent and independent control.

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Gleizes, Céline; Kreutter, Guillaume; Abbas, Malak; Kassem, Mohamad; Constantinescu, Andrei Alexandru; Boisramé-Helms, Julie; Yver, Blandine; Toti, Florence; Kessler, Laurence

2016-02-01

Inflammation and hyperglycaemia are associated with a prothrombotic state. Cell-derived microparticles (MPs) are the conveyors of active procoagulant tissue factor (TF) and circulate at high concentration in diabetic patients. Liraglutide, a glucagon-like peptide (GLP)-1 analogue, is known to promote insulin secretion and β-cell preservation. In this in vitro study, we examined the link between insulin impairment, procoagulant activity and plasma membrane remodelling, under inflammatory conditions. Rin-m5f β-cell function, TF activity mediated by MPs and their modulation by 1 μM liraglutide were examined in a cell cross-talk model. Methyl-β-cyclodextrine (MCD), a cholesterol depletor, was used to evaluate the involvement of raft on TF activity, MP shedding and insulin secretion as well as Soluble N-éthylmaleimide-sensitive-factor Attachment protein Receptor (SNARE)-dependent exocytosis. Cytokines induced a two-fold increase in TF activity at MP surface that was counteracted by liraglutide. Microparticles prompted TF activity on the target cells and a two-fold decrease in insulin secretion via protein kinase A (PKA) and p38 signalling, that was also abolished by liraglutide. Large lipid raft clusters were formed in response to cytokines and liraglutide or MCD-treated cells showed similar patterns. Cells pre-treated by saturating concentration of the GLP-1r antagonist exendin (9-39), showed a partial abolishment of the liraglutide-driven insulin secretion and liraglutide-decreased TF activity. Measurement of caspase 3 cleavage and MP shedding confirmed the contribution of GLP-1r-dependent and -independent pathways. Our results confirm an integrative β-cell response to GLP-1 that targets receptor-mediated signalling and membrane remodelling pointing at the coupling of insulin secretion and inflammation-driven procoagulant events. © 2015 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and

Pharmacological TLR4 Inhibition Protects against Acute and Chronic Fat-Induced Insulin Resistance in Rats.

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Zhang, Ning; Liang, Hanyu; Farese, Robert V; Li, Ji; Musi, Nicolas; Hussey, Sophie E

2015-01-01

To evaluate whether pharmacological TLR4 inhibition protects against acute and chronic fat-induced insulin resistance in rats. For the acute experiment, rats received a TLR4 inhibitor [TAK-242 or E5564 (2x5 mg/kg i.v. bolus)] or vehicle, and an 8-h Intralipid (20%, 8.5 mg/kg/min) or saline infusion, followed by a two-step hyperinsulinemic-euglycemic clamp. For the chronic experiment, rats were subcutaneously implanted with a slow-release pellet of TAK-242 (1.5 mg/d) or placebo. Rats then received a high fat diet (HFD) or a low fat control diet (LFD) for 10 weeks, followed by a two-step insulin clamp. Acute experiment; the lipid-induced reduction (18%) in insulin-stimulated glucose disposal (Rd) was attenuated by TAK-242 and E5564 (the effect of E5564 was more robust), suggesting improved peripheral insulin action. Insulin was able to suppress hepatic glucose production (HGP) in saline- but not lipid-treated rats. TAK-242, but not E5564, partially restored this effect, suggesting improved HGP. Chronic experiment; insulin-stimulated Rd was reduced ~30% by the HFD, but completely restored by TAK-242. Insulin could not suppress HGP in rats fed a HFD and TAK-242 had no effect on HGP. Pharmacological TLR4 inhibition provides partial protection against acute and chronic fat-induced insulin resistance in vivo.

Catch-up growth following fetal growth restriction promotes rapid restoration of fat mass but without metabolic consequences at one year of age.

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Jacques Beltrand

Full Text Available BACKGROUND: Fetal growth restriction (FGR followed by rapid weight gain during early life has been suggested to be the initial sequence promoting central adiposity and insulin resistance. However, the link between fetal and early postnatal growth and the associated anthropometric and metabolic changes have been poorly studied. METHODOLOGY/PRINCIPAL FINDINGS: Over the first year of post-natal life, changes in body mass index, skinfold thickness and hormonal concentrations were prospectively monitored in 94 infants in whom the fetal growth velocity had previously been measured using a repeated standardized procedure of ultrasound fetal measurements. 45 infants, thinner at birth, had experienced previous FGR (FGR+ regardless of birth weight. Growth pattern in the first four months of life was characterized by greater change in BMI z-score in FGR+ (+1.26+/-1.2 vs +0.58 +/-1.17 SD in FGR- resulting in the restoration of BMI and of fat mass to values similar to FGR-, independently of caloric intakes. Growth velocity after 4 months was similar and BMI z-score and fat mass remained similar at 12 months of age. At both time-points, fetal growth velocity was an independent predictor of fat mass in FGR+. At one year, fasting insulin levels were not different but leptin was significantly higher in the FGR+ (4.43+/-1.41 vs 2.63+/-1 ng/ml in FGR-. CONCLUSION: Early catch-up growth is related to the fetal growth pattern itself, irrespective of birth weight, and is associated with higher insulin sensitivity and lower leptin levels after birth. Catch-up growth promotes the restoration of body size and fat stores without detrimental consequences at one year of age on body composition or metabolic profile. The higher leptin concentration at one year may reflect a positive energy balance in children who previously faced fetal growth restriction.

New measure of insulin sensitivity predicts cardiovascular disease better than HOMA estimated insulin resistance.

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Kavita Venkataraman

Full Text Available CONTEXT: Accurate assessment of insulin sensitivity may better identify individuals at increased risk of cardio-metabolic diseases. OBJECTIVES: To examine whether a combination of anthropometric, biochemical and imaging measures can better estimate insulin sensitivity index (ISI and provide improved prediction of cardio-metabolic risk, in comparison to HOMA-IR. DESIGN AND PARTICIPANTS: Healthy male volunteers (96 Chinese, 80 Malay, 77 Indian, 21 to 40 years, body mass index 18-30 kg/m(2. Predicted ISI (ISI-cal was generated using 45 randomly selected Chinese through stepwise multiple linear regression, and validated in the rest using non-parametric correlation (Kendall's tau τ. In an independent longitudinal cohort, ISI-cal and HOMA-IR were compared for prediction of diabetes and cardiovascular disease (CVD, using ROC curves. SETTING: The study was conducted in a university academic medical centre. OUTCOME MEASURES: ISI measured by hyperinsulinemic euglycemic glucose clamp, along with anthropometric measurements, biochemical assessment and imaging; incident diabetes and CVD. RESULTS: A combination of fasting insulin, serum triglycerides and waist-to-hip ratio (WHR provided the best estimate of clamp-derived ISI (adjusted R(2 0.58 versus 0.32 HOMA-IR. In an independent cohort, ROC areas under the curve were 0.77±0.02 ISI-cal versus 0.76±0.02 HOMA-IR (p>0.05 for incident diabetes, and 0.74±0.03 ISI-cal versus 0.61±0.03 HOMA-IR (p<0.001 for incident CVD. ISI-cal also had greater sensitivity than defined metabolic syndrome in predicting CVD, with a four-fold increase in the risk of CVD independent of metabolic syndrome. CONCLUSIONS: Triglycerides and WHR, combined with fasting insulin levels, provide a better estimate of current insulin resistance state and improved identification of individuals with future risk of CVD, compared to HOMA-IR. This may be useful for estimating insulin sensitivity and cardio-metabolic risk in clinical and

Circadian control of insulin secretion is independent of the temporal distribution of feeding

NARCIS (Netherlands)

Kalsbeek, Andries; Strubbe, JH

1998-01-01

To investigate whether there is a circadian regulation of insulin secretion, rats were adapted to a feeding regimen of six meals equally distributed over 24 h. Under these conditions basal glucose and insulin levels increased during the light phase and decreased during the dark phase. Maximal blood

Dual role of proapoptotic BAD in insulin secretion and beta cell survival.

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Danial, Nika N; Walensky, Loren D; Zhang, Chen-Yu; Choi, Cheol Soo; Fisher, Jill K; Molina, Anthony J A; Datta, Sandeep Robert; Pitter, Kenneth L; Bird, Gregory H; Wikstrom, Jakob D; Deeney, Jude T; Robertson, Kirsten; Morash, Joel; Kulkarni, Ameya; Neschen, Susanne; Kim, Sheene; Greenberg, Michael E; Corkey, Barbara E; Shirihai, Orian S; Shulman, Gerald I; Lowell, Bradford B; Korsmeyer, Stanley J

2008-02-01

The proapoptotic BCL-2 family member BAD resides in a glucokinase-containing complex that regulates glucose-driven mitochondrial respiration. Here, we present genetic evidence of a physiologic role for BAD in glucose-stimulated insulin secretion by beta cells. This novel function of BAD is specifically dependent upon the phosphorylation of its BH3 sequence, previously defined as an essential death domain. We highlight the pharmacologic relevance of phosphorylated BAD BH3 by using cell-permeable, hydrocarbon-stapled BAD BH3 helices that target glucokinase, restore glucose-driven mitochondrial respiration and correct the insulin secretory response in Bad-deficient islets. Our studies uncover an alternative target and function for the BAD BH3 domain and emphasize the therapeutic potential of phosphorylated BAD BH3 mimetics in selectively restoring beta cell function. Furthermore, we show that BAD regulates the physiologic adaptation of beta cell mass during high-fat feeding. Our findings provide genetic proof of the bifunctional activities of BAD in both beta cell survival and insulin secretion.

IRS-1: essential for insulin- and IL-4-stimulated mitogenesis in hematopoietic cells.

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Wang, L M; Myers, M G; Sun, X J; Aaronson, S A; White, M; Pierce, J H

1993-09-17

Although several interleukin-3 (IL-3)-dependent cell lines proliferate in response to IL-4 or insulin, the 32D line does not. Insulin and IL-4 sensitivity was restored to 32D cells by expression of IRS-1, the principal substrate of the insulin receptor. Although 32D cells possessed receptors for both factors, they lacked the IRS-1--related protein, 4PS, which becomes phosphorylated by tyrosine in insulin- or IL-4--responsive lines after stimulation. These results indicate that factors that bind unrelated receptors can use similar mitogenic signaling pathways in hematopoietic cells and that 4PS and IRS-1 are functionally similar proteins that are essential for insulin- and IL-4--induced proliferation.

The insulin-resistant phenotype of polycystic ovary syndrome

DEFF Research Database (Denmark)

Svendsen, Pernille Fog; Madsbad, Sten; Nilas, Lisbeth

2009-01-01

OBJECTIVE: To investigate the individual parameters included in the diagnosis of polycystic ovary syndrome (PCOS), and their impact on insulin sensitivity. DESIGN: Cross-sectional study. SETTING: Department of Obstetrics and Gynaecology, Copenhagen University Hospital, Hvidovre, Denmark. PATIENT...... assessment IR index. We found no significant association between ovarian morphology and insulin sensitivity or between menstrual frequency and insulin sensitivity. CONCLUSION(S): The PCOS is associated with IR. Body mass index, hyperandrogenemia, and hyperandrogenism are independent predictors of low insulin...

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

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Kimball Scot R

2011-05-01

Full Text Available Abstract Background Diabetic retinopathy (DR is a leading cause of blindness in working age adults. Approximately 95% of patients with Type 1 diabetes develop some degree of retinopathy within 25 years of diagnosis despite normalization of blood glucose by insulin therapy. The goal of this study was to identify molecular changes in the rodent retina induced by diabetes that are not normalized by insulin replacement and restoration of euglycemia. Methods The retina transcriptome (22,523 genes and transcript variants was examined after three months of streptozotocin-induced diabetes in male Sprague Dawley rats with and without insulin replacement for the later one and a half months of diabetes. Selected gene expression changes were confirmed by qPCR, and also examined in independent control and diabetic rats at a one month time-point. Results Transcriptomic alterations in response to diabetes (1376 probes were clustered according to insulin responsiveness. More than half (57% of diabetes-induced mRNA changes (789 probes observed at three months were fully normalized to control levels with insulin therapy, while 37% of probes (514 were only partially normalized. A small set of genes (5%, 65 probes was significantly dysregulated in the insulin-treated diabetic rats. qPCR confirmation of findings and examination of a one month time point allowed genes to be further categorized as prevented or rescued with insulin therapy. A subset of genes (Ccr5, Jak3, Litaf was confirmed at the level of protein expression, with protein levels recapitulating changes in mRNA expression. Conclusions These results provide the first genome-wide examination of the effects of insulin therapy on retinal gene expression changes with diabetes. While insulin clearly normalizes the majority of genes dysregulated in response to diabetes, a number of genes related to inflammatory processes, microvascular integrity, and neuronal function are still altered in expression in

Estrogen restores brain insulin sensitivity in ovariectomized non-obese rats, but not in ovariectomized obese rats.

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Pratchayasakul, Wasana; Chattipakorn, Nipon; Chattipakorn, Siriporn C

2014-06-01

We previously demonstrated that obesity caused the reduction of peripheral and brain insulin sensitivity and that estrogen therapy improved these defects. However, the beneficial effect of estrogen on brain insulin sensitivity and oxidative stress in either ovariectomy alone or ovariectomy with obesity models has not been determined. We hypothesized that ovariectomy alone or ovariectomy with obesity reduces brain insulin sensitivity and increases brain oxidative stress, which are reversed by estrogen treatment. Thirty female rats were assigned as either sham-operated or ovariectomized. After the surgery, each group was fed either a normal diet or high-fat diet for 12 weeks. At week 13, rats in each group received either the vehicle or estradiol for 30 days. At week 16, blood and brain were collected for determining the peripheral and brain insulin sensitivity as well as brain oxidative stress. We found that ovariectomized rats and high-fat diet fed rats incurred obesity, reduced peripheral and brain insulin sensitivity, and increased brain oxidative stress. Estrogen ameliorated peripheral insulin sensitivity in these rats. However, the beneficial effect of estrogen on brain insulin sensitivity and brain oxidative stress was observed only in ovariectomized normal diet-fed rats, but not in ovariectomized high fat diet-fed rats. Our results suggested that reduced brain insulin sensitivity and increased brain oxidative stress occurred after either ovariectomy or obesity. However, the reduced brain insulin sensitivity and the increased brain oxidative stress in ovariectomy with obesity could not be ameliorated by estrogen treatment. Copyright © 2014 Elsevier Inc. All rights reserved.

Voluntary wheel running selectively augments insulin-stimulated vasodilation in arterioles from white skeletal muscle of insulin-resistant rats.

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Mikus, Catherine R; Roseguini, Bruno T; Uptergrove, Grace M; Morris, E Matthew; Rector, Randy Scott; Libla, Jessica L; Oberlin, Douglas J; Borengasser, Sarah J; Taylor, Angelina M; Ibdah, Jamal A; Laughlin, Maurice Harold; Thyfault, John P

2012-11-01

Exercise (RUN) prevents declines in insulin-mediated vasodilation, an important component of insulin-mediated glucose disposal, in rats prone to obesity and insulin resistance. Determine whether RUN (1) improves insulin-stimulated vasodilation after insulin resistance has been established, and (2) differentially affects arterioles from red and white muscle. Insulin signaling and vasoreactivity to insulin (1-1000 μIU/mL) were assessed in 2A from the Gw and Gr of SED OLETF rats at 12 and 20 weeks of age (SED12, SED20) and those undergoing RUN (RUN20) or caloric restriction (CR20; to match body weight of RUN) from 12 to 20 weeks. Glucose and insulin responses to i.p. glucose were reduced in RUN20, elevated in SED20 (p RUN20 (p RUN selectively improved insulin-mediated vasodilation in Gw 2As, in part through attenuated ET-1 sensitivity/production, an adaptation that was independent of changes in adiposity and may contribute to enhanced insulin-stimulated glucose disposal. © 2012 John Wiley & Sons Ltd.

Insulin in the brain: sources, localization and functions.

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Ghasemi, Rasoul; Haeri, Ali; Dargahi, Leila; Mohamed, Zahurin; Ahmadiani, Abolhassan

2013-02-01

Historically, insulin is best known for its role in peripheral glucose homeostasis, and insulin signaling in the brain has received less attention. Insulin-independent brain glucose uptake has been the main reason for considering the brain as an insulin-insensitive organ. However, recent findings showing a high concentration of insulin in brain extracts, and expression of insulin receptors (IRs) in central nervous system tissues have gathered considerable attention over the sources, localization, and functions of insulin in the brain. This review summarizes the current status of knowledge of the peripheral and central sources of insulin in the brain, site-specific expression of IRs, and also neurophysiological functions of insulin including the regulation of food intake, weight control, reproduction, and cognition and memory formation. This review also considers the neuromodulatory and neurotrophic effects of insulin, resulting in proliferation, differentiation, and neurite outgrowth, introducing insulin as an attractive tool for neuroprotection against apoptosis, oxidative stress, beta amyloid toxicity, and brain ischemia.

GLP-1 Restores Altered Insulin and Glucagon Secretion in Posttransplantation Diabetes

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Halden, Thea A S; Egeland, Erlend J; Åsberg, Anders

2016-01-01

OBJECTIVE: Development of posttransplantation diabetes (PTDM) is characterized by reduced insulin secretion and sensitivity. We aimed to investigate whether hyperglucagonemia could play a role in PTDM and to examine the insulinotropic and glucagonostatic effects of the incretin hormone glucagon...... h of infusion, a 2-h hyperglycemic clamp (fasting plasma glucose + 5 mmol/L) was established. Five grams of arginine was given as an intravenous bolus 10 min before termination of the clamp. RESULTS: Fasting concentrations of glucagon (P = 0.92) and insulin (P = 0.23) were similar between the groups...... to arginine (P = 0.01) but similar glucagon and proinsulin responses compared with control subjects. In the preclamp phase, GLP-1 lowered fasting plasma glucose to the same extent in both groups but reduced glucagon only in PTDM patients. During hyperglycemic clamp, GLP-1 reduced glucagon concentrations...

Diminished hepatic insulin removal in obesity

International Nuclear Information System (INIS)

Cano, I.; Salvador, J.; Rodriguez, R.; Arraiza, M.C.; Goena, M.; Barberia, J.J.; Moncada, E.

1986-01-01

Peripheral insulin and C-peptide levels during oral glucose load were measured in 20 obese and 23 normal weight nondiabetic subjects. The fasting C-peptide to insulin molar ratios (Cp/I), as well as the relation between incremental areas of the two polypeptides (ACp-AI)/ACp, were used as relative measures of the hepatic insulin extraction (HIE). The insulin and C-peptide basal levels as well as incremental areas under plasma curves were higher in the obese subjects (P<0.001). HIE was lower in obeses than in controls assessed in the fasting state (P<0.05), as well as after glucose load (P<0.001). Nevertheless, obeses and controls with similar insulin fasting levels showed identical hepatic insulin extraction in fasting or after glucose load. HIE was independent of obesity degree, but was related to insulin basal levels (r=-0.60, P<0.01). This study suggests the hypothesis that the decreased hepatic insulin extraction in obeses is a result of the chronically increased insulin delivery to the liver and is not a consequence of obesity, although a contributory role cannot be ruled out

Diminished hepatic insulin removal in obesity

Energy Technology Data Exchange (ETDEWEB)

Cano, I; Salvador, J; Rodriguez, R; Arraiza, M C; Goena, M; Barberia, J J; Moncada, E

1986-01-01

Peripheral insulin and C-peptide levels during oral glucose load were measured in 20 obese and 23 normal weight nondiabetic subjects. The fasting C-peptide to insulin molar ratios (Cp/I), as well as the relation between incremental areas of the two polypeptides (ACp-AI)/ACp, were used as relative measures of the hepatic insulin extraction (HIE). The insulin and C-peptide basal levels as well as incremental areas under plasma curves were higher in the obese subjects (P<0.001). HIE was lower in obeses than in controls assessed in the fasting state (P<0.05), as well as after glucose load (P<0.001). Nevertheless, obeses and controls with similar insulin fasting levels showed identical hepatic insulin extraction in fasting or after glucose load. HIE was independent of obesity degree, but was related to insulin basal levels (r=-0.60, P<0.01). This study suggests the hypothesis that the decreased hepatic insulin extraction in obeses is a result of the chronically increased insulin delivery to the liver and is not a consequence of obesity, although a contributory role cannot be ruled out.

[Metabolic profile in obese patients with obstructive sleep apnea. A comparison between patients with insulin resistance and with insulin sensitivity].

Science.gov (United States)

Dumitrache-Rujinski, Stefan; Dinu, Ioana; Călcăianu, George; Erhan, Ionela; Cocieru, Alexandru; Zaharia, Dragoş; Toma, Claudia Lucia; Bogdan, Miron Alexandru

2014-01-01

Obstructive sleep apnea syndrome (OSAS) may induce metabolic abnormalities through intermittent hypoxemia and simpathetic activation. It is difficult to demonstrate an independent role of OSAS in the occurrence of metabolic abnormalities, as obesity represents an important risk factor for both OSAS and metabolic abnormalities. to assess the relations between insulin resistance (IR), insulin sensitivity (IS), OSAS severity and nocturnal oxyhaemoglobin levels in obese, nondiabetic patients with daytime sleepiness. We evaluated 99 consecutive, obese, nondiabetic patients (fasting glycemia 5/hour and daytime sleepiness) by an ambulatory six channel cardio-respiratory polygraphy. Hight, weight serum triglycerides (TG), high density lipoprotein-cholesterol (HDL-C) levels were evaluated. Correlations between Apneea Hypopnea Index (AHI), Oxygen Desaturation Index (ODI), average and lowest oxyhaemoglobin saturation (SaO), body mass index (BMI) and insulin resistance or sensitivity were assesed. IR was defined as a TG/ HDL-Cratio > 3, and insulin sensitivity (IS) as a TG/HDL-C ratio obese nondiabetic patients. Preserving insulin sensitivity is more likely when oxyhaemoglobin levels are higher and ODI is lower. Mean lowest nocturnal SaO2 levels seems to be independently involved in the development of insulin resistance as no statistically significant differences were found for BMI between the two groups.

Beta-cell function is associated with carotid intima-media thickness independently of insulin resistance in healthy individuals

DEFF Research Database (Denmark)

Roussel, Ronan; Natali, Andrea; Balkau, Beverley

2016-01-01

Objective: It is a common belief that early atherosclerosis in prediabetes is causally linked to endothelial insulin resistance. Another condition, a low insulin secretion, may be associated with insufficient insulin action on the vascular wall and consequently favor atherosclerosis. Our aim...... was to test this hypothesis in people without diabetes, taking into account the gold-standard measurement of insulin sensitivity, a major confounder in the relationship between insulin secretion and atherosclerosis. Methods: We studied the European Relationship between Insulin Sensitivity and Cardiovascular...... Risk cohort of 451 men and 593 women (44±8 years, mean±SD) who were free of diabetes, hypertension, dyslipidemia, and other known chronic or acute conditions. All underwent an oral glucose tolerance test, a euglycemic-hyperinsulinemic clamp (M/I measured insulin sensitivity), and B-mode carotid...

Estradiol Protects Proopiomelanocortin Neurons Against Insulin Resistance.

Science.gov (United States)

Qiu, Jian; Bosch, Martha A; Meza, Cecilia; Navarro, Uyen-Vy; Nestor, Casey C; Wagner, Edward J; Rønnekleiv, Oline K; Kelly, Martin J

2018-02-01

Insulin resistance is at the core of the metabolic syndrome, and men exhibit a higher incidence of metabolic syndrome than women in early adult life, but this sex advantage diminishes sharply when women reach the postmenopausal state. Because 17β-estradiol (E2) augments the excitability of the anorexigenic proopiomelanocortin (POMC) neurons, we investigated the neuroprotective effects of E2 against insulin resistance in POMC neurons from diet-induced obese (DIO) female and male mice. The efficacy of insulin to activate canonical transient receptor potential 5 (TRPC5) channels and depolarize POMC neurons was significantly reduced in DIO male mice but not in DIO female mice. However, the insulin response in POMC neurons was abrogated in ovariectomized DIO females but restored with E2 replacement. E2 increased T-type calcium channel Cav3.1 messenger RNA (mRNA) expression and whole-cell currents but downregulated stromal-interaction molecule 1 mRNA, which rendered POMC neurons more excitable and responsive to insulin-mediated TRPC5 channel activation. Moreover, E2 prevented the increase in suppressor of cytokine signaling-3 mRNA expression with DIO as seen in DIO males. As proof of principle, insulin [intracerebroventricular injection into the third ventricle (ICV)] decreased food intake and increased metabolism in female but not male guinea pigs fed a high-fat diet. The uncoupling of the insulin receptor from its downstream effector system was corroborated by the reduced expression of phosphorylated protein kinase B in the arcuate nucleus of male but not female guinea pigs following insulin. Therefore, E2 protects female POMC neurons from insulin resistance by enhancing POMC neuronal excitability and the coupling of insulin receptor to TRPC5 channel activation. Copyright © 2018 Endocrine Society.

Dietary fat drives whole-body insulin resistance and promotes intestinal inflammation independent of body weight gain

DEFF Research Database (Denmark)

Jensen, Benjamin Anderschou Holbech; Nielsen, Thomas Svava; Fritzen, Andreas Mæchel

2016-01-01

body glucose homeostasis was evaluated by insulin and glucose tolerance tests as well as by a hyperinsulinemic euglycemic clamp experiment. RESULTS: Compared with LFD-fed reference mice, HFD-fed mice, irrespective of protein:carbohydrate ratio, exhibited impaired glucose tolerance, whereas...... no differences were observed during insulin tolerance tests. The hyperinsulinemic euglycemic clamp revealed tissue-specific effects on glucose homeostasis in all HFD-fed groups. HFD-fed mice exhibited decreased insulin-stimulated glucose uptake in white but not in brown adipose tissue, and sustained endogenous...... glucose production under insulin-stimulated conditions. We observed no impairment of insulin-stimulated glucose uptake in skeletal muscles of different fiber type composition. HFD-feeding altered the gut microbiota composition paralleled by increased expression of pro-inflammatory cytokines and genes...

Similar weight-adjusted insulin secretion and insulin sensitivity in short-duration late autoimmune diabetes of adulthood (LADA) and Type 2 diabetes

DEFF Research Database (Denmark)

Juhl, C B; Bradley, U; Holst, Jens Juul

2014-01-01

AIMS: To explore insulin sensitivity and insulin secretion in people with latent autoimmune diabetes in adulthood (LADA) compared with that in people with Type 2 diabetes. METHODS: A total of 12 people with LADA, defined as glutamic acid decarboxylase (GAD) antibody positivity and > 1 year...... of insulin independency (group A) were age-matched pairwise to people with Type 2 diabetes (group B) and to six people with Type 2 diabetes of similar age and BMI (group C). β-cell function (first-phase insulin secretion and assessment of insulin pulsatility), insulin sensitivity (hyperinsulinemic......-euglycemic clamp) and metabolic response during a mixed meal were studied. RESULTS: Both first-phase insulin secretion and insulin release during the meal were greater (P = 0.05 and P = 0.009, respectively) in Type 2 diabetes as compared with LADA; these differences were lost on adjustment for BMI (group C...

Insulin secretion and action in North Indian women during pregnancy.

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Arora, G P; Almgren, P; Thaman, R G; Pal, A; Groop, L; Vaag, A; Prasad, R B; Brøns, C

2017-10-01

The relative roles(s) of impaired insulin secretion vs. insulin resistance in the development of gestational diabetes mellitus depend upon multiple risk factors and diagnostic criteria. Here, we explored their relative contribution to gestational diabetes as defined by the WHO 1999 (GDM1999) and adapted WHO 2013 (GDM2013) criteria, excluding the 1-h glucose value, in a high-risk Indian population from Punjab. Insulin secretion (HOMA2-B) and insulin action (HOMA2-IR) were assessed in 4665 Indian women with or without gestational diabetes defined by the GDM1999 or adapted GDM2013 criteria. Gestational diabetes defined using both criteria was associated with decreased insulin secretion compared with pregnant women with normal glucose tolerance. Women with gestational diabetes defined by the adapted GDM2013, but not GDM1999 criteria, were more insulin resistant than pregnant women with normal glucose tolerance, and furthermore displayed lower insulin secretion than GDM1999 women. Urban habitat, illiteracy, high age and low BMI were independently associated with reduced insulin secretion, whereas Sikh religion, increasing age and BMI, as well as a family history of diabetes were independently associated with increased insulin resistance. Gestational diabetes risk factors influence insulin secretion and action in North Indian women in a differential manner. Gestational diabetes classified using the adapted GDM2013 compared with GDM1999 criteria is associated with more severe impairments of insulin secretion and action. © 2017 Diabetes UK.

Repopulation of the atrophied thymus in diabetic rats by insulin-like growth factor I

International Nuclear Information System (INIS)

Binz, K.; Joller, P.; Froesch, P.; Binz, H.; Zapf, J.; Froesch, E.R.

1990-01-01

Atrophy of the thymus is one of the consequences of severe insulin deficiency. The authors describe here that the weight and the architecture of the thymus of diabetic rats is restored towards normal not only by insulin but also by insulin-like growth factor I (IGF-I) treatment. In contrast to insulin, this effect of IGF-I occurs despite persisting hyperglycemia and adrenal hyperplasia. They also investigated the in vivo effect of IGF-I on replication and differentiation of thymocytes from streptozotocin-induced diabetic rats. Thymocytes from diabetic rats incorporated less [ 3 H]thymidine than did thymocytes from healthy rats. Insulin, as well as IGF-I treatment of diabetic rats increased [ 3 H]thymidine incorporation by thymocytes. Flow cytometry of thymocytes labeled with monoclonal antibodies revealed a decreased expression of the Thy-1 antigen in diabetic rats compared with control rats. In addition, a major deficiency of thymocytes expressing simultaneously the W3/25 and the Ox8 antigens was observed. These changes were restored towards normal by insulin as well as by IGF-I treatment. The antibody response to a T cell-dependent antigen (bovine serum albumin) was comparable in normal and diabetic rats. They conclude that IGF-I has important effects on the thymocyte number and the presence of CD4 + /CD8 + immature cells in the thymus of diabetic rats despite persisting hyperglycemia. However, helper T-cell function for antibody production appears to be preserved even in the severely diabetic state

FoxO/Daf-16 restored thrashing movement reduced by heat stress in Caenorhabditis elegans.

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Furuhashi, Tsubasa; Sakamoto, Kazuichi

2014-04-01

Many studies on thermotolerance have been done in Caenorhabditis elegans in order to extend survival under heat stress; Daf-16, a homolog of FoxO in C. elegans, was detected as the key factor in thermotolerance. However, the recovery process from heat stress damage has been seldom discussed. In this study, we analyzed the roles of FoxO/Daf-16 on the recovery from heat stress damage by monitoring thrashing movement. Heat shock reduced the movement, which was restored by culturing at 20°C. Thrashing movement was not restored in the daf-16 mutant, which suggests that Daf-16 is one of the essential factors in repairing the damage. Movement restoration was promoted in the daf-2 mutant, a homolog of insulin/IGF-1-like receptor, in a daf-16-dependent manner. In addition, heat stress decreased the expression of daf-28 and ins-7, agonists of Daf-2. Taken together, these results revealed that FoxO/Daf-16 removes heat stress damage and restores movement via inhibition of the insulin-like signaling pathway in C. elegans, suggesting that FoxO/Daf-16 plays a critical role in thermotolerance. Copyright © 2014 Elsevier Inc. All rights reserved.

Proximity to Delivery Alters Insulin Sensitivity and Glucose Metabolism in Pregnant Mice.

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Musial, Barbara; Fernandez-Twinn, Denise S; Vaughan, Owen R; Ozanne, Susan E; Voshol, Peter; Sferruzzi-Perri, Amanda N; Fowden, Abigail L

2016-04-01

In late pregnancy, maternal insulin resistance occurs to support fetal growth, but little is known about insulin-glucose dynamics close to delivery. This study measured insulin sensitivity in mice in late pregnancy at day 16 (D16) and near term at D19. Nonpregnant (NP) and pregnant mice were assessed for metabolite and hormone concentrations, body composition by DEXA, tissue insulin signaling protein abundance by Western blotting, glucose tolerance and utilization, and insulin sensitivity using acute insulin administration and hyperinsulinemic-euglycemic clamps with [(3)H]glucose infusion. Whole-body insulin resistance occurred in D16 pregnant dams in association with basal hyperinsulinemia, insulin-resistant endogenous glucose production, and downregulation of several proteins in hepatic and skeletal muscle insulin signaling pathways relative to NP and D19 values. Insulin resistance was less pronounced at D19, with restoration of NP insulin concentrations, improved hepatic insulin sensitivity, and increased abundance of hepatic insulin signaling proteins. At D16, insulin resistance at whole-body, tissue, and molecular levels will favor fetal glucose acquisition, while improved D19 hepatic insulin sensitivity will conserve glucose for maternal use in anticipation of lactation. Tissue sensitivity to insulin, therefore, alters differentially with proximity to delivery in pregnant mice, with implications for human and other species. © 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

Nonalcoholic Fatty Liver Disease Is Prevalent in Women With Prior Gestational Diabetes Mellitus and Independently Associated With Insulin Resistance and Waist Circumference

DEFF Research Database (Denmark)

Foghsgaard, Signe; Andreasen, Camilla; Vedtofte, Louise

2017-01-01

, insulin resistance (P = 0.0057) and waist circumference (P = 0.0109) were independently associated with NAFLD. CONCLUSIONS: NAFLD was prevalent in this cohort of relatively young and nonseverely obese women with pGDM who are considered healthy apart from their increased risk for diabetes. Insulin......OBJECTIVE: Type 2 diabetes increases the risk of nonalcoholic fatty liver disease (NAFLD), which is a potentially reversible condition but is also associated with progressive fibrosis and cirrhosis. Women with prior gestational diabetes mellitus (pGDM) have a higher risk for NAFLD. RESEARCH DESIGN...... AND METHODS: One hundred women without diabetes who had pGDM (median [interquartile range]: age 38.6 [6.4] years; BMI 31.0 [6.2] kg/m(2)) and 11 healthy control subjects without NAFLD (age 37.9 [7.8] years; BMI 28.1 [0.8] kg/m(2)) underwent a 75-g oral glucose tolerance test (OGTT), DXA whole-body scan...

Dietary Sodium Restriction Decreases Insulin Secretion Without Affecting Insulin Sensitivity in Humans

Science.gov (United States)

Byrne, Loretta M.; Yu, Chang; Wang, Thomas J.; Brown, Nancy J.

2014-01-01

Context: Interruption of the renin-angiotensin-aldosterone system prevents incident diabetes in high-risk individuals, although the mechanism remains unclear. Objective: To test the hypothesis that activation of the endogenous renin-angiotensin-aldosterone system or exogenous aldosterone impairs insulin secretion in humans. Design: We conducted a randomized, blinded crossover study of aldosterone vs vehicle and compared the effects of a low-sodium versus a high-sodium diet. Setting: Academic clinical research center. Participants: Healthy, nondiabetic, normotensive volunteers. Interventions: Infusion of exogenous aldosterone (0.7 μg/kg/h for 12.5 h) or vehicle during low or high sodium intake. Low sodium (20 mmol/d; n = 12) vs high sodium (160 mmol/d; n = 17) intake for 5–7 days. Main Outcome Measures: Change in acute insulin secretory response assessed during hyperglycemic clamps while in sodium balance during a low-sodium vs high-sodium diet during aldosterone vs vehicle. Results: A low-sodium diet increased endogenous aldosterone and plasma renin activity, and acute glucose-stimulated insulin (−16.0 ± 5.6%; P = .007) and C-peptide responses (−21.8 ± 8.4%; P = .014) were decreased, whereas the insulin sensitivity index was unchanged (−1.0 ± 10.7%; P = .98). Aldosterone infusion did not affect the acute insulin response (+1.8 ± 4.8%; P = .72) or insulin sensitivity index (+2.0 ± 8.8%; P = .78). Systolic blood pressure and serum potassium were similar during low and high sodium intake and during aldosterone infusion. Conclusions: Low dietary sodium intake reduces insulin secretion in humans, independent of insulin sensitivity. PMID:25029426

Altered expression and insulin-induced trafficking of Na+-K+-ATPase in rat skeletal muscle

DEFF Research Database (Denmark)

Galuska, Dana; Kotova, Olga; Barres, Romain

2009-01-01

Skeletal muscle Na(+)-K(+)-ATPase plays a central role in the clearance of K(+) from the extracellular fluid, therefore maintaining blood [K(+)]. Na(+)-K(+)-ATPase activity in peripheral tissue is impaired in insulin resistant states. We determined effects of high-fat diet (HFD) and exercise......(+)-K(+)-ATPase activity after 4 wk of HFD. Exercise training restored alpha(1)-, alpha(2)-, and beta(1)-subunit expression and Na(+)-K(+)-ATPase activity to control levels and reduced beta(2)-subunit expression 2.2-fold (P ... phospholemman. Phospholemman mRNA and protein expression were increased after HFD and restored to control levels after ET. Insulin-stimulated translocation of the alpha(2)-subunit to plasma membrane was impaired by HFD, whereas alpha(1)-subunit translocation remained unchanged. Alterations in sodium pump...

Restoration of Lepr in β cells of Lepr null mice does not prevent hyperinsulinemia and hyperglycemia

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Anna M. D'souza

2017-06-01

Full Text Available Objective: The adipose-derived hormone leptin plays an important role in regulating body weight and glucose homeostasis. Leptin receptors are expressed in the central nervous system as well as peripheral tissues involved in regulating glucose homeostasis, including insulin-producing β cells of the pancreas. Previous studies assessing the role of leptin receptors in β cells used Cre-loxP to disrupt the leptin receptor gene (Lepr in β cells, but variable results were obtained. Furthermore, recombination of Lepr was observed in the hypothalamus or exocrine pancreas, in addition to the β cells, and Lepr in non-β cells may have compensated for the loss of Lepr in β cells, thus making it difficult to assess the direct effects of Lepr in β cells. To determine the significance of Lepr exclusively in β cells, we chose to selectively restore Lepr in β cells of Lepr null mice (LeprloxTB/loxTB. Materials and methods: We used a mouse model in which endogenous expression of Lepr was disrupted by a loxP-flanked transcription blocker (LeprloxTB/loxTB, but was restored by Cre recombinase knocked into the Ins1 gene, which is specifically expressed in β cells (Ins1Cre. We bred LeprloxTB/loxTB and Ins1Cre mice to generate LeprloxTB/loxTB and LeprloxTB/loxTB Ins1Cre mice, as well as Leprwt/wt and Leprwt/wt Ins1Cre littermate mice. Male and female mice were weighed weekly between 6 and 11 weeks of age and fasting blood glucose was measured during this time. Oral glucose was administered to mice aged 7–12 weeks to assess glucose tolerance and insulin secretion. Relative β and α cell area and islet size were also assessed by immunostaining and analysis of pancreas sections of 12–14 week old mice. Results: Male and female LeprloxTB/loxTB mice, lacking whole-body expression of Lepr, had a phenotype similar to db/db mice characterized by obesity, hyperinsulinemia, glucose intolerance, and impaired glucose stimulated insulin secretion. Despite restoring

New measure of insulin sensitivity predicts cardiovascular disease better than HOMA estimated insulin resistance.

Science.gov (United States)

Venkataraman, Kavita; Khoo, Chin Meng; Leow, Melvin K S; Khoo, Eric Y H; Isaac, Anburaj V; Zagorodnov, Vitali; Sadananthan, Suresh A; Velan, Sendhil S; Chong, Yap Seng; Gluckman, Peter; Lee, Jeannette; Salim, Agus; Tai, E Shyong; Lee, Yung Seng

2013-01-01

Accurate assessment of insulin sensitivity may better identify individuals at increased risk of cardio-metabolic diseases. To examine whether a combination of anthropometric, biochemical and imaging measures can better estimate insulin sensitivity index (ISI) and provide improved prediction of cardio-metabolic risk, in comparison to HOMA-IR. Healthy male volunteers (96 Chinese, 80 Malay, 77 Indian), 21 to 40 years, body mass index 18-30 kg/m(2). Predicted ISI (ISI-cal) was generated using 45 randomly selected Chinese through stepwise multiple linear regression, and validated in the rest using non-parametric correlation (Kendall's tau τ). In an independent longitudinal cohort, ISI-cal and HOMA-IR were compared for prediction of diabetes and cardiovascular disease (CVD), using ROC curves. The study was conducted in a university academic medical centre. ISI measured by hyperinsulinemic euglycemic glucose clamp, along with anthropometric measurements, biochemical assessment and imaging; incident diabetes and CVD. A combination of fasting insulin, serum triglycerides and waist-to-hip ratio (WHR) provided the best estimate of clamp-derived ISI (adjusted R(2) 0.58 versus 0.32 HOMA-IR). In an independent cohort, ROC areas under the curve were 0.77±0.02 ISI-cal versus 0.76±0.02 HOMA-IR (p>0.05) for incident diabetes, and 0.74±0.03 ISI-cal versus 0.61±0.03 HOMA-IR (pHOMA-IR. This may be useful for estimating insulin sensitivity and cardio-metabolic risk in clinical and epidemiological settings.

Detection of Independent Associations of Plasma Lipidomic Parameters with Insulin Sensitivity Indices Using Data Mining Methodology.

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Steffi Kopprasch

Full Text Available Glucolipotoxicity is a major pathophysiological mechanism in the development of insulin resistance and type 2 diabetes mellitus (T2D. We aimed to detect subtle changes in the circulating lipid profile by shotgun lipidomics analyses and to associate them with four different insulin sensitivity indices.The cross-sectional study comprised 90 men with a broad range of insulin sensitivity including normal glucose tolerance (NGT, n = 33, impaired glucose tolerance (IGT, n = 32 and newly detected T2D (n = 25. Prior to oral glucose challenge plasma was obtained and quantitatively analyzed for 198 lipid molecular species from 13 different lipid classes including triacylglycerls (TAGs, phosphatidylcholine plasmalogen/ether (PC O-s, sphingomyelins (SMs, and lysophosphatidylcholines (LPCs. To identify a lipidomic signature of individual insulin sensitivity we applied three data mining approaches, namely least absolute shrinkage and selection operator (LASSO, Support Vector Regression (SVR and Random Forests (RF for the following insulin sensitivity indices: homeostasis model of insulin resistance (HOMA-IR, glucose insulin sensitivity index (GSI, insulin sensitivity index (ISI, and disposition index (DI. The LASSO procedure offers a high prediction accuracy and and an easier interpretability than SVR and RF.After LASSO selection, the plasma lipidome explained 3% (DI to maximal 53% (HOMA-IR variability of the sensitivity indexes. Among the lipid species with the highest positive LASSO regression coefficient were TAG 54:2 (HOMA-IR, PC O- 32:0 (GSI, and SM 40:3:1 (ISI. The highest negative regression coefficient was obtained for LPC 22:5 (HOMA-IR, TAG 51:1 (GSI, and TAG 58:6 (ISI.Although a substantial part of lipid molecular species showed a significant correlation with insulin sensitivity indices we were able to identify a limited number of lipid metabolites of particular importance based on the LASSO approach. These few selected lipids with the closest

I222 crystal form of despentapeptide (B26-B30) insulin provides new insights into the properties of monomeric insulin.

Science.gov (United States)

Whittingham, Jean L; Youshang, Zhang; Záková, Lenka; Dodson, Eleanor J; Turkenburg, Johan P; Brange, Jens; Dodson, G Guy

2006-05-01

Despentapeptide (des-B26-B30) insulin (DPI), an active modified insulin, has been crystallized in the presence of 20% acetic acid pH 2. A crystal structure analysis to 1.8 A spacing (space group I222) revealed that the DPI molecule, which is unable to make beta-strand interactions for physiological dimer formation and is apparently monomeric in solution, formed an alternative lattice-generated dimer. The formation of this dimer involved interactions between surfaces which included the B9-B19 alpha-helices (usually buried by the dimer-dimer contacts within the native hexamer). The two crystallographically independent molecules within the dimer were essentially identical and were similar in conformation to T-state insulin as seen in the T(6) insulin hexamer. An unusual feature of each molecule in the dimer was the presence of two independent conformations at the B-chain C-terminus (residues B20-B25). Both conformations were different from that of native insulin, involving a 3.5 A displacement of the B20-B23 beta-turn and a repositioning of residue PheB25 such that it made close van der Waals contact with the main body of the molecule, appearing to stabilize the B-chain C-terminus.

Anaesthesia generates neuronal insulin resistance by inducing hypothermia

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Sutherland Calum

2008-10-01

Full Text Available Abstract Background Anaesthesia is commonly employed prior to surgical investigations and to permit icv injections in rodents. Indeed it is standard practise in many studies examining the subsequent actions of hormones and growth factors on the brain. Recent evidence that the basal activity of specific intracellular signalling proteins can be affected by anaesthesia prompted us to examine the effect of anaesthesia not only on the basal activity but also the insulin sensitivity of the major insulin signalling pathways. Results We find that urethane- and ketamine-induced anaesthesia results in rapid activation of the phosphatidylinositol (PI 3-kinase-protein kinase B (PKB signalling pathway in the brain, increases tau phosphorylation while at the same time reducing basal activity of the Ras-ERK pathway. Subsequent injection of insulin does not alter the activity of either the PI 3-kinase or ERK signalling pathways, indicating a degree of neuronal molecular insulin resistance. However, if body temperature is maintained during anaesthesia then there is no alteration in the basal activity of these signalling molecules. Subsequent response of both pathways to insulin injection is restored. Conclusion The data is consistent with a hypothermia related alteration in neuronal signalling following anaesthesia, and emphasises the importance of maintaining the body temperature of rodents when monitoring insulin (or growth factor/neurotrophic agent action in the brain of anesthetised rodents.

Fasting insulin, insulin resistance and risk of hypertension in the general population: A meta-analysis.

Science.gov (United States)

Wang, Feng; Han, Lili; Hu, Dayi

2017-01-01

Studies on the association of fasting insulin concentrations or insulin resistance with subsequent risk of hypertension have yielded conflicting results. To quantitatively assess the association of fasting insulin concentrations or homeostasis model assessment insulin resistance (HOMA-IR) with incident hypertension in a general population by performing a meta-analysis. We searched the PubMed and Embase databases until August 31, 2016 for prospective observational studies investigating the elevated fasting insulin concentrations or HOMA-IR with subsequent risk of hypertension in the general population. Pooled risk ratio (RR) and 95% confidence interval (CI) of hypertension was calculated for the highest versus the lowest category of fasting insulin or HOMA-IR. Eleven studies involving 10,230 hypertension cases were identified from 55,059 participants. Meta-analysis showed that the pooled adjusted RR of hypertension was 1.54 (95% CI 1.34-1.76) for fasting insulin concentrations and 1.43 (95% CI 1.27-1.62) for HOMA-IR comparing the highest to the lowest category. Subgroup analysis results showed that the association of fasting insulin concentrations with subsequent risk of hypertension seemed more pronounced in women (RR 2.07; 95% CI 1.19-3.60) than in men (RR 1.48; 95% CI 1.17-1.88). This meta-analysis suggests that elevated fasting insulin concentrations or insulin resistance as estimated by homeostasis model assessment is independently associated with an exacerbated risk of hypertension in the general population. Early intervention of hyperinsulinemia or insulin resistance may help clinicians to identify the high risk of hypertensive population. Copyright © 2016 Elsevier B.V. All rights reserved.

Restorative Yoga and Metabolic Risk Factors: The Practicing Restorative Yoga vs. Stretching for the Metabolic Syndrome (PRYSMS) randomized trial

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Kanaya, Alka M.; Araneta, Maria Rosario G.; Pawlowsky, Sarah B.; Barrett-Connor, Elizabeth; Grady, Deborah; Vittinghoff, Eric; Schembri, Michael; Chang, Ann; Carrion-Petersen, Mary Lou; Coggins, Traci; Tanori, Daniah; Armas, Jean M.; Cole, Roger J.

2014-01-01

Aims Intensive lifestyle change prevents type 2 diabetes but is difficult to sustain. Preliminary evidence suggests that yoga may improve metabolic factors. We tested a restorative yoga intervention vs. active stretching for metabolic outcomes. Methods In 2009–2012, we conducted a 48-week randomized trial comparing restorative yoga vs. stretching among underactive adults with the metabolic syndrome at the Universities of California, San Francisco and San Diego. We provided lifestyle counseling and a tapering series of 90-minute group classes in the 24-week intervention period and 24-week maintenance period. Fasting and 2-hour glucose, HbA1c, triglycerides, HDL-cholesterol, insulin, systolic blood pressure, visceral fat, and quality of life were assessed at baseline, 6- and 12-months. Results 180 participants were randomized and 135 (75%) completed the trial. At 12 months, fasting glucose decreased more in the yoga group than in the stretching group (−0.35 mmol/L vs. −0.03 mmol/L; p=0.002); there were no other significant differences between groups. At 6 months favorable changes within the yoga group included reductions in fasting glucose, insulin, and HbA1c and an increase in HDL-cholesterol that were not sustained at 1 year except changes in fasting glucose. The stretching group had a significant reduction in triglycerides at 6 months which was not sustained at 1 year but had improved quality of life at both time-points. Conclusions Restorative yoga was marginally better than stretching for improving fasting glucose but not other metabolic factors. PMID:24418351

Are Independent Fiscal Institutions Really Independent?

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Slawomir Franek

2015-08-01

Full Text Available In the last decade the number of independent fiscal institutions (known also as fiscal councils has tripled. They play an important oversight role over fiscal policy-making in democratic societies, especially as they seek to restore public finance stability in the wake of the recent financial crisis. Although common functions of such institutions include a role in analysis of fiscal policy, forecasting, monitoring compliance with fiscal rules or costing of spending proposals, their roles, resources and structures vary considerably across countries. The aim of the article is to determine the degree of independence of such institutions based on the analysis of the independence index of independent fiscal institutions. The analysis of this index values may be useful to determine the relations between the degree of independence of fiscal councils and fiscal performance of particular countries. The data used to calculate the index values will be derived from European Commission and IMF, which collect sets of information about characteristics of activity of fiscal councils.

Kinetics of intraperitoneally infused insulin in rats - Functional implications for the bioartificial pancreas

NARCIS (Netherlands)

de Vos, P; Vegter, D; de Haan, B.J; Strubbe, J.H.; Bruggink, J.E.; van Schilfgaarde, R

Intraperitoneal transplantation of encapsulated islets can restore normoglycemia in diabetic recipients but not normal glucose tolerance nor normal insulin responses to a physiological stimulus. This study investigates whether the intraperitoneal implantation site as such contributes to the

Regulation of Muscle Pyruvate Dehydrogenase Complex in Insulin Resistance: Effects of Exercise and Dichloroacetate

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Dumitru Constantin-Teodosiu

2013-10-01

Full Text Available Since the mitochondrial pyruvate dehydrogenase complex (PDC controls the rate of carbohydrate oxidation, impairment of PDC activity mediated by high-fat intake has been advocated as a causative factor for the skeletal muscle insulin resistance, metabolic syndrome, and the onset of type 2 diabetes (T2D. There are also situations where muscle insulin resistance can occur independently from high-fat dietary intake such as sepsis, inflammation, or drug administration though they all may share the same underlying mechanism, i.e., via activation of forkhead box family of transcription factors, and to a lower extent via peroxisome proliferator-activated receptors. The main feature of T2D is a chronic elevation in blood glucose levels. Chronic systemic hyperglycaemia is toxic and can lead to cellular dysfunction that may become irreversible over time due to deterioration of the pericyte cell's ability to provide vascular stability and control to endothelial proliferation. Therefore, it may not be surprising that T2D's complications are mainly macrovascular and microvascular related, i.e., neuropathy, retinopathy, nephropathy, coronary artery, and peripheral vascular diseases. However, life style intervention such as exercise, which is the most potent physiological activator of muscle PDC, along with pharmacological intervention such as administration of dichloroacetate or L-carnitine can prove to be viable strategies for treating muscle insulin resistance in obesity and T2D as they can potentially restore whole body glucose disposal.

Novel and Reversible Mechanisms of Smoking-Induced Insulin Resistance in Humans

OpenAIRE

Bergman, Bryan C.; Perreault, Leigh; Hunerdosse, Devon; Kerege, Anna; Playdon, Mary; Samek, Ali M.; Eckel, Robert H.

2012-01-01

Smoking is the most common cause of preventable morbidity and mortality in the United States, in part because it is an independent risk factor for the development of insulin resistance and type 2 diabetes. However, mechanisms responsible for smoking-induced insulin resistance are unclear. In this study, we found smokers were less insulin sensitive compared with controls, which increased after either 1 or 2 weeks of smoking cessation. Improvements in insulin sensitivity after smoking cessation...

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.

Genome-wide association study of the modified Stumvoll Insulin Sensitivity Index identifies BCL2 and FAM19A2 as novel insulin sensitivity loci

DEFF Research Database (Denmark)

Walford, Geoffrey A; Gustafsson, Stefan; Rybin, Denis

2016-01-01

of the modified Stumvoll Insulin Sensitivity Index (ISI) within the Meta-Analyses of Glucose and Insulin-related traits Consortium. Discovery was performed in 16,753 individuals, and replication was attempted for the 23 most significant novel loci in 13,354 independent individuals. Association with ISI was tested...

Caffeine and contraction synergistically stimulate 5'-AMP-activated protein kinase and insulin-independent glucose transport in rat skeletal muscle.

Science.gov (United States)

Tsuda, Satoshi; Egawa, Tatsuro; Kitani, Kazuto; Oshima, Rieko; Ma, Xiao; Hayashi, Tatsuya

2015-10-01

5'-Adenosine monophosphate-activated protein kinase (AMPK) has been identified as a key mediator of contraction-stimulated insulin-independent glucose transport in skeletal muscle. Caffeine acutely stimulates AMPK in resting skeletal muscle, but it is unknown whether caffeine affects AMPK in contracting muscle. Isolated rat epitrochlearis muscle was preincubated and then incubated in the absence or presence of 3 mmol/L caffeine for 30 or 120 min. Electrical stimulation (ES) was used to evoke tetanic contractions during the last 10 min of the incubation period. The combination of caffeine plus contraction had additive effects on AMPKα Thr(172) phosphorylation, α-isoform-specific AMPK activity, and 3-O-methylglucose (3MG) transport. In contrast, caffeine inhibited basal and contraction-stimulated Akt Ser(473) phosphorylation. Caffeine significantly delayed muscle fatigue during contraction, and the combination of caffeine and contraction additively decreased ATP and phosphocreatine contents. Caffeine did not affect resting tension. Next, rats were given an intraperitoneal injection of caffeine (60 mg/kg body weight) or saline, and the extensor digitorum longus muscle was dissected 15 min later. ES of the sciatic nerve was performed to evoke tetanic contractions for 5 min before dissection. Similar to the findings from isolated muscles incubated in vitro, the combination of caffeine plus contraction in vivo had additive effects on AMPK phosphorylation, AMPK activity, and 3MG transport. Caffeine also inhibited basal and contraction-stimulated Akt phosphorylation in vivo. These findings suggest that caffeine and contraction synergistically stimulate AMPK activity and insulin-independent glucose transport, at least in part by decreasing muscle fatigue and thereby promoting energy consumption during contraction. © 2015 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological

Caffeine and contraction synergistically stimulate 5′-AMP-activated protein kinase and insulin-independent glucose transport in rat skeletal muscle

Science.gov (United States)

Tsuda, Satoshi; Egawa, Tatsuro; Kitani, Kazuto; Oshima, Rieko; Ma, Xiao; Hayashi, Tatsuya

2015-01-01

5′-Adenosine monophosphate-activated protein kinase (AMPK) has been identified as a key mediator of contraction-stimulated insulin-independent glucose transport in skeletal muscle. Caffeine acutely stimulates AMPK in resting skeletal muscle, but it is unknown whether caffeine affects AMPK in contracting muscle. Isolated rat epitrochlearis muscle was preincubated and then incubated in the absence or presence of 3 mmol/L caffeine for 30 or 120 min. Electrical stimulation (ES) was used to evoke tetanic contractions during the last 10 min of the incubation period. The combination of caffeine plus contraction had additive effects on AMPKα Thr172 phosphorylation, α-isoform-specific AMPK activity, and 3-O-methylglucose (3MG) transport. In contrast, caffeine inhibited basal and contraction-stimulated Akt Ser473 phosphorylation. Caffeine significantly delayed muscle fatigue during contraction, and the combination of caffeine and contraction additively decreased ATP and phosphocreatine contents. Caffeine did not affect resting tension. Next, rats were given an intraperitoneal injection of caffeine (60 mg/kg body weight) or saline, and the extensor digitorum longus muscle was dissected 15 min later. ES of the sciatic nerve was performed to evoke tetanic contractions for 5 min before dissection. Similar to the findings from isolated muscles incubated in vitro, the combination of caffeine plus contraction in vivo had additive effects on AMPK phosphorylation, AMPK activity, and 3MG transport. Caffeine also inhibited basal and contraction-stimulated Akt phosphorylation in vivo. These findings suggest that caffeine and contraction synergistically stimulate AMPK activity and insulin-independent glucose transport, at least in part by decreasing muscle fatigue and thereby promoting energy consumption during contraction. PMID:26471759

Fanconi anemia links reactive oxygen species to insulin resistance and obesity.

Science.gov (United States)

Li, Jie; Sipple, Jared; Maynard, Suzette; Mehta, Parinda A; Rose, Susan R; Davies, Stella M; Pang, Qishen

2012-10-15

Insulin resistance is a hallmark of obesity and type 2 diabetes. Reactive oxygen species (ROS) have been proposed to play a causal role in insulin resistance. However, evidence linking ROS to insulin resistance in disease settings has been scant. Since both oxidative stress and diabetes have been observed in patients with the Fanconi anemia (FA), we sought to investigate the link between ROS and insulin resistance in this unique disease model. Mice deficient for the Fanconi anemia complementation group A (Fanca) or Fanconi anemia complementation group C (Fancc) gene seem to be diabetes-prone, as manifested by significant hyperglycemia and hyperinsulinemia, and rapid weight gain when fed with a high-fat diet. These phenotypic features of insulin resistance are characterized by two critical events in insulin signaling: a reduction in tyrosine phosphorylation of the insulin receptor (IR) and an increase in inhibitory serine phosphorylation of the IR substrate-1 in the liver, muscle, and fat tissues from the insulin-challenged FA mice. High levels of ROS, spontaneously accumulated or generated by tumor necrosis factor alpha in these insulin-sensitive tissues of FA mice, were shown to underlie the FA insulin resistance. Treatment of FA mice with the natural anti-oxidant Quercetin restores IR signaling and ameliorates the diabetes- and obesity-prone phenotypes. Finally, pairwise screen identifies protein-tyrosine phosphatase (PTP)-α and stress kinase double-stranded RNA-dependent protein kinase (PKR) that mediate the ROS effect on FA insulin resistance. These findings establish a pathogenic and mechanistic link between ROS and insulin resistance in a unique human disease setting. ROS accumulation contributes to the insulin resistance in FA deficiency by targeting both PTP-α and PKR.

Noncanonical Wnt signaling promotes obesity-induced adipose tissue inflammation and metabolic dysfunction independent of adipose tissue expansion.

Science.gov (United States)

Fuster, José J; Zuriaga, María A; Ngo, Doan Thi-Minh; Farb, Melissa G; Aprahamian, Tamar; Yamaguchi, Terry P; Gokce, Noyan; Walsh, Kenneth

2015-04-01

Adipose tissue dysfunction plays a pivotal role in the development of insulin resistance in obese individuals. Cell culture studies and gain-of-function mouse models suggest that canonical Wnt proteins modulate adipose tissue expansion. However, no genetic evidence supports a role for endogenous Wnt proteins in adipose tissue dysfunction, and the role of noncanonical Wnt signaling remains largely unexplored. Here we provide evidence from human, mouse, and cell culture studies showing that Wnt5a-mediated, noncanonical Wnt signaling contributes to obesity-associated metabolic dysfunction by increasing adipose tissue inflammation. Wnt5a expression is significantly upregulated in human visceral fat compared with subcutaneous fat in obese individuals. In obese mice, Wnt5a ablation ameliorates insulin resistance, in parallel with reductions in adipose tissue inflammation. Conversely, Wnt5a overexpression in myeloid cells augments adipose tissue inflammation and leads to greater impairments in glucose homeostasis. Wnt5a ablation or overexpression did not affect fat mass or adipocyte size. Mechanistically, Wnt5a promotes the expression of proinflammatory cytokines by macrophages in a Jun NH2-terminal kinase-dependent manner, leading to defective insulin signaling in adipocytes. Exogenous interleukin-6 administration restores insulin resistance in obese Wnt5a-deficient mice, suggesting a central role for this cytokine in Wnt5a-mediated metabolic dysfunction. Taken together, these results demonstrate that noncanonical Wnt signaling contributes to obesity-induced insulin resistance independent of adipose tissue expansion. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

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

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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.

BPN, a marine-derived PTP1B inhibitor, activates insulin signaling and improves insulin resistance in C2C12 myotubes.

Science.gov (United States)

Xu, Qi; Luo, Jiao; Wu, Ning; Zhang, Renshuai; Shi, Dayong

2018-01-01

Insulin resistance is a key feature of type 2 diabetes mellitus (T2DM) and is characterized by defects in insulin signaling. Protein tyrosine phosphatase 1B (PTP1B) is a major negative regulator of insulin signaling cascade and has attracted intensive investigation in recent T2DM therapy study. BPN, a marine-derived bromophenol compound, was isolated from the red alga Rhodomela confervoides. This study investigated the effects of BPN on the insulin signaling pathway in insulin-resistant C2C12 myotubes by inhibiting PTP1B. Molecular docking study and analysis of small- molecule interaction with PTP1B all showed BPN inhibited PTP1B activity via binding to the catalytic site through hydrogen bonds. We then found that BPN permeated into C2C12 myotubes, on the one hand, activated insulin signaling in an insulin-independent manner in C2C12 cells; on the other hand, ameliorated palmitate-induced insulin resistance through augmenting insulin sensitivity. Moreover, our studies also showed that PTP1B inhibition by BPN increased glucose uptake in normal and insulin-resistant C2C12 myotubes through glucose transporter 4 (GLUT4) translocation. Taken together, BPN activates insulin signaling and alleviates insulin resistance and represents a potential candidate for further development as an antidiabetic agent. Copyright © 2017 Elsevier B.V. All rights reserved.

Provision of Atraumatic Restorative Treatment (ART) restorations to Chinese pre-school children--a 30-month evaluation.

Science.gov (United States)

Lo, E C; Holmgren, C J

2001-01-01

The objectives of this study were: to provide restorations using the ART approach to pre-school children in Southern China in a kindergarten environment, using a high-strength glass-ionomer restorative material; to assess the acceptability of this approach and to evaluate on a longitudinal basis the restorations placed. A total of 170 ART restorations were placed in 95 children, aged 5.1 +/- 0.7 years, by seven final-year dental students using standard ART procedures and hand instruments. The restorations were evaluated every six months thereafter by two calibrated independent examiners using explorers and mouth-mirrors. 93% of the children reported that they did not feel pain during treatment and 86% were willing to receive ART restorations again. The cumulative 12- and 30-month survival rates of Class I restorations were 91% and 79%, respectively. The corresponding figures for Class V restorations were 79% and 70%, while those for Class II restorations were 75% and 51%. The failure rates of Class III and IV restorations were high with more than half of them scored as missing within the first year. The ART approach was shown to be acceptable to Chinese pre-school children for providing restorative dental care outside the traditional clinical setting. The success rates were high for Class I and V restorations in primary teeth, modest for Class II, and low for Class III and IV restorations.

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

Directory of Open Access Journals (Sweden)

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

Pleotropic effects of leptin to reverse insulin resistance and diabetic ketoacidosis

DEFF Research Database (Denmark)

Perry, Rachel J; Petersen, Kitt Falk; Shulman, Gerald I.

2016-01-01

In this review we discuss the mechanisms for the pleotropic effects of leptin replacement therapy to reverse liver and muscle insulin resistance in lipodystrophic individuals, as well as insulin-independent effects of leptin replacement therapy to suppress white adipose tissue lipolysis, hepatic...

Selective insulin resistance in hepatocyte senescence

International Nuclear Information System (INIS)

Aravinthan, Aloysious; Challis, Benjamin; Shannon, Nicholas; Hoare, Matthew; Heaney, Judith; Alexander, Graeme J.M.

2015-01-01

Insulin resistance has been described in association with chronic liver disease for decades. Hepatocyte senescence has been demonstrated in chronic liver disease and as many as 80% of hepatocytes show a senescent phenotype in advanced liver disease. The aim of this study was to understand the role of hepatocyte senescence in the development of insulin resistance. Senescence was induced in HepG2 cells via oxidative stress. The insulin metabolic pathway was studied in control and senescent cells following insulin stimulation. GLUT2 and GLUT4 expressions were studied in HepG2 cells and human liver tissue. Further, GLUT2 and GLUT4 expressions were studied in three independent chronic liver disease cohorts. Signalling impairment distal to Akt in phosphorylation of AS160 and FoxO1 was evident in senescent HepG2 cells. Persistent nuclear localisation of FoxO1 was demonstrated in senescent cells despite insulin stimulation. Increased GLUT4 and decreased GLUT2 expressions were evident in senescent cells, human cirrhotic liver tissue and publically available liver disease datasets. Changes in GLUT expressions were associated with a poor clinical prognosis. In conclusion, selective insulin resistance is evident in senescent HepG2 cells and changes in GLUT expressions can be used as surrogate markers of hepatocyte senescence. - Highlights: • Senescent hepatocytes demonstrate selective insulin resistance. • GLUT changes act as markers of hepatocyte senescence and have prognostic value. • Study offers insight into long noticed intimacy of cirrhosis and insulin resistance

Selective insulin resistance in hepatocyte senescence

Energy Technology Data Exchange (ETDEWEB)

Aravinthan, Aloysious [Division of Gastroenterology and Hepatology, Department of Medicine, University of Cambridge, Cambridge (United Kingdom); Challis, Benjamin [Institute of Metabolic Sciences, University of Cambridge, Cambridge (United Kingdom); Shannon, Nicholas [Cancer Research UK Cambridge Institute, Cambridge (United Kingdom); Hoare, Matthew [Division of Gastroenterology and Hepatology, Department of Medicine, University of Cambridge, Cambridge (United Kingdom); Cancer Research UK Cambridge Institute, Cambridge (United Kingdom); Heaney, Judith [Division of Gastroenterology and Hepatology, Department of Medicine, University of Cambridge, Cambridge (United Kingdom); Foundation for Liver Research, Institute of Hepatology, London (United Kingdom); Alexander, Graeme J.M., E-mail: gja1000@doctors.org.uk [Division of Gastroenterology and Hepatology, Department of Medicine, University of Cambridge, Cambridge (United Kingdom)

2015-02-01

Insulin resistance has been described in association with chronic liver disease for decades. Hepatocyte senescence has been demonstrated in chronic liver disease and as many as 80% of hepatocytes show a senescent phenotype in advanced liver disease. The aim of this study was to understand the role of hepatocyte senescence in the development of insulin resistance. Senescence was induced in HepG2 cells via oxidative stress. The insulin metabolic pathway was studied in control and senescent cells following insulin stimulation. GLUT2 and GLUT4 expressions were studied in HepG2 cells and human liver tissue. Further, GLUT2 and GLUT4 expressions were studied in three independent chronic liver disease cohorts. Signalling impairment distal to Akt in phosphorylation of AS160 and FoxO1 was evident in senescent HepG2 cells. Persistent nuclear localisation of FoxO1 was demonstrated in senescent cells despite insulin stimulation. Increased GLUT4 and decreased GLUT2 expressions were evident in senescent cells, human cirrhotic liver tissue and publically available liver disease datasets. Changes in GLUT expressions were associated with a poor clinical prognosis. In conclusion, selective insulin resistance is evident in senescent HepG2 cells and changes in GLUT expressions can be used as surrogate markers of hepatocyte senescence. - Highlights: • Senescent hepatocytes demonstrate selective insulin resistance. • GLUT changes act as markers of hepatocyte senescence and have prognostic value. • Study offers insight into long noticed intimacy of cirrhosis and insulin resistance.

Plasma HDL-cholesterol and triglycerides, but not LDL-cholesterol, are associated with insulin secretion in non-diabetic subjects.

Science.gov (United States)

Natali, Andrea; Baldi, Simona; Bonnet, Fabrice; Petrie, John; Trifirò, Silvia; Tricò, Domenico; Mari, Andrea

2017-04-01

Experimental data support the notion that lipoproteins might directly affect beta cell function, however clinical data are sparse and inconsistent. We aimed at verifying whether, independently of major confounders, serum lipids are associated with alterations in insulin secretion or clearance non-diabetic subjects. Cross sectional and observational prospective (3.5yrs), multicentre study in which 1016 non-diabetic volunteers aged 30-60yrs. and with a wide range of BMI (20.0-39.9kg/m 2 ) were recruited in a setting of University hospital ambulatory care (RISC study). baseline fasting lipids, fasting and OGTT-induced insulin secretion and clearance (measured by glucose and C-peptide modeling), peripheral insulin sensitivity (by the euglycemic clamp). Lipids and OGTT were repeated in 980 subjects after 3.5years. LDL-cholesterol did not show independent associations with fasting or stimulated insulin secretion or clearance. After accounting for potential confounders, HDL-cholesterol displayed negative and triglycerides positive independent associations with fasting and OGTT insulin secretion; neither with insulin clearance. Low HDL-cholesterol and high triglycerides were associated with an increase in glucose-dependent and a decrease in non-glucose-dependent insulin secretion. Over 3.5years both an HDL-cholesterol decline and a triglycerides rise were associated with an increase in fasting insulin secretion independent of changes in body weight or plasma glucose. LDL-cholesterol does not seem to influence any major determinant of insulin bioavailability while low HDL-cholesterol and high triglycerides might contribute to sustain the abnormalities in insulin secretion that characterize the pre-diabetic state. Copyright © 2017 Elsevier Inc. All rights reserved.

Insulin secretion and action in North Indian women during pregnancy

DEFF Research Database (Denmark)

Arora, G P; Almgren, P; Thaman, R G

2017-01-01

. RESULTS: Gestational diabetes defined using both criteria was associated with decreased insulin secretion compared with pregnant women with normal glucose tolerance. Women with gestational diabetes defined by the adapted GDM2013, but not GDM1999 criteria, were more insulin resistant than pregnant women......AIM: The relative roles(s) of impaired insulin secretion vs. insulin resistance in the development of gestational diabetes mellitus depend upon multiple risk factors and diagnostic criteria. Here, we explored their relative contribution to gestational diabetes as defined by the WHO 1999 (GDM1999...... independently associated with increased insulin resistance. CONCLUSIONS: Gestational diabetes risk factors influence insulin secretion and action in North Indian women in a differential manner. Gestational diabetes classified using the adapted GDM2013 compared with GDM1999 criteria is associated with more...

Oral administration of soybean peptide Vglycin normalizes fasting glucose and restores impaired pancreatic function in Type 2 diabetic Wistar rats.

Science.gov (United States)

Jiang, Hua; Feng, Jueping; Du, Zhongxia; Zhen, Hui; Lin, Mei; Jia, Shaohui; Li, Tao; Huang, Xinyuan; Ostenson, Claes-Goran; Chen, Zhengwang

2014-09-01

Vglycin, a natural 37-residue polypeptide isolated from pea seeds in which six half-cysteine residues are embedded in three pairs of disulfide bonds, is resistant to digestive enzymes and has antidiabetic potential. To investigate the pharmacological activity of Vglycin in vivo and to examine the mechanisms involved, the therapeutic effect of Vglycin in diabetic rats was examined. Diabetes was induced in Wistar rats by high-fat diet and multiple streptozotocin intraperitoneal injections. Diabetic rats were treated daily with Vglycin for 4 weeks. Body weight, food intake, fasting plasma glucose and insulin levels were assayed weekly. Glucose and insulin tolerance tests were conducted on Day 29. Subsequently, levels of p-Akt in the liver and pancreas and cleaved PARP, Pdx-1 and insulin in the pancreas were detected by immunoblotting. The morphology of the pancreas and the insulin expression in the pancreas were analyzed by hematoxylin-eosin staining and immunohistochemistry, respectively. Furthermore, human liver-derived cell lines were used to explore the in vitro effects of Vglycin on insulin sensitivity and glucose uptake. Chronic treatment with Vglycin normalized fasting glucose levels in diabetic rats. The improvement in glucose homeostasis and the increased insulin sensitivity mediated by restored insulin signaling likely contributed to decreased food intake and reduced body weight. Vglycin protected pancreatic cells from damage by streptozotocin. Although insulin synthesis and secretion in impaired β-cell were not significantly elevated, islets morphology was improved in the Vglycin-treated groups. These results suggest that Vglycin could be useful in Type 2 diabetes for restoring impaired insulin signaling, glucose tolerance and pancreatic function. Copyright © 2014 Elsevier Inc. All rights reserved.

Causality of small and large intestinal microbiota in weight regulation and insulin resistance

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Torsten P.M. Scheithauer

2016-09-01

Conclusions: Interventions aimed to restoring gut microbial homeostasis, such as ingestion of specific fibers or therapeutic microbes, are promising strategies to reduce insulin resistance and the related metabolic abnormalities in obesity, metabolic syndrome, and type 2 diabetes. This article is part of a special issue on microbiota.

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)

Bone metabolism in adolescent girls with eating disorders and weight loss: independent effects of weight change, insulin-like growth factor-1 and oestradiol.

Science.gov (United States)

Swenne, Ingemar; Stridsberg, Mats

2015-03-01

Adolescents with eating disorders (ED) are at risk of developing osteoporosis if weight is not recovered. Previous investigations do not separate the effects of weight change per se from those of concomitant hormonal changes. In this investigation serum osteocalcin (OC), C-terminal telopeptide of collagen (CTX), insulin-like growth factor-1 (IGF-1) and oestradiol were measured at assessment of 498 girls with ED and during weight gain of 59 girls. At assessment, OC concentrations were associated independently with weight (change), IGF-1 and oestradiol. Low weight, a high rate of weight loss and the hormone concentrations were associated with low OC. Low weight and high rate of weight loss were associated with high CTX concentrations but there were no associations independent of weight (change) with the hormones. During weight recovery, OC and CTX were independently and positively associated with weight, weight gain, IGF-1 and oestradiol. Bone metabolism markers are related to weight change independently of IGF-1 and oestradiol during both weight loss and weight gain. During weight gain, when pubertal development and growth are resumed there is an additional independent positive association between the markers and IGF-1 and oestradiol. These relationships are strongest in premenarcheal girls.

Biphasic insulin-releasing effect of BTS 67 582 in rats.

Science.gov (United States)

Storey, D A; Bailey, C J

1998-12-01

BTS 67 582 (1,1-dimethyl-2(2-morpholinophenyl)guanidine fumarate) is being developed as a short-acting anti-diabetic insulin secretagogue. The effect of BTS 67 582 on the phasic pattern of insulin release was assessed in anaesthetized normal rats by measuring arterial plasma insulin concentrations while arterial glucose concentrations were fixed at 6, 8.5 and 12.5 mM. Intravenous BTS 67 582 (10 mg kg(-1)) induced an immediate but transient increase in insulin concentrations which declined by 10 min (first phase). This was followed by a smaller but sustained increase in insulin concentrations (second phase). The increment from basal to peak insulin release (0-2 min) was independent of glucose, but the first phase was maintained for longer and the second phase was greater at the highest concentration of glucose (12.5 mM). BTS 67 582 also extended the first-phase insulin response to a standard intravenous glucose challenge and enhanced the rate of glucose disappearance by approximately 12%. Thus BTS 67 582 causes biphasic stimulation of insulin release and augments the insulin-releasing effect of glucose.

Disruption of the mitochondria-associated ER membrane (MAM) plays a central role in palmitic acid-induced insulin resistance.

Science.gov (United States)

Shinjo, Satoko; Jiang, Shuying; Nameta, Masaaki; Suzuki, Tomohiro; Kanai, Mai; Nomura, Yuta; Goda, Nobuhito

2017-10-01

The mitochondria-associated ER membrane (MAM) is a specialized subdomain of ER that physically connects with mitochondria. Although disruption of inter-organellar crosstalk via the MAM impairs cellular homeostasis, its pathological significance in insulin resistance in type 2 diabetes mellitus remains unclear. Here, we reveal the importance of reduced MAM formation in the induction of fatty acid-evoked insulin resistance in hepatocytes. Palmitic acid (PA) repressed insulin-stimulated Akt phosphorylation in HepG2 cells within 12h. Treatment with an inhibitor of the ER stress response failed to restore PA-mediated suppression of Akt activation. Mitochondrial reactive oxygen species (ROS) production did not increase in PA-treated cells. Even short-term exposure (3h) to PA reduced the calcium flux from ER to mitochondria, followed by a significant decrease in MAM contact area, suggesting that PA suppressed the functional interaction between ER and mitochondria. Forced expression of mitofusin-2, a critical component of the MAM, partially restored MAM contact area and ameliorated the PA-elicited suppression of insulin sensitivity with Ser473 phosphorylation of Akt selectively improved. These results suggest that loss of proximity between ER and mitochondria, but not perturbation of homeostasis in the two organelles individually, plays crucial roles in PA-evoked Akt inactivation in hepatic insulin resistance. Copyright © 2017 Elsevier Inc. All rights reserved.

Doxycycline-Regulated 3T3-L1 Preadipocyte Cell Line with Inducible, Stable Expression of Adenoviral E4orf1 Gene: A Cell Model to Study Insulin-Independent Glucose Disposal

OpenAIRE

Krishnapuram, Rashmi; Dhurandhar, Emily J.; Dubuisson, Olga; Hegde, Vijay; Dhurandhar, Nikhil V.

2013-01-01

Impaired glycemic control and excessive adiposity are major risk factors for Type 2 Diabetes mellitus. In rodent models, Ad36, a human adenovirus, improves glycemic control, independent of dietary fat intake or adiposity. It is impractical to use Ad36 for therapeutic action. Instead, we identified that E4orf1 protein of Ad36, mediates its anti-hyperglycemic action independent of insulin signaling. To further evaluate the therapeutic potential of E4orf1 to improve glycemic control, we establis...

High intensity interval training improves liver and adipose tissue insulin sensitivity

Science.gov (United States)

Marcinko, Katarina; Sikkema, Sarah R.; Samaan, M. Constantine; Kemp, Bruce E.; Fullerton, Morgan D.; Steinberg, Gregory R.

2015-01-01

Objective Endurance exercise training reduces insulin resistance, adipose tissue inflammation and non-alcoholic fatty liver disease (NAFLD), an effect often associated with modest weight loss. Recent studies have indicated that high-intensity interval training (HIIT) lowers blood glucose in individuals with type 2 diabetes independently of weight loss; however, the organs affected and mechanisms mediating the glucose lowering effects are not known. Intense exercise increases phosphorylation and inhibition of acetyl-CoA carboxylase (ACC) by AMP-activated protein kinase (AMPK) in muscle, adipose tissue and liver. AMPK and ACC are key enzymes regulating fatty acid metabolism, liver fat content, adipose tissue inflammation and insulin sensitivity but the importance of this pathway in regulating insulin sensitivity with HIIT is unknown. Methods In the current study, the effects of 6 weeks of HIIT were examined using obese mice with serine–alanine knock-in mutations on the AMPK phosphorylation sites of ACC1 and ACC2 (AccDKI) or wild-type (WT) controls. Results HIIT lowered blood glucose and increased exercise capacity, food intake, basal activity levels, carbohydrate oxidation and liver and adipose tissue insulin sensitivity in HFD-fed WT and AccDKI mice. These changes occurred independently of weight loss or reductions in adiposity, inflammation and liver lipid content. Conclusions These data indicate that HIIT lowers blood glucose levels by improving adipose and liver insulin sensitivity independently of changes in adiposity, adipose tissue inflammation, liver lipid content or AMPK phosphorylation of ACC. PMID:26909307

Function of insulin in snail brain in associative learning.

Science.gov (United States)

Kojima, S; Sunada, H; Mita, K; Sakakibara, M; Lukowiak, K; Ito, E

2015-10-01

Insulin is well known as a hormone regulating glucose homeostasis across phyla. Although there are insulin-independent mechanisms for glucose uptake in the mammalian brain, which had contributed to a perception of the brain as an insulin-insensitive organ for decades, the finding of insulin and its receptors in the brain revolutionized the concept of insulin signaling in the brain. However, insulin's role in brain functions, such as cognition, attention, and memory, remains unknown. Studies using invertebrates with their open blood-vascular system have the promise of promoting a better understanding of the role played by insulin in mediating/modulating cognitive functions. In this review, the relationship between insulin and its impact on long-term memory (LTM) is discussed particularly in snails. The pond snail Lymnaea stagnalis has the ability to undergo conditioned taste aversion (CTA), that is, it associatively learns and forms LTM not to respond with a feeding response to a food that normally elicits a robust feeding response. We show that molluscan insulin-related peptides are up-regulated in snails exhibiting CTA-LTM and play a key role in the causal neural basis of CTA-LTM. We also survey the relevant literature of the roles played by insulin in learning and memory in other phyla.

Adiposity-independent hypoadiponectinemia as a potential marker of insulin resistance and inflammation in schizophrenia patients treated with second generation antipsychotics.

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Sapra, Mamta; Lawson, Donna; Iranmanesh, Ali; Varma, Anjali

2016-07-01

The purpose of this study was to explore body fat independent effect of second generation antipsychotics (SGAs) on measures of glucose and adipokine homeostasis, and markers of inflammation. Eight non-diabetic men with schizophrenia (age: 55±3years, BMI: 29.7±1.2kg/m(2)) on SGAs were studied after an overnight fast. DXA and single-cut CT of abdomen were respectively used for the assessment of total body and abdominal fat. Blood samples were collected for measurements of glucose, insulin, leptin, adiponectin, C-reactive protein (CRP), and TNF-α. Data in schizophrenic subjects were compared to eight age (55±2.8years) and BMI (29.6±1.1kg/m(2)) matched healthy men. The results were significant for markedly decreased serum adiponectin in schizophrenia patients (4.6±0.9 vs 11.1±1.5ng/mL, p=0.001). Lower levels of adiponectin in schizophrenia men were associated with significant increases in insulin resistance (4.2±0.7 vs 1.7±0.4, p=0.004), CRP (3.5±1.2 vs 1.2±0.3, p=0.037), and leptin (12±1.4 vs 8.5±1.4ng/mL, p=0.05). Various measures of adiposity, including fat mass index (FMI) and abdominal fat were not different in the two study groups. These findings in the context of comparable age and total body/abdominal fat mass are assumed to be either disease specific, and/or treatment inflicted. The definitive invoking etiology and a presumptive role of hypoadiponectinemia in the development of insulin resistance and increased risk of inflammation warrant future investigation. Published by Elsevier B.V.

Concentrated insulins: the new basal insulins

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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

Maternal insulin therapy does not restore foetoplacental endothelial dysfunction in gestational diabetes mellitus

NARCIS (Netherlands)

Subiabre, Mario; Silva, Luis; Villalobos-Labra, Roberto; Toledo, Fernando; Paublo, Mario; López, Marcia A.; Salsoso, Rocío; Pardo, Fabián; Leiva, Andrea; Sobrevia, Luis

Pregnant women diagnosed with gestational diabetes mellitus subjected to diet (GDMd) that do not reach normal glycaemia are passed to insulin therapy (GDMi). GDMd associates with increased human cationic amino acid transporter 1 (hCAT-1)-mediated transport of L-arginine and nitric oxide synthase

Sirt1 regulates insulin secretion by repressing UCP2 in pancreatic beta cells.

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Laura Bordone

2006-02-01

Full Text Available Sir2 and insulin/IGF-1 are the major pathways that impinge upon aging in lower organisms. In Caenorhabditis elegans a possible genetic link between Sir2 and the insulin/IGF-1 pathway has been reported. Here we investigate such a link in mammals. We show that Sirt1 positively regulates insulin secretion in pancreatic beta cells. Sirt1 represses the uncoupling protein (UCP gene UCP2 by binding directly to the UCP2 promoter. In beta cell lines in which Sirt1 is reduced by SiRNA, UCP2 levels are elevated and insulin secretion is blunted. The up-regulation of UCP2 is associated with a failure of cells to increase ATP levels after glucose stimulation. Knockdown of UCP2 restores the ability to secrete insulin in cells with reduced Sirt1, showing that UCP2 causes the defect in glucose-stimulated insulin secretion. Food deprivation induces UCP2 in mouse pancreas, which may occur via a reduction in NAD (a derivative of niacin levels in the pancreas and down-regulation of Sirt1. Sirt1 knockout mice display constitutively high UCP2 expression. Our findings show that Sirt1 regulates UCP2 in beta cells to affect insulin secretion.

Plasma kisspeptin levels are associated with insulin secretion in nondiabetic individuals.

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Francesco Andreozzi

Full Text Available To evaluate if plasma kisspeptin concentrations are associated with insulin secretion, as suggested by recent in vitro studies, independently of confounders. 261 nondiabetic subjects were stratified into tertiles according to kisspeptin values. Insulin secretion was assessed using indexes derived from oral glucose tolerance test (OGTT. After adjusting for age, gender, and BMI, subjects in the highest (tertile 3 kisspeptin group exhibited significantly lower values of insulinogenic index, corrected insulin response (CIR30, and Stumvoll indexes for first-phase and second-phase insulin release as compared with low (tertile 1 or intermediate (tertile 2 kisspeptin groups. Univariate correlations between kisspeptin concentration and metabolic variables showed that kisspeptin concentration was significantly and positively correlated with age, blood pressure, and 2-h post-load glucose, and inversely correlated with BMI, and waist circumference. There was an inverse relationship between kisspeptin levels and OGTT-derived indexes of glucose-stimulated insulin secretion. A multivariable regression analysis in a model including all the variables significantly correlated with kisspeptin concentration showed thar age (β = -0.338, P<0.0001, BMI (β = 0.272, P<0.0001, 2-h post-load glucose (β = -0.229, P<0.0001, and kisspeptin (β = -0.105, P = 0.03 remained associated with insulinogenic index. These factors explained 34.6% of the variance of the insulinogenic index. In conclusion, kisspeptin concentrations are associated with insulin secretion independently of important determinants of glucose homeostasis such as gender, age, adiposity, 2-h post-load glucose, and insulin sensitivity.

Living without insulin: the role of leptin signaling in the hypothalamus

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Teppei eFujikawa

2015-03-01

Full Text Available Since its discovery in 1922, insulin has been thought to be required for normal metabolic homeostasis and survival. However, this view would need to be revised as recent results from different laboratories have convincingly indicated that life without insulin is possible in rodent models. These data indicate that particular neuronal circuitries, which include hypothalamic leptin-responsive neurons, are empowered with the capability of permitting life in complete absence of insulin. Here, we review the neuronal and peripheral mechanisms by which leptin signaling in the central nervous system (CNS regulates glucose metabolism in an insulin-independent manner.

Insulin Regulates Hepatic Triglyceride Secretion and Lipid Content via Signaling in the Brain.

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Scherer, Thomas; Lindtner, Claudia; O'Hare, James; Hackl, Martina; Zielinski, Elizabeth; Freudenthaler, Angelika; Baumgartner-Parzer, Sabina; Tödter, Klaus; Heeren, Joerg; Krššák, Martin; Scheja, Ludger; Fürnsinn, Clemens; Buettner, Christoph

2016-06-01

Hepatic steatosis is common in obesity and insulin resistance and results from a net retention of lipids in the liver. A key mechanism to prevent steatosis is to increase secretion of triglycerides (TG) packaged as VLDLs. Insulin controls nutrient partitioning via signaling through its cognate receptor in peripheral target organs such as liver, muscle, and adipose tissue and via signaling in the central nervous system (CNS) to orchestrate organ cross talk. While hepatic insulin signaling is known to suppress VLDL production from the liver, it is unknown whether brain insulin signaling independently regulates hepatic VLDL secretion. Here, we show that in conscious, unrestrained male Sprague Dawley rats the infusion of insulin into the third ventricle acutely increased hepatic TG secretion. Chronic infusion of insulin into the CNS via osmotic minipumps reduced the hepatic lipid content as assessed by noninvasive (1)H-MRS and lipid profiling independent of changes in hepatic de novo lipogenesis and food intake. In mice that lack the insulin receptor in the brain, hepatic TG secretion was reduced compared with wild-type littermate controls. These studies identify brain insulin as an important permissive factor in hepatic VLDL secretion that protects against hepatic steatosis. © 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

Urea impairs β cell glycolysis and insulin secretion in chronic kidney disease

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Koppe, Laetitia; Nyam, Elsa; Vivot, Kevin; Manning Fox, Jocelyn E.; Dai, Xiao-Qing; Nguyen, Bich N.; Attané, Camille; Moullé, Valentine S.; MacDonald, Patrick E.; Ghislain, Julien

2016-01-01

Disorders of glucose homeostasis are common in chronic kidney disease (CKD) and are associated with increased mortality, but the mechanisms of impaired insulin secretion in this disease remain unclear. Here, we tested the hypothesis that defective insulin secretion in CKD is caused by a direct effect of urea on pancreatic β cells. In a murine model in which CKD is induced by 5/6 nephrectomy (CKD mice), we observed defects in glucose-stimulated insulin secretion in vivo and in isolated islets. Similarly, insulin secretion was impaired in normal mouse and human islets that were cultured with disease-relevant concentrations of urea and in islets from normal mice treated orally with urea for 3 weeks. In CKD mouse islets as well as urea-exposed normal islets, we observed an increase in oxidative stress and protein O-GlcNAcylation. Protein O-GlcNAcylation was also observed in pancreatic sections from CKD patients. Impairment of insulin secretion in both CKD mouse and urea-exposed islets was associated with reduced glucose utilization and activity of phosphofructokinase 1 (PFK-1), which could be reversed by inhibiting O-GlcNAcylation. Inhibition of O-GlcNAcylation also restored insulin secretion in both mouse models. These results suggest that insulin secretory defects associated with CKD arise from elevated circulating levels of urea that increase islet protein O-GlcNAcylation and impair glycolysis. PMID:27525435

Rebelling against the (Insulin Resistance: A Review of the Proposed Insulin-Sensitizing Actions of Soybeans, Chickpeas, and Their Bioactive Compounds

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Jaime L. Clark

2018-03-01

Full Text Available Insulin resistance is a major risk factor for diseases such as type 2 diabetes and metabolic syndrome. Current methods for management of insulin resistance include pharmacological therapies and lifestyle modifications. Several clinical studies have shown that leguminous plants such as soybeans and pulses (dried beans, dried peas, chickpeas, lentils are able to reduce insulin resistance and related type 2 diabetes parameters. However, to date, no one has summarized the evidence supporting a mechanism of action for soybeans and pulses that explains their ability to lower insulin resistance. While it is commonly assumed that the biological activities of soybeans and pulses are due to their antioxidant activities, these bioactive compounds may operate independent of their antioxidant properties and, thus, their ability to potentially improve insulin sensitivity via alternative mechanisms needs to be acknowledged. Based on published studies using in vivo and in vitro models representing insulin resistant states, the proposed mechanisms of action for insulin-sensitizing actions of soybeans, chickpeas, and their bioactive compounds include increasing glucose transporter-4 levels, inhibiting adipogenesis by down-regulating peroxisome proliferator-activated receptor-γ, reducing adiposity, positively affecting adipokines, and increasing short-chain fatty acid-producing bacteria in the gut. Therefore, this review will discuss the current evidence surrounding the proposed mechanisms of action for soybeans and certain pulses, and their bioactive compounds, to effectively reduce insulin resistance.

Perivascular adipose tissue control of insulin-induced vasoreactivity in muscle is impaired in db/db mice

DEFF Research Database (Denmark)

Meijer, Rick I; Bakker, Wineke; Alta, Caro-Lynn A F

2013-01-01

in muscle, the underlying mechanisms, and how obesity disturbs this vasodilation. Insulin-induced vasoreactivity of resistance arteries was studied with PVAT from C57BL/6 or db/db mice. PVAT weight in muscle was higher in db/db mice compared with C57BL/6 mice. PVAT from C57BL/6 mice uncovered insulin......-induced vasodilation; this vasodilation was abrogated with PVAT from db/db mice. Blocking adiponectin abolished the vasodilator effect of insulin in the presence of C57BL/6 PVAT, and adiponectin secretion was lower in db/db PVAT. To investigate this interaction further, resistance arteries of AMPKa2(+/+) and AMPKa2......-induced vasodilation in an adiponectin-dependent manner. In conclusion, PVAT controls insulin-induced vasoreactivity in the muscle microcirculation through secretion of adiponectin and subsequent AMPKa2 signaling. PVAT from obese mice inhibits insulin-induced vasodilation, which can be restored by inhibition of JNK....

The macrophage A2B adenosine receptor regulates tissue insulin sensitivity.

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Hillary Johnston-Cox

Full Text Available High fat diet (HFD-induced type 2 diabetes continues to be an epidemic with significant risk for various pathologies. Previously, we identified the A2b adenosine receptor (A2bAR, an established regulator of inflammation, as a regulator of HFD-induced insulin resistance. In particular, HFD was associated with vast upregulation of liver A2bAR in control mice, and while mice lacking this receptor showed augmented liver inflammation and tissue insulin resistance. As the A2bAR is expressed in different tissues, here, we provide the first lead to cellular mechanism by demonstrating that the receptor's influence on tissue insulin sensitivity is mediated via its expression in macrophages. This was shown using a newly generated transgenic mouse model expressing the A2bAR gene in the macrophage lineage on an otherwise A2bAR null background. Reinstatement of macrophage A2bAR expression in A2bAR null mice fed HFD restored insulin tolerance and tissue insulin signaling to the level of control mice. The molecular mechanism for this effect involves A2bAR-mediated changes in cyclic adenosine monophosphate in macrophages, reducing the expression and release of inflammatory cytokines, which downregulate insulin receptor-2. Thus, our results illustrate that macrophage A2bAR signaling is needed and sufficient for relaying the protective effect of the A2bAR against HFD-induced tissue inflammation and insulin resistance in mice.

Insulin Pump Malfunction During Hospitalization: Two Case Reports.

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Faulds, Eileen R; Wyne, Kathleen L; Buschur, Elizabeth O; McDaniel, Jodi; Dungan, Kathleen

2016-06-01

Insulin pump malfunctions and failures continue to occur; however, more severe malfunctions such as the "runaway pump" phenomenon are rarely reported. This article describes two cases of pump malfunction in which pump users appear to have received an unsolicited bolus of insulin resulting in severe episodes of hypoglycemia during hospitalization. Both cases of insulin pump malfunction occurred in the inpatient setting at a large academic medical center in the United States. An analysis of the corresponding insulin pump downloads was performed. The Food and Drug Administration's (FDA's) Manufacturer and User Facility Device Experience (MAUDE) database was searched for similar cases involving Medtronic (Northridge, CA) insulin pumps using the terms "pump," "infusion," "insulin AND malfunction AND Medtronic." The two cases described show remarkable similarities, each demonstrating a severe hypoglycemic event preceded by an infusion site change followed by an alarm. In both cases a rapid spraying of insulin was reported. The insulin pump downloads validated much of the patients' and medical staff's descriptions of events. The FDA's MAUDE database search revealed 425 cases meeting our search term criteria. All cases were reviewed. Seven cases were identified involving independent movement of the reservoir piston. The cases detailed are the first to describe an insulin pump malfunction of this nature in the hospital setting involving unsolicited insulin boluses leading to severe hypoglycemia. The cases are particularly compelling in that they were witnessed by medical personnel. Providers and patients should receive instruction education on the recognition and management of insulin pump malfunction.

Rosiglitazone Reduces Plasma Levels of Inflammatory and Hemostatic Biomarkers and Improves Global Endothelial Function in Habitual Heavy Smokers Without Diabetes Mellitus or Metabolic Syndrome

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I-Chih Chen

2010-02-01

Conclusion: Rosiglitazone significantly reduces plasma levels of inflammatory and hemostatic biomarkers, and restores global endothelial dysfunction, independently from insulin sensitization, in healthy smokers.

Post-transcriptional gene silencing of ribosomal protein S6 kinase 1 restores insulin action in leucine-treated skeletal muscle

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Deshmukh, A; Salehzadeh, F; Metayer-Coustard, S

2009-01-01

Excessive nutrients, especially amino acids, impair insulin action on glucose metabolism in skeletal muscle. We tested the hypothesis that the branched-chain amino acid leucine reduces acute insulin action in primary myotubes via a negative feedback mechanism involving ribosomal protein S6 kinase 1...... to excessive leucine. In conclusion, S6K1 plays an important role in the regulation of insulin action on glucose metabolism in skeletal muscle....

Obese but not normal-weight women with polycystic ovary syndrome are characterized by metabolic and microvascular insulin resistance.

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Ketel, Iris J G; Stehouwer, Coen D A; Serné, Erik H; Korsen, Ted J M; Hompes, Peter G A; Smulders, Yvo M; de Jongh, Renate T; Homburg, Roy; Lambalk, Cornelis B

2008-09-01

Polycystic ovary syndrome (PCOS) and obesity are associated with diabetes and cardiovascular disease, but it is unclear to what extent PCOS contributes independently of obesity. The objective of the study was to investigate whether insulin sensitivity and insulin's effects on the microcirculation are impaired in normal-weight and obese women with PCOS. Thirty-five women with PCOS (19 normal weight and 16 obese) and 27 age- and body mass index-matched controls (14 normal weight and 13 obese) were included. Metabolic Insulin sensitivity (isoglycemic-hyperinsulinemic clamp) and microvascular insulin sensitivity [endothelium dependent (acetylcholine [ACh])] and endothelium-independent [sodium nitroprusside (SNP)] vasodilation with laser Doppler flowmetry was assessed at baseline and during hyperinsulinemia. Metabolic insulin sensitivity (M/I value) and the area under the response curves to ACh and SNP curves were measured to assess microcirculatory function at baseline and during insulin infusion (microvascular insulin sensitivity). Obese women were more insulin resistant than normal-weight women (P PCOS women were more resistant than obese controls (P = 0.02). In contrast, normal-weight women with PCOS had similar insulin sensitivity, compared with normal-weight women without PCOS. Baseline responses to ACh showed no difference in the four groups. ACh responses during insulin infusion were significantly greater in normal-weight PCOS and controls than in obese PCOS and controls. PCOS per se had no significant influence on ACh responses during insulin infusion. During hyperinsulinemia, SNP-dependent vasodilatation did not significantly increase, compared with baseline in the four groups. PCOS per se was not associated with impaired metabolic insulin sensitivity in normal-weight women but aggravates impairment of metabolic insulin sensitivity in obese women. In obese but not normal-weight women, microvascular and metabolic insulin sensitivity are decreased, independent

A Unifying Organ Model of Pancreatic Insulin Secretion.

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Andrea De Gaetano

Full Text Available The secretion of insulin by the pancreas has been the object of much attention over the past several decades. Insulin is known to be secreted by pancreatic β-cells in response to hyperglycemia: its blood concentrations however exhibit both high-frequency (period approx. 10 minutes and low-frequency oscillations (period approx. 1.5 hours. Furthermore, characteristic insulin secretory response to challenge maneuvers have been described, such as frequency entrainment upon sinusoidal glycemic stimulation; substantial insulin peaks following minimal glucose administration; progressively strengthened insulin secretion response after repeated administration of the same amount of glucose; insulin and glucose characteristic curves after Intra-Venous administration of glucose boli in healthy and pre-diabetic subjects as well as in Type 2 Diabetes Mellitus. Previous modeling of β-cell physiology has been mainly directed to the intracellular chain of events giving rise to single-cell or cell-cluster hormone release oscillations, but the large size, long period and complex morphology of the diverse responses to whole-body glucose stimuli has not yet been coherently explained. Starting with the seminal work of Grodsky it was hypothesized that the population of pancreatic β-cells, possibly functionally aggregated in islets of Langerhans, could be viewed as a set of independent, similar, but not identical controllers (firing units with distributed functional parameters. The present work shows how a single model based on a population of independent islet controllers can reproduce very closely a diverse array of actually observed experimental results, with the same set of working parameters. The model's success in reproducing a diverse array of experiments implies that, in order to understand the macroscopic behaviour of the endocrine pancreas in regulating glycemia, there is no need to hypothesize intrapancreatic pacemakers, influences between different

Insulin sensitivity and carotid intima-media thickness

DEFF Research Database (Denmark)

Kozakova, Michaela; Natali, Andrea; Dekker, Jacqueline

2013-01-01

Despite a wealth of experimental data in animal models, the independent association of insulin resistance with early carotid atherosclerosis in man has not been demonstrated. APPROACH AND RESULTS: We studied a European cohort of 525 men and 655 women (mean age, 44±8 years) free of conditions known...... to affect carotid wall (diabetes mellitus, hypertension, and dyslipidemia). All subjects received an oral glucose tolerance test, a euglycemic hyperinsulinemic clamp (M/I as a measure of insulin sensitivity), and B-mode carotid ultrasound. In 833 participants (380 men), the carotid ultrasound was repeated...

Extrinsic factors promoting insulin producing cell-differentiation and insulin expression enhancement-hope for diabetics.

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Dave, Shruti

2013-11-01

Diabetes mellitus (DM) is considered to be an autoimmune disorder leading to destruction of beta-cells resulting in to a loss of blood sugar control. Attempts using many pharmacological compositions including exogenous insulin have failed to show tight control of glycemia and associated manifestations. Stem cells are considered a potential tool for the supply of insulin-producing cells (IPC) generation in vitro. Stem cell differentiation in to pancreatic lineages requires influence of both intrinsic and extrinsic factors. Application of islet growth factors is considered to be potential for enhancement of beta-cell replication, function and survival. Use of certain extrinsic factors is known to facilitate expression of transcription factors known to be important for beta-cell differentiation and production of insulin enabling IPC generation. Hierarchies of secreted signals and transcription factors have been identified by studies from several laboratories that guide cell differentiation in to IPC. This knowledge provides insights for in vitro IPC differentiation from stem cells. Current advancement in medical knowledge promises an insulin independency for DM patients. The review sheds light on few specific extrinsic factors which facilitate differentiation of stem cells in to IPC in vitro have been discussed; which can be proven as a potential therapeutic option for treatment of DM and associated diseases.

[Targeting the brain through the nose. Effects of intranasally administered insulin].

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Brünner, Y F; Benedict, C; Freiherr, J

2013-08-01

The assumption that the human brain is an insulin-independent organ was disproved with the discovery of insulin receptors in the central nervous system in the year 1978. Evidence has been provided for a high density of insulin receptors in brain regions responsible for cognitive memory processes (hippocampus) and for the regulation of appetite (hypothalamus). Accordingly, in animal studies an increased insulin level in the central nervous system leads to an improvement of hippocampal memory function and a decrease of food intake. Similar results were obtained in humans using the method of intranasal administration of insulin. Intranasal insulin reaches the brain and the cerebrospinal fluid via the olfactory epithelium and olfactory nerve fiber bundles leading through the lamina cribrosa to the olfactory bulb. Thus, this method renders the investigation of specific insulin effects in humans possible. The therapeutic potential of an intranasal insulin administration for the treatment of diseases for which an imbalance of the central nervous insulin metabolism is discussed (e.g. Alzheimer's disease, diabetes mellitus and obesity) can only be estimated with the help of further clinical studies.

LPS-Induced Low-Grade Inflammation Increases Hypothalamic JNK Expression and Causes Central Insulin Resistance Irrespective of Body Weight Changes.

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Rorato, Rodrigo; Borges, Beatriz de Carvalho; Uchoa, Ernane Torres; Antunes-Rodrigues, José; Elias, Carol Fuzeti; Elias, Lucila Leico Kagohara

2017-07-04

Metabolic endotoxemia contributes to low-grade inflammation in obesity, which causes insulin resistance due to the activation of intracellular proinflammatory pathways, such as the c-Jun N-terminal Kinase (JNK) cascade in the hypothalamus and other tissues. However, it remains unclear whether the proinflammatory process precedes insulin resistance or it appears because of the development of obesity. Hypothalamic low-grade inflammation was induced by prolonged lipopolysaccharide (LPS) exposure to investigate if central insulin resistance is induced by an inflammatory stimulus regardless of obesity. Male Wistar rats were treated with single (1 LPS) or repeated injections (6 LPS) of LPS (100 μg/kg, IP) to evaluate the phosphorylation of the insulin receptor substrate-1 (IRS1), Protein kinase B (AKT), and JNK in the hypothalamus. Single LPS increased the expression of pIRS1, pAKT, and pJNK, whereas the repeated LPS treatment failed to recruit pIRS1 and pAKT. The 6 LPS treated rats showed increased total JNK and pJNK. The 6 LPS rats became unresponsive to the hypophagic effect induced by central insulin administration (12 μM/5 μL, ICV). Prolonged exposure to LPS (24 h) impaired the insulin-induced AKT phosphorylation and the translocation of the transcription factor forkhead box protein O1 (FoxO1) from the nucleus to the cytoplasm of the cultured hypothalamic GT1-7 cells. Central administration of the JNK inhibitor (20 μM/5 μL, ICV) restored the ability of insulin to phosphorylate IRS1 and AKT in 6 LPS rats. The present data suggest that an increased JNK activity in the hypothalamus underlies the development of insulin resistance during prolonged exposure to endotoxins. Our study reveals that weight gain is not mandatory for the development of hypothalamic insulin resistance and the blockade of proinflammatory pathways could be useful for restoring the insulin signaling during prolonged low-grade inflammation as seen in obesity.

Circulating zonulin, a marker of intestinal permeability, is increased in association with obesity-associated insulin resistance.

Science.gov (United States)

Moreno-Navarrete, José María; Sabater, Mònica; Ortega, Francisco; Ricart, Wifredo; Fernández-Real, José Manuel

2012-01-01

Zonulin is the only physiological mediator known to regulate intestinal permeability reversibly by modulating intercellular tight junctions. To investigate the relationship between intestinal permeability and obesity-associated metabolic disturbances in humans, we aimed to study circulating zonulin according to obesity and insulin resistance. Circulating zonulin (ELISA) was measured in 123 caucasian men in association with inflammatory and metabolic parameters (including minimal model-measured insulin sensitivity). Circulating zonulin increased with body mass index (BMI), waist to hip ratio (WHR), fasting insulin, fasting triglycerides, uric acid and IL-6, and negatively correlated with HDL-cholesterol and insulin sensitivity. In multiple regression analysis, insulin sensitivity (p = 0.002) contributed independently to circulating zonulin variance, after controlling for the effects of BMI, fasting triglycerides and age. When circulating IL-6 was added to this model, only BMI (p = 0.01) contributed independently to circulating zonulin variance. In conclusion, the relationship between insulin sensitivity and circulating zonulin might be mediated through the obesity-related circulating IL-6 increase.

Hyperinsulinism and polycystic ovary syndrome (PCOS): role of insulin clearance.

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Amato, M C; Vesco, R; Vigneri, E; Ciresi, A; Giordano, C

2015-12-01

Insulin resistance and compensatory hyperinsulinism are the predominant metabolic defects in polycystic ovary syndrome (PCOS). However, hyperinsulinism, as well as being compensatory, can also express a condition of reduced insulin clearance. Our aim was to evaluate the differences in insulin action and metabolism between women with PCOS (with normal glucose tolerance) and age- and BMI-matched women with prediabetes (without hyperandrogenism and ovulatory disorders). 22 women with PCOS and 21 age/BMI-matched women with prediabetes were subjected to a Hyperinsulinemic-euglycemic clamp and an Oral Glucose tolerance Test (OGTT). Insulin sensitivity was assessed by the glucose infusion rate during clamp (M value); insulin secretion by Insulinogenic index, Oral Disposition Index (DIo) and AUC(2h-insulin) during OGTT; and insulin clearance by the metabolic clearance rate of insulin (MCRI) during clamp. Women with PCOS showed significantly higher levels of AUC(2h-insulin) (p PCOS [420 (IQR 227-588) vs. 743 (IQR 597-888) ml m(-2) min(-1): p PCOS group, a strong independent inverse correlation was only observed between MCRI and AUC(2h-insulin) (PCOS: β:-0.878; p PCOS there is peripheral insulin sensitivity similar to that of women with prediabetes. What sets PCOS apart is the hyperinsulinism, today still simplistically defined "compensatory"; actually this is mainly related to decreased insulin clearance whose specific causes and dynamics have yet to be clarified.

Adipocytokine Associations with Insulin Resistance in British South Asians

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D. R. Webb

2013-01-01

Full Text Available Aims. Adipocytokines are implicated in the pathogenesis of type 2 diabetes and may represent identifiable precursors of metabolic disease within high-risk groups. We investigated adiponectin, leptin, and TNF-α and assessed the contribution of these molecules to insulin resistance in south Asians. Hypothesis. South Asians have adverse adipocytokine profiles which associate with an HOMA-derived insulin resistance phenotype. Methods. We measured adipocytokine concentrations in south Asians with newly diagnosed impaired glucose tolerance or Type 2 Diabetes Mellitus in a case-control study. 158 (48.5% males volunteers aged 25–75 years with risk factors for diabetes but no known vascular or metabolic disease provided serum samples for ELISA and bioplex assays. Results. Total adiponectin concentration progressively decreased across the glucose spectrum in both sexes. A reciprocal trend in leptin concentration was observed only in south Asian men. Adiponectin but not leptin independently associated with HOMA-derived insulin resistance after logistic multivariate regression. Conclusion. Diasporic south Asian populations have an adverse adipocytokine profile which deteriorates further with glucose dysregulation. Insulin resistance is inversely associated with adiponectin independent of BMI and waist circumference in south Asians, implying that adipocytokine interplay contributes to the pathogenesis of metabolic disease in this group.

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

C1qTNF-related protein 1 improve insulin resistance by reducing phosphorylation of serine 1101 in insulin receptor substrate 1.

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Xin, Yaping; Zhang, Dongming; Fu, Yanqin; Wang, Chongxian; Li, Qingju; Tian, Chenguang; Zhang, Suhe; Lyu, Xiaodong

2017-08-30

C1qTNF-related protein 1 (CTRP1) is independently associated with type 2 diabetes. However, the relationship between CTRP1 and insulin resistance is still not established. This study aimed to explore the role of CTRP1 under the situation of insulin resistance in adipose tissue. Plasma CTRP1 level was investigated in type 2 diabetic subjects (n = 35) and non-diabetic subjects (n = 35). The relationship between CTRP1 and phosphorylation of multi insulin receptor substrate 1 (IRS-1) serine (Ser) sites was further explored. Our data showed that Plasma CTRP1 was higher and negative correlation with insulin resistance in diabetic subjects (r = -0.283, p = 0.018). Glucose utilisation test revealed that the glucose utilisation rate of mature adipocytes was improved by CTRP1 in the presence of insulin. CTRP1 was not only related to IRS-1 protein, but also negatively correlated with IRS-1 Ser1101 phosphorylation (r = -0.398, p = 0.031). Furthermore, Phosphorylation levels of IRS-1 Ser1101 were significantly lower after incubation with 40 ng/mL CTRP1 in mature adipocytes than those with no intervention (p insulin resistance by reducing the phosphorylation of IRS-1 Ser1101, induced in the situation of insulin resistance as a feedback adipokine.

Higher glucose, insulin and insulin resistance (HOMA-IR) in childhood predict adverse cardiovascular risk in early adulthood: the Pune Children's Study.

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Yajnik, Chittaranjan S; Katre, Prachi A; Joshi, Suyog M; Kumaran, Kalyanaraman; Bhat, Dattatray S; Lubree, Himangi G; Memane, Nilam; Kinare, Arun S; Pandit, Anand N; Bhave, Sheila A; Bavdekar, Ashish; Fall, Caroline H D

2015-07-01

The Pune Children's Study aimed to test whether glucose and insulin measurements in childhood predict cardiovascular risk factors in young adulthood. We followed up 357 participants (75% follow-up) at 21 years of age who had undergone detailed measurements at 8 years of age (glucose, insulin, HOMA-IR and other indices). Oral glucose tolerance, anthropometry, plasma lipids, BP, carotid intima-media thickness (IMT) and arterial pulse wave velocity (PWV) were measured at 21 years. Higher fasting glucose, insulin and HOMA-IR at 8 years predicted higher glucose, insulin, HOMA-IR, BP, lipids and IMT at 21 years. A 1 SD change in 8 year variables was associated with a 0.10-0.27 SD change at 21 years independently of obesity/adiposity at 8 years of age. A greater rise in glucose-insulin variables between 8 and 21 years was associated with higher cardiovascular risk factors, including PWV. Participants whose HOMA-IR measurement remained in the highest quartile (n = 31) had a more adverse cardiovascular risk profile compared with those whose HOMA-IR measurement remained in the lowest quartile (n = 28). Prepubertal glucose-insulin metabolism is associated with adult cardiovascular risk and markers of atherosclerosis. Our results support interventions to improve glucose-insulin metabolism in childhood to reduce cardiovascular risk in later life.

Phospho-BAD BH3 Mimicry Protects β Cells and Restores Functional β Cell Mass in Diabetes

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Sanda Ljubicic

2015-02-01

Full Text Available Strategies that simultaneously enhance the survival and glucose responsiveness of insulin-producing β cells will greatly augment β cell replacement therapies in type 1 diabetes (T1D. We show that genetic and pharmacologic mimetics of the phosphorylated BCL-2 homology 3 (BH3 domain of BAD impart β-cell-autonomous protective effects in the face of stress stimuli relevant to β cell demise in T1D. Importantly, these benefits translate into improved engraftment of donor islets in transplanted diabetic mice, increased β cell viability in islet grafts, restoration of insulin release, and diabetes reversal. Survival of β cells in this setting is not merely due to the inability of phospho-BAD to suppress prosurvival BCL-2 proteins but requires its activation of the glucose-metabolizing enzyme glucokinase. Thus, BAD phospho-BH3 mimetics may prove useful in the restoration of functional β cell mass in diabetes.

Colloidal gold-labeled insulin complex. Characterization and binding to adipocytes.

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Moll, U M; Thun, C; Pfeiffer, E F

1986-01-01

Biologically active insulin gold complex was used as an ultrastructural marker to study insulin binding sites, uptake, and internalization in isolated rat adipocytes. The preparation conditions for monodispersed particles, ca. 16 nm in diameter and loaded with approximately 100 insulin molecules, are reported. The complex is stable for at least six weeks. Single particles or small clusters were scattered across the cell membrane. The distribution of unbound receptors seemed to be independent of the extensive system of pre-existing surface connected vesicles in adipocytes. The uptake of particles took place predominantly via non-coated pinocytotic invaginations; clathrin-coated pits did not seem to be important for this process. Lysosome-like structures contained aggregates of 10-15 particles. These data suggest that insulin gold complex is a useful marker for the specific labeling of insulin binding sites.

Dynamic Metabolomics Reveals that Insulin Primes the Adipocyte for Glucose Metabolism

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James R. Krycer

2017-12-01

Full Text Available Insulin triggers an extensive signaling cascade to coordinate adipocyte glucose metabolism. It is considered that the major role of insulin is to provide anabolic substrates by activating GLUT4-dependent glucose uptake. However, insulin stimulates phosphorylation of many metabolic proteins. To examine the implications of this on glucose metabolism, we performed dynamic tracer metabolomics in cultured adipocytes treated with insulin. Temporal analysis of metabolite concentrations and tracer labeling revealed rapid and distinct changes in glucose metabolism, favoring specific glycolytic branch points and pyruvate anaplerosis. Integrating dynamic metabolomics and phosphoproteomics data revealed that insulin-dependent phosphorylation of anabolic enzymes occurred prior to substrate accumulation. Indeed, glycogen synthesis was activated independently of glucose supply. We refer to this phenomenon as metabolic priming, whereby insulin signaling creates a demand-driven system to “pull” glucose into specific anabolic pathways. This complements the supply-driven regulation of anabolism by substrate accumulation and highlights an additional role for insulin action in adipocyte glucose metabolism.

Secondary Droop for Frequency and Voltage Restoration in Microgrids

DEFF Research Database (Denmark)

Nutkani, Inam Ullah; Peng, Wang; Blaabjerg, Frede

2015-01-01

Droop based autonomous control offers several advantages such as communication independence, plug-n-play capability and enhanced reliability of the system. Despite these advantages, frequency and voltage of droop controlled microgrid varies with the load change which is one of the major drawback...... of the droop control. Presently, the frequency and voltage restoration in microgrid is achieved through secondary control using low bandwidth communication links. This paper presents secondary-droop based frequency and voltage restoration method which is fully autonomous and independent of communication links....... With the proposed method, the microgrid frequency and voltage can be restored back to nominal value without affecting the power sharing performance of the generation sources. The proposed scheme performance has been validated in simulation for several cases of active and reactive power load conditions....

Insulin Clearance Is Associated with Hepatic Lipase Activity and Lipid and Adiposity Traits in Mexican Americans.

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Artak Labadzhyan

Full Text Available Reduction in insulin clearance plays an important role in the compensatory response to insulin resistance. Given the importance of this trait to the pathogenesis of diabetes, a deeper understanding of its regulation is warranted. Our goal was to identify metabolic and cardiovascular traits that are independently associated with metabolic clearance rate of insulin (MCRI. We conducted a cross-sectional analysis of metabolic and cardiovascular traits in 765 participants from the Mexican-American Coronary Artery Disease (MACAD project who had undergone blood sampling, oral glucose tolerance test, euglycemic-hyperinsulinemic clamp, dual-energy X-ray absorptiometry, and carotid ultrasound. We assessed correlations of MCRI with traits from seven domains, including anthropometry, biomarkers, cardiovascular, glucose homeostasis, lipase activity, lipid profile, and liver function tests. We found inverse independent correlations between MCRI and hepatic lipase (P = 0.0004, insulin secretion (P = 0.0002, alanine aminotransferase (P = 0.0045, total fat mass (P = 0.014, and diabetes (P = 0.03. MCRI and apolipoprotein A-I exhibited a positive independent correlation (P = 0.035. These results generate a hypothesis that lipid and adiposity associated traits related to liver function may play a role in insulin clearance.

Identification of metformin poor responders, requiring supplemental insulin, during randomization of metformin versus insulin for the control of gestational diabetes mellitus.

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Ashoush, Sherif; El-Said, Mourrad; Fathi, Hisham; Abdelnaby, Mohamed

2016-06-01

To evaluate glycemic control among women with gestational diabetes mellitus (GDM) under insulin versus metformin (with or without insulin supplementation), and to identify metformin poor responders requiring supplemental insulin. In Ain Shams University Hospital, mothers with 26-32-week GDM pregnancies, failing diet control, were randomized to receive metformin (n = 47) or insulin (n = 48). The primary outcome was glycemic control. Secondary outcomes included maternal weight, parameters predicting successful metformin monotherapy, neonatal hypoglycemia, and birthweight. Women using metformin (23.4% needing supplemental insulin) gained less weight (P metformin group was related to initial body mass index, HbA1c, oral glucose tolerance test (GTT), and first week mean glucose level. The 1-h glucose level during initial GTT (Hr1-GTT) and the mean fasting glucose level during the first week of therapy (Wk1-mFG) were the two independent parameters associated with requiring supplemental insulin. Women with Hr1-GTT >212 mg/dL and Wk1-mFG >95 mg/dL had a risk ratio of 58.6 (95%CI: 3.68-933.35, P = 0.004) and 11.5 (95%CI: 2.77-47.34,= 0.0008), respectively for needing supplemental insulin during the course of the study compared with women without. Metformin is an effective and safe alternative to insulin in GDM. Women using metformin (± supplemental insulin) had similar glycemic control, less weight gain, and similar rates of side-effects as those on insulin monotherapy. Insulin supplementation to metformin therapy was more likely with elevated Hr1-GTT and Wk1-mFG. © 2016 Japan Society of Obstetrics and Gynecology.

Nutritional Modulation of Insulin Resistance

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Martin O. Weickert

2012-01-01

Full Text Available Insulin resistance has been proposed as the strongest single predictor for the development of Type 2 Diabetes (T2DM. Chronic oversupply of energy from food, together with inadequate physical activity, have been recognized as the most relevant factors leading to overweight, abdominal adiposity, insulin resistance, and finally T2DM. Conversely, energy reduced diets almost invariably to facilitate weight loss and reduce abdominal fat mass and insulin resistance. However, sustained weight loss is generally difficult to achieve, and distinct metabolic characteristics in patients with T2DM further compromise success. Therefore, investigating the effects of modulating the macronutrient composition of isoenergetic diets is an interesting concept that may lead to additional important insights. Metabolic effects of various different dietary concepts and strategies have been claimed, but results from randomized controlled studies and particularly from longer-term-controlled interventions in humans are often lacking. However, some of these concepts are supported by recent research, at least in animal models and short-term studies in humans. This paper provides an update of the current literature regarding the role of nutrition in the modulation of insulin resistance, which includes the discussion of weight-loss-independent metabolic effects of commonly used dietary concepts.

New twist on neuronal insulin receptor signaling in health, disease, and therapeutics.

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Wada, Akihiko; Yokoo, Hiroki; Yanagita, Toshihiko; Kobayashi, Hideyuki

2005-10-01

Long after the pioneering studies documenting the existence of insulin (year 1967) and insulin receptor (year 1978) in brain, the last decade has witnessed extraordinary progress in the understanding of brain region-specific multiple roles of insulin receptor signalings in health and disease. In the hypothalamus, insulin regulates food intake, body weight, peripheral fat deposition, hepatic gluconeogenesis, reproductive endocrine axis, and compensatory secretion of counter-regulatory hormones to hypoglycemia. In the hippocampus, insulin promotes learning and memory, independent of the glucoregulatory effect of insulin. Defective insulin receptor signalings are associated with the dementia in normal aging and patients with age-related neurodegenerative diseases (e.g., Alzheimer's disease); the cognitive impairment can be reversed with systemic administration of insulin in the euglycemic condition. Intranasal administration of insulin enhances memory and mood and decreases body weight in healthy humans, without causing hypoglycemia. In the hypothalamus, insulin-induced activation of the phosphoinositide 3-kinase pathway followed by opening of ATP-sensitive K+ channel has been shown to be related to multiple effects of insulin. However, the precise molecular mechanisms of insulin's pleiotropic effects still remain obscure. More importantly, much remains unknown about the quality control mechanisms ensuring correct conformational maturation of the insulin receptor, and the cellular mechanisms regulating density of cell surface functional insulin receptors.

Doxycycline-regulated 3T3-L1 preadipocyte cell line with inducible, stable expression of adenoviral E4orf1 gene: a cell model to study insulin-independent glucose disposal.

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Krishnapuram, Rashmi; Dhurandhar, Emily J; Dubuisson, Olga; Hegde, Vijay; Dhurandhar, Nikhil V

2013-01-01

Impaired glycemic control and excessive adiposity are major risk factors for Type 2 Diabetes mellitus. In rodent models, Ad36, a human adenovirus, improves glycemic control, independent of dietary fat intake or adiposity. It is impractical to use Ad36 for therapeutic action. Instead, we identified that E4orf1 protein of Ad36, mediates its anti-hyperglycemic action independent of insulin signaling. To further evaluate the therapeutic potential of E4orf1 to improve glycemic control, we established a stable 3T3-L1 cell system in which E4orf1 expression can be regulated. The development and characterization of this cell line is described here. Full-length adenoviral-36 E4orf1 cDNA obtained by PCR was cloned into a tetracycline responsive element containing vector (pTRE-Tight-E4orf1). Upon screening dozens of pTRE-Tight-E4orf1 clones, we identified the one with the highest expression of E4orf1 in response to doxycycline treatment. Furthermore, using this inducible system we characterized the ability of E4orf1 to improve glucose disposal in a time dependent manner. This stable cell line offers a valuable resource to carefully study the novel signaling pathways E4orf1 uses to enhance cellular glucose disposal independent of insulin.

Doxycycline-regulated 3T3-L1 preadipocyte cell line with inducible, stable expression of adenoviral E4orf1 gene: a cell model to study insulin-independent glucose disposal.

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Rashmi Krishnapuram

Full Text Available Impaired glycemic control and excessive adiposity are major risk factors for Type 2 Diabetes mellitus. In rodent models, Ad36, a human adenovirus, improves glycemic control, independent of dietary fat intake or adiposity. It is impractical to use Ad36 for therapeutic action. Instead, we identified that E4orf1 protein of Ad36, mediates its anti-hyperglycemic action independent of insulin signaling. To further evaluate the therapeutic potential of E4orf1 to improve glycemic control, we established a stable 3T3-L1 cell system in which E4orf1 expression can be regulated. The development and characterization of this cell line is described here. Full-length adenoviral-36 E4orf1 cDNA obtained by PCR was cloned into a tetracycline responsive element containing vector (pTRE-Tight-E4orf1. Upon screening dozens of pTRE-Tight-E4orf1 clones, we identified the one with the highest expression of E4orf1 in response to doxycycline treatment. Furthermore, using this inducible system we characterized the ability of E4orf1 to improve glucose disposal in a time dependent manner. This stable cell line offers a valuable resource to carefully study the novel signaling pathways E4orf1 uses to enhance cellular glucose disposal independent of insulin.

Insulin-like growth factor II messenger RNA-binding protein-3 is an independent prognostic factor in uterine leiomyosarcoma.

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Yasutake, Nobuko; Ohishi, Yoshihiro; Taguchi, Kenichi; Hiraki, Yuka; Oya, Masafumi; Oshiro, Yumi; Mine, Mari; Iwasaki, Takeshi; Yamamoto, Hidetaka; Kohashi, Kenichi; Sonoda, Kenzo; Kato, Kiyoko; Oda, Yoshinao

2018-04-01

The aim of this study was to identify the prognostic factors of uterine leiomyosarcoma (ULMS). We reviewed 60 cases of surgically resected ULMSs and investigated conventional clinicopathological factors, together with the expression of insulin-like growth factor II messenger RNA-binding protein-3 (IMP3), hormone receptors and cell cycle regulatory markers by immunohistochemistry. Mediator complex subunit 12 (MED12) mutation analysis was also performed. Univariate analyses revealed that advanced stage (P < 0.0001), older age (P = 0.0244) and IMP3 expression (P = 0.0011) were significant predictors of a poor outcome. Multivariate analysis revealed advanced stage (P < 0.0001) and IMP3 (P = 0.0373) as independent predictors of a poor prognosis. Expressions of cell cycle markers and hormone receptors, and MED12 mutations (12% in ULMSs) were not identified as prognostic markers in this study. IMP3 expression in ULMS could be a marker of a poor prognosis. © 2017 John Wiley & Sons Ltd.

Characterization of the growth of murine fibroblasts that express human insulin receptors. II. Interaction of insulin with other growth factors

International Nuclear Information System (INIS)

Randazzo, P.A.; Jarett, L.

1990-01-01

The effects of insulin-like growth factor-1 (IGF-1), epidermal growth factor (EGF), platelet-derived growth factor (PDGF), and insulin on DNA synthesis were studied in murine fibroblasts transfected with an expression vector containing human insulin receptor cDNA (NIH 3T3/HIR) and the parental NIH 3T3 cells. In NIH 3T3/HIR cells, individual growth factors in serum-free medium stimulated DNA synthesis with the following relative efficacies: insulin greater than or equal to 10% fetal calf serum greater than PDGF greater than IGF-1 much greater than EGF. In comparison, the relative efficacies of these factors in stimulating DNA synthesis by NIH 3T3 cells were 10% fetal calf serum greater than PDGF greater than EGF much greater than IGF-1 = insulin. In NIH 3T3/HIR cells, EGF was synergistic with 1-10 ng/ml insulin but not with 100 ng/ml insulin or more. Synergy of PDGF or IGF-1 with insulin was not detected. In the parental NIH 3T3 cells, insulin and IGF-1 were found to be synergistic with EGF (1 ng/ml), PDGF (100 ng/ml), and PDGF plus EGF. In NIH 3T3/HIR cells, the lack of interaction of insulin with other growth factors was also observed when the percentage of cells synthesizing DNA was examined. Despite insulin's inducing only 60% of NIH 3T3/HIR cells to incorporate thymidine, addition of PDGF, EGF, or PDGF plus EGF had no further effect. In contrast, combinations of growth factors resulted in 95% of the parental NIH 3T3 cells synthesizing DNA. The independence of insulin-stimulated DNA synthesis from other mitogens in the NIH 3T3/HIR cells is atypical for progression factor-stimulated DNA synthesis and is thought to be partly the result of insulin receptor expression in an inappropriate context or quantity

Insulin-like growth factor I has independent effects on bone matrix formation and cell replication

International Nuclear Information System (INIS)

Hock, J.M.; Centrella, M.; Canalis, E.

1988-01-01

The effects of insulin-like growth factor-I (IGF-I) and insulin on bone matrix synthesis and bone cell replication were studied in cultured 21-day-old fetal rat calvariae. Histomorphometry techniques were developed to measure the incorporation of [2,3- 3 H]proline and [methyl- 3 H]thymidine into bone matrix and bone cell nuclei, respectively, using autoradiographs of sagittal sections of calvariae cultured with IGF-I, insulin, or vehicle for up to 96 h. To confirm an effect on bone formation, IGF-I was also studied for its effects on [ 3 H]proline incorporation into collagenase-digestible protein (CDP) and noncollagen protein and on [ 3 H]thymidine incorporation into acid-precipitable material (DNA). IGF-I at 10(-9)-10(-7) M significantly increased the rate of bone matrix apposition and CDP after 24 h by 45-50% and increased cell labeling by 8-fold in the osteoprogenitor cell zone, by 4-fold in the osteoblast cell zone, and by 2-fold in the periosteal fibroblast zone. Insulin at 10(-9)-10(-6) M also increased matrix apposition rate and CDP by 40-50%, but increased cell labeling by 2-fold only at a concentration of 10(-7) M or higher and then only in the osteoprogenitor cell zone. When hydroxyurea was added to IGF-I-treated bones, the effects of IGF-I on DNA synthesis were abolished, but the increase in bone matrix apposition induced by IGF-I was only partly diminished. In conclusion, IGF-I stimulates matrix synthesis in calvariae, an effect that is partly, although not completely, dependent on its stimulatory effect on DNA synthesis

Effect of rosiglitazone on insulin resistance, growth factors, and reproductive disturbances in women with polycystic ovary syndrome.

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Belli, Susana H; Graffigna, Mabel N; Oneto, Adriana; Otero, Patricia; Schurman, Leon; Levalle, Oscar A

2004-03-01

To evaluate the effects of rosiglitazone on insulin resistance, growth factors, and reproductive disturbances in women with polycystic ovary syndrome (PCOS). Prospective study. Women with PCOS attending as outpatients of the Endocrine Division, Hospital Durand, Buenos Aires. Twenty-four insulin-resistant women with PCOS. Hormonal evaluations and a standardized oral glucose tolerance test before and after a 3-month trial of 4 mg of rosiglitazone daily. Serum LH, FSH, T, IGF-1, IGFBP-1, IGFBP-3, leptin, 17alpha-hydroxyprogesterone, insulin, and glucose concentrations. The area under insulin curve (AUC-insulin), the HOMA index (insulin resistance), the QUICKI index (insulin sensitivity), and the beta-cell function were calculated. Body mass index (BMI) and the waist/hip ratio were evaluated. A significant decrease was observed in serum fasting insulin, AUC insulin, HOMA index, beta-cell function, IGF-1, LH, and waist/hip ratio. The QUICKI index and IGFBP-1 increased significantly. Serum sex hormone-binding globulin, androgens, leptin, IGFBP-3, and BMI remained unchanged. Twenty-two of 23 females had their menses restored, and three patients became pregnant. One patient was excluded because she became pregnant at the second month. Associated with the decrease in LH, rosiglitazone improved insulin-resistance parameters and normalized the menstrual cycle, which suggests that this drug could improve the endocrine-reproductive condition in insulin-resistant women with PCOS.

Variation in C-reactive protein following weight loss in obese insulin resistant postmenopausal women: is there an independent contribution of lean body mass?

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Barsalani, R; Riesco, É; Perreault, K; Imbeault, P; Brochu, M; Dionne, I J

2015-03-01

We showed that obese insulin resistant postmenopausal women are characterized by higher lean body mass and elevated C-reactive protein. Although counterintuitive, we hypothesized that losses in muscle mass following caloric restriction and increase in muscle quality will be associated with improvements in glucose homeostasis through decreases in C-reactive protein. To determine 1) if improvements in C-reactive protein concentrations occurs through losses in lean body mass; and 2) if decreases in C-reactive protein levels contribute to improvements in insulin sensitivity. 50 postmenopausal women (body mass index>26 kg/m(²)) with impaired glucose disposal (program. Outcome measures were: Glucose disposal rate: M value (by hyperinsulinemic-euglycemic clamp), body composition (total, trunk, and appendicluar). LBM and FM by DXA), LBM index (LBM (kg)/height (m(2)), body fat distribution (VAT and SAT by CT scan) and plasma high-sensitive C-reactive protein (hsCRP) and interleukin-6 (Il-6). Significant correlations were observed between Δ hsCRP levels with Δ Il-6 (r=0.33, p≤0.05), Δ total LBM index (r=0.44, p≤0.01), Δ trunk LBM (r=0.38, p≤0.01) Δ SAT (r=0.35, p≤0.05) and ∆ glucose disposal rate (r=- 0.44, p≤0.01). After including all the correlated variables in Stepwise linear regression model, Δ LBM index was the only independent predictor of the reduction in hsCRP levels (R(2)=0.20, p≤0.01). Losses in total lean body mass are independently associated with improvements in inflammatory state (CRP levels) in obese postmenopausal women with impaired glucose disposal. © Georg Thieme Verlag KG Stuttgart · New York.

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

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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

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.

The Effect of a Diet Moderately High in Protein and Fiber on Insulin Sensitivity Measured Using the Dynamic Insulin Sensitivity and Secretion Test (DISST

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Lisa Te Morenga

2017-11-01

Full Text Available Evidence shows that weight loss improves insulin sensitivity but few studies have examined the effect of macronutrient composition independently of weight loss on direct measures of insulin sensitivity. We randomised 89 overweight or obese women to either a standard diet (StdD, that was intended to be low in fat and relatively high in carbohydrate (n = 42 or to a relatively high protein (up to 30% of energy, relatively high fibre (>30 g/day diet (HPHFib (n = 47 for 10 weeks. Advice regarding strict adherence to energy intake goals was not given. Insulin sensitivity and secretion was assessed by a novel method—the Dynamic Insulin Sensitivity and Secretion Test (DISST. Although there were significant improvements in body composition and most cardiometabolic risk factors on HPHFib, insulin sensitivity was reduced by 19.3% (95% CI: 31.8%, 4.5%; p = 0.013 in comparison with StdD. We conclude that the reduction in insulin sensitivity after a diet relatively high in both protein and fibre, despite cardiometabolic improvements, suggests insulin sensitivity may reflect metabolic adaptations to dietary composition for maintenance of glucose homeostasis, rather than impaired metabolism.

Obese children and adolescents have elevated nighttime blood pressure independent of insulin resistance and arterial stiffness

DEFF Research Database (Denmark)

Hvidt, Kristian N; Olsen, Michael H; Holm, Jens-Christian

2014-01-01

BACKGROUND: Insulin resistance has been related to elevated blood pressure (BP) in obese children and may adversely affect the vasculature by arterial stiffening. The objective was to investigate whether daytime and nighttime BP were elevated and related to insulin resistance and arterial stiffness...... in obese children and adolescents. METHODS: Ninety-two obese patients aged 10-18 years were compared with 49 healthy control individuals. Insulin resistance was measured as the homeostatic assessment model (HOMA), and arterial stiffness was measured as carotid-femoral pulse wave velocity (cfPWV). RESULTS......: Mean ± SD daytime systolic BP (SBP) (obese: 125±8.3mm Hg; control: 121±10.1mm Hg; P = 0.03) and nighttime SBP (obese: 108±10.7mm Hg; control: 102±8.2mm Hg; P = 0.0001) were higher in the obese group when compared with the control group. No difference was found in daytime diastolic BP (DBP), whereas...

Insulin analogues and cancer: a note of caution

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Joseph A.M.J.L. eJanssen

2014-05-01

Full Text Available Abstract In view of the lifelong exposure and large patient populations involved, insulin analogues with an increased mitogenic effect in comparison to human insulin may potentially constitute a major health problem, since these analogues may possibly induce the growth of pre-existing neoplasms. At present, the available data suggest that insulin analogues are safe. In line with these findings, we observed that serum of diabetic patients treated with insulin analogues, compared to that of diabetic patients treated with human insulin, did not induce an increased phosphorylation of tyrosine residues of the insulin-like growth factor-I receptor (IGF-IR. However, the classical model of the IGF-IR signaling may be insufficient to explain (all mitogenic effects of insulin analogues since also non-canonical signaling pathways of the IGF-IR may play a major role in this respect. Although phosphorylation of tyrosine residues of the IGF-IR is generally considered to be the initial activation step within the intracellular IGF-IR signaling pathway, it has been found that cells undergo a signaling switch under hyperglycemic conditions. After this switch, a completely different mechanism is utilized to activate the mitogenic (mitogen-activated protein kinase (MAPK pathways of the IGF-IR that is independent from tyrosine phosphorylation of the IGF-IR. At present it is unknown whether activation of this alternative intracellular pathway of the IGF-IR occurs during hyperglycemia in vivo and whether it is stronger in patients treated with (some insulin analogues than in patients treated with human insulin. In addition, it is unknown whether the insulin receptors (IRs also undergo a signaling switch during hyperglycemia. This should be investigated in future studies. Finally, relative overexpression of IR isoform A (IR-A in (pre cancer tissues may play a key role in the development and progression of human cancers during treatment with insulin (analogues. Further

[The effect of N-stearoylethanolamine on liver phospholipid composition of rats with insulin resistance caused by alimentary obesity].

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Onopchenko, O V; Kosiakova, H V; Horid'ko, T M; Klimashevskyĭ, V M; Hula, N M

2014-01-01

We used alimentary obesity-induced insulin resistance (IR) model in rats to investigate the influence of N-stearoylethanolamine on the content of phospholipids and their fatty acid composition. Our results show that prolonged high-fat diet triggers considerable aberrations in the composition of main phospholipids in the liver and can be one of the causes of IR in rats. In particular, the increase of phosphatidylcholine, phosphatidylethanolamine and significant decrease of other phospholipids: lysophosphatidylcholine, lysophosphatidylethanolamine, sphingomyelin, phosphatidylinositol, phosphatidylserine and diphosphaglicerol were observed. The levels of monounsaturated (erucic, nervonic, oleic) and polyunsaturated (eicosatrienoic, docosatrienoic, arachidonic) fatty acids were increased; meanwhile the content of diunsaturated acids was decreased. The NSE administration (50 mg/kg of body weight) caused restoration of the phospholipids content in the liver of rats with diet-induced IR that highly correlated with the decrease in plasma insulin level and the improvement of insulin sensitivity. Moreover, the effect of NSE was accompanied by the normalization of fatty acids composition of phospholipids that could be related to modulating influence of NSE on the activity of the main fatty acid desaturases. It is known that the imbalance in phospholipid composition of the rat liver causes substantial metabolic alterations that are associated with the development of IR. Accordingly, the compensations of the imbalance by NSE can help to restore insulin sensitivity, inhibit the development of obesity, IR and type 2 diabetes.

Impact of the Type of Continuous Insulin Administration on Metabolism in a Diabetic Rat Model

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A. Schaschkow

2016-01-01

Full Text Available Exogenous insulin is the only treatment available for type 1 diabetic patients and is mostly administered by subcutaneous (SC injection in a basal and bolus scheme using insulin pens (injection or pumps (preimplanted SC catheter. Some divergence exists between these two modes of administration, since pumps provide better glycaemic control compared to injections in humans. The aim of this study was to compare the impacts of two modes of insulin administration (single injections of long-acting insulin or pump delivery of rapid-acting insulin at the same dosage (4 IU/200 g/day on rat metabolism and tissues. The rat weight and blood glucose levels were measured periodically after treatment. Immunostaining for signs of oxidative stress and for macrophages was performed on the liver and omental tissues. The continuous insulin delivery by pumps restored normoglycaemia, which induced the reduction of both reactive oxygen species and macrophage infiltration into the liver and omentum. Injections controlled the glucose levels for only a short period of time and therefore tissue stress and inflammation were elevated. In conclusion, the insulin administration mode has a crucial impact on rat metabolic parameters, which has to be taken into account when studies are designed.

Association Between Insulin Resistance and Bone Structure in Nondiabetic Postmenopausal Women

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Finkelstein, Joel S.; Bouxsein, Mary L.; Yu, Elaine W.

2016-01-01

Context: The clinical consequences of insulin resistance and hyperinsulinemia on bone remain largely unknown. Objective: The objective of the study was to evaluate the effect of insulin resistance on peripheral bone geometry, volumetric bone mineral density (vBMD), bone microarchitecture, and estimated bone strength. Design, Setting, and Participants: This cross-sectional study included 146 postmenopausal, nondiabetic Caucasian women (mean age 60.3 ± 2.7 y) who were participating in the Study of Women's Health Across the Nation. Interventions: There were no interventions. Main Outcome Measures: High-resolution peripheral quantitative computed tomography was used to assess bone density and microstructure at the distal radius and tibia. Fasting insulin and glucose were measured and insulin resistance was estimated using homeostasis model assessment of insulin resistance (HOMA-IR), with higher values indicating greater insulin resistance. Results: There was a negative association between HOMA-IR and bone size and a positive association between HOMA-IR and total vBMD, trabecular vBMD, trabecular thickness, and cortical thickness at the radius and tibia. These relationships remained, even after adjusting for body weight and other potential covariates (eg, time since menopause, cigarette smoking, physical activity, prior use of osteoporosis medications or glucocorticoids). Conclusions: In nondiabetic, postmenopausal women, insulin resistance was associated with smaller bone size, greater volumetric bone mineral density, and generally favorable bone microarchitecture at weight-bearing and nonweight-bearing skeletal sites. These associations were independent of body weight and other potential covariates, suggesting that hyperinsulinemia directly affects bone structure independent of obesity and may explain, in part, the higher trabecular bone density and favorable trabecular microarchitecture seen in individuals with type 2 diabetes mellitus. PMID:27243136

Induction of insulin secretion in engineered liver cells by nitric oxide

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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.

Circulating zonulin, a marker of intestinal permeability, is increased in association with obesity-associated insulin resistance.

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José María Moreno-Navarrete

Full Text Available Zonulin is the only physiological mediator known to regulate intestinal permeability reversibly by modulating intercellular tight junctions. To investigate the relationship between intestinal permeability and obesity-associated metabolic disturbances in humans, we aimed to study circulating zonulin according to obesity and insulin resistance. Circulating zonulin (ELISA was measured in 123 caucasian men in association with inflammatory and metabolic parameters (including minimal model-measured insulin sensitivity. Circulating zonulin increased with body mass index (BMI, waist to hip ratio (WHR, fasting insulin, fasting triglycerides, uric acid and IL-6, and negatively correlated with HDL-cholesterol and insulin sensitivity. In multiple regression analysis, insulin sensitivity (p = 0.002 contributed independently to circulating zonulin variance, after controlling for the effects of BMI, fasting triglycerides and age. When circulating IL-6 was added to this model, only BMI (p = 0.01 contributed independently to circulating zonulin variance. In conclusion, the relationship between insulin sensitivity and circulating zonulin might be mediated through the obesity-related circulating IL-6 increase.

Fasting insulin, insulin resistance, and risk of cardiovascular or all-cause mortality in non-diabetic adults: a meta-analysis.

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Zhang, Xiaohong; Li, Jun; Zheng, Shuiping; Luo, Qiuyun; Zhou, Chunmei; Wang, Chaoyang

2017-10-31

Studies on elevated fasting insulin or insulin resistance (IR) and cardiovascular or all-cause mortality risk in non-diabetic individuals have yielded conflicting results. This meta-analysis aimed to evaluate the association of elevated fasting insulin levels or IR as defined by homeostasis model assessment of IR (HOMA-IR) with cardiovascular or all-cause mortality in non-diabetic adults. We searched for relevant studies in PubMed and Emabse databases until November 2016. Only prospective observational studies investigating the association of elevated fasting insulin levels or HOMA-IR with cardiovascular or all-cause mortality risk in non-diabetic adults were included. Risk ratio (RR) with its 95% confidence intervals (CIs) was pooled for the highest compared with the lowest category of fasting insulin levels or HOMA-IR. Seven articles involving 26976 non-diabetic adults were included. The pooled, adjusted RR of all-cause mortality comparing the highest with the lowest category was 1.13 (95% CI: 1.00-1.27; P =0.058) for fasting insulin levels and 1.34 (95% CI: 1.11-1.62; P =0.002) for HOMA-IR, respectively. When comparing the highest with the lowest category, the pooled adjusted RR of cardiovascular mortality was 2.11 (95% CI: 1.01-4.41; P =0.048) for HOMA-IR in two studies and 1.40 (95% CI: 0.49-3.96; P =0.526) for fasting insulin levels in one study. IR as measured by HOMA-IR but not fasting insulin appears to be independently associated with greater risk of cardiovascular or all-cause mortality in non-diabetic adults. However, the association of fasting insulin and HOMA-IR with cardiovascular mortality may be unreliable due to the small number of articles included. © 2017 The Author(s).

Activation of IGF-1 and insulin signaling pathways ameliorate mitochondrial function and energy metabolism in Huntington's Disease human lymphoblasts.

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Naia, Luana; Ferreira, I Luísa; Cunha-Oliveira, Teresa; Duarte, Ana I; Ribeiro, Márcio; Rosenstock, Tatiana R; Laço, Mário N; Ribeiro, Maria J; Oliveira, Catarina R; Saudou, Frédéric; Humbert, Sandrine; Rego, A Cristina

2015-02-01

Huntington's disease (HD) is an inherited neurodegenerative disease caused by a polyglutamine repeat expansion in the huntingtin protein. Mitochondrial dysfunction associated with energy failure plays an important role in this untreated pathology. In the present work, we used lymphoblasts obtained from HD patients or unaffected parentally related individuals to study the protective role of insulin-like growth factor 1 (IGF-1) versus insulin (at low nM) on signaling and metabolic and mitochondrial functions. Deregulation of intracellular signaling pathways linked to activation of insulin and IGF-1 receptors (IR,IGF-1R), Akt, and ERK was largely restored by IGF-1 and, at a less extent, by insulin in HD human lymphoblasts. Importantly, both neurotrophic factors stimulated huntingtin phosphorylation at Ser421 in HD cells. IGF-1 and insulin also rescued energy levels in HD peripheral cells, as evaluated by increased ATP and phosphocreatine, and decreased lactate levels. Moreover, IGF-1 effectively ameliorated O2 consumption and mitochondrial membrane potential (Δψm) in HD lymphoblasts, which occurred concomitantly with increased levels of cytochrome c. Indeed, constitutive phosphorylation of huntingtin was able to restore the Δψm in lymphoblasts expressing an abnormal expansion of polyglutamines. HD lymphoblasts further exhibited increased intracellular Ca(2+) levels before and after exposure to hydrogen peroxide (H2O2), and decreased mitochondrial Ca(2+) accumulation, being the later recovered by IGF-1 and insulin in HD lymphoblasts pre-exposed to H2O2. In summary, the data support an important role for IR/IGF-1R mediated activation of signaling pathways and improved mitochondrial and metabolic function in HD human lymphoblasts.

Should leptin replace insulin as a lifetime monotherapy for diabetes type 1 and 2?

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Kalra, Satya P

2013-10-01

Evidence accumulated during the last decade has affirmed that adipocyte leptin insufficiency in the hypothalamus is the primary etiological factor in the pathogenesis of diabetes type 1 and 2 and related metabolic morbidities. Leptin insufficiency disrupts the relay of hypothalamic regulatory information along three descending pathways to the organs in the periphery that normally participate in maintenance of glucose homeostasis on a minute-to-minute basis throughout lifetime. Reinstatement of leptin sufficiency in the hypothalamus by either systemic or central injections, or its provision selectively in the hypothalamus with the aid of gene therapy extinguished hyperglycemia and normalized blood glucose stably during the entire course of treatment in a variety of animal models of diabetes type 1 and 2. In follow-up clinical trials, twice daily leptin treatment in leptinopenic and insulinopenic type 1 diabetics and leptinopenic and hyperinsulinemic type 2 diabetics with congenital lipodystrophy or acquired lipoatrophy normalized blood glucose without any discernible adverse effects during the extended course of treatment. Taken together, these findings have amply endorsed the efficacy of leptin therapy to restore glucose homeostasis in insulin-deficient as well as hyperinsulinemic diabetic patients. Consequently, restoration of optimal hypothalmic signaling to reinstate glucose homeostasis with leptin is a highly suitable new therapeutic strategy to ameliorate diabetes type 1 and 2 for the lifetime and to replace the currently in vogue insulin monotherapy. In view of the relentless challenges posed by the worldwide epidemic of diabetes and soaring treatment costs, taken together with the well-known shortcomings of therapies based on restoring insulin signaling, it is highly critical and timely to undertake new clinical trials that ascertain appropriate dosage and route of leptin delivery to the hypothalamus capable of safely sustaining stable glycemia for lifetime.

Should leptin replace insulin as a lifetime monotherapy for diabetes type 1 and 2?

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Satya P Kalra

2013-01-01

Full Text Available Evidence accumulated during the last decade has affirmed that adipocyte leptin insufficiency in the hypothalamus is the primary etiological factor in the pathogenesis of diabetes type 1 and 2 and related metabolic morbidities. Leptin insufficiency disrupts the relay of hypothalamic regulatory information along three descending pathways to the organs in the periphery that normally participate in maintenance of glucose homeostasis on a minute-to-minute basis throughout lifetime. Reinstatement of leptin sufficiency in the hypothalamus by either systemic or central injections, or its provision selectively in the hypothalamus with the aid of gene therapy extinguished hyperglycemia and normalized blood glucose stably during the entire course of treatment in a variety of animal models of diabetes type 1 and 2. In follow-up clinical trials, twice daily leptin treatment in leptinopenic and insulinopenic type 1 diabetics and leptinopenic and hyperinsulinemic type 2 diabetics with congenital lipodystrophy or acquired lipoatrophy normalized blood glucose without any discernible adverse effects during the extended course of treatment. Taken together, these findings have amply endorsed the efficacy of leptin therapy to restore glucose homeostasis in insulin-deficient as well as hyperinsulinemic diabetic patients. Consequently, restoration of optimal hypothalmic signaling to reinstate glucose homeostasis with leptin is a highly suitable new therapeutic strategy to ameliorate diabetes type 1 and 2 for the lifetime and to replace the currently in vogue insulin monotherapy. In view of the relentless challenges posed by the worldwide epidemic of diabetes and soaring treatment costs, taken together with the well-known shortcomings of therapies based on restoring insulin signaling, it is highly critical and timely to undertake new clinical trials that ascertain appropriate dosage and route of leptin delivery to the hypothalamus capable of safely sustaining stable

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.

Is fasting leptin associated with insulin resistance among nondiabetic individuals? The Miami Community Health Study

DEFF Research Database (Denmark)

Donahue, R P; Prineas, R J; Donahue, R D

1999-01-01

Whether serum leptin levels are associated with insulin resistance independent of the effects of hyperinsulinemia and adiposity is an important unanswered question. We examined the relationship between the rate of insulin-mediated glucose uptake and serum leptin concentrations among nondiabetic men...

Prior AICAR stimulation increases insulin sensitivity in mouse skeletal muscle in an AMPK-dependent manner

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Kjøbsted, Rasmus; Treebak, Jonas Thue; Fentz, Joachim

2015-01-01

Acute exercise increases glucose uptake in skeletal muscle by an insulin-independent mechanism. In the period after exercise insulin sensitivity to increase glucose uptake is enhanced. The molecular mechanisms underpinning this phenomenon are poorly understood, but appear to involve an increased ...

Insulin signaling displayed a differential tissue-specific response to low-dose dihydrotestosterone in female mice.

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Andrisse, Stanley; Billings, Katelyn; Xue, Ping; Wu, Sheng

2018-04-01

Hyperandrogenemia and hyperinsulinemia are believed to play prominent roles in polycystic ovarian syndrome (PCOS). We explored the effects of low-dose dihydrotestosterone (DHT), a model of PCOS, on insulin signaling in metabolic and reproductive tissues in a female mouse model. Insulin resistance in the energy storage tissues is associated with type 2 diabetes. Insulin signaling in the ovaries and pituitary either directly or indirectly stimulates androgen production. Energy storage and reproductive tissues were isolated and molecular assays were performed. Livers and white adipose tissue (WAT) from DHT mice displayed lower mRNA and protein expression of insulin signaling intermediates. However, ovaries and pituitaries of DHT mice exhibited higher expression levels of insulin signaling genes/proteins. Insulin-stimulated p-AKT levels were blunted in the livers and WAT of the DHT mice but increased or remained the same in the ovaries and pituitaries compared with controls. Glucose uptake decreased in liver and WAT but was unchanged in pituitary and ovary of DHT mice. Plasma membrane GLUTs were decreased in liver and WAT but increased in ovary and pituitary of DHT mice. Skeletal muscle insulin-signaling genes were not lowered in DHT mice compared with control. DHT mice did not display skeletal muscle insulin resistance. Insulin-stimulated glucose transport increased in skeletal muscles of DHT mice compared with controls. DHT mice were hyperinsulinemic. However, the differential mRNA and protein expression pattern was independent of hyperinsulinemia in cultured hepatocytes and pituitary cells. These findings demonstrate a differential effect of DHT on the insulin-signaling pathway in energy storage vs. reproductive tissues independent of hyperinsulinemia.

Weight-sparing effect of insulin detemir: a consequence of central nervous system-mediated reduced energy intake?

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Russell-Jones, D; Danne, T; Hermansen, K; Niswender, K; Robertson, K; Thalange, N; Vasselli, J R; Yildiz, B; Häring, H U

2015-10-01

Insulin therapy is often associated with adverse weight gain. This is attributable, at least in part, to changes in energy balance and insulin's anabolic effects. Adverse weight gain increases the risk of poor macrovascular outcomes in people with diabetes and should therefore be mitigated if possible. Clinical studies have shown that insulin detemir, a basal insulin analogue, exerts a unique weight-sparing effect compared with other basal insulins. To understand this property, several hypotheses have been proposed. These explore the interplay of efferent and afferent signals between the muscles, brain, liver, renal and adipose tissues in response to insulin detemir and comparator basal insulins. The following models have been proposed: insulin detemir may reduce food intake through direct or indirect effects on the central nervous system (CNS); it may have favourable actions on hepatic glucose metabolism through a selective effect on the liver, or it may influence fluid homeostasis through renal effects. Studies have consistently shown that insulin detemir reduces energy intake, and moreover, it is clear that this shift in energy balance is not a consequence of reduced hypoglycaemia. CNS effects may be mediated by direct action, by indirect stimulation by peripheral mediators and/or via a more physiological counter-regulatory response to insulin through restoration of the hepatic-peripheral insulin gradient. Although the precise mechanism remains unclear, it is likely that the weight-sparing effect of insulin detemir can be explained by a combination of mechanisms. The evidence for each hypothesis is considered in this review. © 2015 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

The Effects of Peripheral and Central High Insulin on Brain Insulin Signaling and Amyloid-β in Young and Old APP/PS1 Mice.

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Stanley, Molly; Macauley, Shannon L; Caesar, Emily E; Koscal, Lauren J; Moritz, Will; Robinson, Grace O; Roh, Joseph; Keyser, Jennifer; Jiang, Hong; Holtzman, David M

2016-11-16

Hyperinsulinemia is a risk factor for late-onset Alzheimer's disease (AD). In vitro experiments describe potential connections between insulin, insulin signaling, and amyloid-β (Aβ), but in vivo experiments are needed to validate these relationships under physiological conditions. First, we performed hyperinsulinemic-euglycemic clamps with concurrent hippocampal microdialysis in young, awake, behaving APP swe /PS1 dE9 transgenic mice. Both a postprandial and supraphysiological insulin clamp significantly increased interstitial fluid (ISF) and plasma Aβ compared with controls. We could detect no increase in brain, ISF, or CSF insulin or brain insulin signaling in response to peripheral hyperinsulinemia, despite detecting increased signaling in the muscle. Next, we delivered insulin directly into the hippocampus of young APP/PS1 mice via reverse microdialysis. Brain tissue insulin and insulin signaling was dose-dependently increased, but ISF Aβ was unchanged by central insulin administration. Finally, to determine whether peripheral and central high insulin has differential effects in the presence of significant amyloid pathology, we repeated these experiments in older APP/PS1 mice with significant amyloid plaque burden. Postprandial insulin clamps increased ISF and plasma Aβ, whereas direct delivery of insulin to the hippocampus significantly increased tissue insulin and insulin signaling, with no effect on Aβ in old mice. These results suggest that the brain is still responsive to insulin in the presence of amyloid pathology but increased insulin signaling does not acutely modulate Aβ in vivo before or after the onset of amyloid pathology. Peripheral hyperinsulinemia modestly increases ISF and plasma Aβ in young and old mice, independent of neuronal insulin signaling. The transportation of insulin from blood to brain is a saturable process relevant to understanding the link between hyperinsulinemia and AD. In vitro experiments have found direct connections

Glucose homeostasis in mice is transglutaminase 2 independent.

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Siiri E Iismaa

Full Text Available Transglutaminase type 2 (TG2 has been reported to be a candidate gene for maturity onset diabetes of the young (MODY because three different mutations that impair TG2 transamidase activity have been found in 3 families with MODY. TG2 null (TG2(-/- mice have been reported to be glucose intolerant and have impaired glucose-stimulated insulin secretion (GSIS. Here we rigorously evaluated the role of TG2 in glucose metabolism using independently generated murine models of genetic TG2 disruption, which show no compensatory enhanced expression of other TGs in pancreatic islets or other tissues. First, we subjected chow- or fat-fed congenic SV129 or C57BL/6 wild type (WT and TG2(-/- littermates, to oral glucose gavage. Blood glucose and serum insulin levels were similar for both genotypes. Pancreatic islets isolated from these animals and analysed in vitro for GSIS and cholinergic potentiation of GSIS, showed no significant difference between genotypes. Results from intraperitoneal glucose tolerance tests (GTTs and insulin tolerance tests (ITTs were similar for both genotypes. Second, we directly investigated the role of TG2 transamidase activity in insulin secretion using a coisogenic model that expresses a mutant form of TG2 (TG2(R579A, which is constitutively active for transamidase activity. Intraperitoneal GTTs and ITTs revealed no significant differences between WT and TG2(R579A/R579A mice. Given that neither deletion nor constitutive activation of TG2 transamidase activity altered basal responses, or responses to a glucose or insulin challenge, our data indicate that glucose homeostasis in mice is TG2 independent, and question a link between TG2 and diabetes.

Four-year evolution of insulin regimens, glycaemic control, hypoglycaemia and body weight after starting insulin therapy in type 2 diabetes across three continents.

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Home, Philip D; Dain, Marie-Paule; Freemantle, Nick; Kawamori, Ryuzo; Pfohl, Martin; Brette, Sandrine; Pilorget, Valérie; Scherbaum, Werner A; Vespasiani, Giacomo; Vincent, Maya; Balkau, Beverley

2015-05-01

It is of interest to understand how insulin therapy currently evolves in clinical practice, in the years after starting insulin in people with type 2 diabetes. We aimed to describe this evolution prospectively over 4 years, to assist health care planning. People who had started any insulin were identified from 12 countries on three continents. Baseline, then yearly follow-up, data were extracted from clinical records over 4 years. Of the 2999 eligible people, 2272 were followed over 4 years. When starting insulin, mean (SD) duration of diabetes was 10.6 (7.8) years, HbA1c 9.5 (2.0)% (80 [22]mmol/mol) and BMI 29.3 (6.3)kg/m(2). Initial insulin therapy was basal 52%, premix 23%, mealtime+basal 14%, mealtime 8% and other 3%; at 4 years, 30%, 25%, 33%, 2% and 5%, respectively, with 5% not on insulin. Insulin dose was 20.2U/day at the start and 45.8U/day at year 4. There were 1258 people (55%) on their original regimen at 4 years, and this percentage differed according to baseline insulin regimen. HbA1c change was -2.0 (2.2)% (-22 [24]mmol/mol) and was similar by final insulin regimen. Hypoglycaemia prevalence was <20% in years 1-4. Body weight change was mostly in year 1, and was very variable, mean +2.7 (7.5)kg at year 4. Different insulin regimens were started in people with differing characteristics, and they evolved differently; insulin dose, hypoglycaemia and body weight change were diverse and largely independent of regimen. Copyright © 2015 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

Effects of Endogenous Androgens and Abdominal Fat Distribution on the Interrelationship Between Insulin and Non-Insulin-Mediated Glucose Uptake in Females

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Ezeh, Uche; Pall, Marita; Mathur, Ruchi; Dey, Damini; Berman, Daniel; Chen, Ida Y.; Dumesic, Daniel A.

2013-01-01

Background: Polycystic ovary syndrome (PCOS) is associated with hyperandrogenism and insulin resistance. Glucose disposal occurs via noninsulin-mediated glucose uptake (NIMGU) and insulin-mediated glucose uptake (IMGU). It is unknown whether in PCOS NIMGU increases to compensate for declining IMGU and whether androgens and fat distribution influence this relationship. Objectives: The objective of the study was to compare in women with PCOS and controls the interrelationship between NIMGU [ie, glucose effectiveness (Sg)] and IMGU [ie, the insulin sensitivity index (Si)] and the role of androgens and fat distribution. Participants: Twenty-eight PCOS (by National Institutes of Health 1990 criteria) and 28 control (age, race, and body mass index matched) women were prospectively studied. A subset of 16 PCOS subjects and 16 matched controls also underwent abdominal computed tomography. Main Outcome Measures: Glucose disposal (by a frequently sampled iv glucose tolerance test), circulating androgens, and abdominal fat distribution [by waist to hip ratio and visceral (VAT) and sc (SAT) adipose tissue content] were measured. Results: PCOS women had lower mean Si and similar Sg and abdominal fat distribution compared with controls. PCOS women with Si below the PCOS median (more insulin resistant) had a lower mean Sg than controls with Si above the control median (more insulin sensitive). In PCOS only, body mass index, free T, modified Ferriman-Gallwey score, and waist to hip ratio independently predicted Sg, whereas Si did not. In PCOS, VAT and SAT independently and negatively predicted Si and Sg, respectively. Conclusion: The decreased IMGU in PCOS is not accompanied by a compensatory increase in NIMGU or associated with excessive VAT accumulation. Increased general obesity, SAT, and hyperandrogenism are primary predictors of the deterioration of NIMGU in PCOS. PMID:23450052

Pancreatic Islet Cell Transplantation: A new era in transplantation

OpenAIRE

Warnock, Garth L.; Rajotte, Ray V.

1992-01-01

Transplantation of insulin-producing tissue offers a physiologic approach to restoration of glycemic control. Whereas transplantation of vascularized pancreatic grafts has recently achieved encouraging results, pancreatic islet cell transplantation holds the promise of low morbidity and reduced requirements for agressive immunosuppression for recipients. Islet cell transplantation was recently demonstrated to induce euglycemia with insulin independence.

Interactive roles of Ras, insulin receptor substrate-1, and proteins with Src homology-2 domains in insulin signaling in Xenopus oocytes.

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Chuang, L M; Hausdorff, S F; Myers, M G; White, M F; Birnbaum, M J; Kahn, C R

1994-11-04

Insulin receptor substrate-1 (IRS-1) serves as the major immediate substrate of insulin/insulin-like growth factor (IGF)-1 receptors and following tyrosine phosphorylation binds to specific Src homology-2 (SH2) domain-containing proteins including the p85 subunit of phosphatidylinositol (PI) 3-kinase and GRB2, a molecule believed to link IRS-1 to the Ras pathway. To investigate how these SH2-containing signaling molecules interact to regulate insulin/IGF-1 action, IRS-1, glutathione S-transferase (GST)-SH2 domain fusion proteins and Ras proteins were microinjected into Xenopus oocytes. We found that pleiotropic insulin actions are mediated by IRS-1 through two independent, but convergent, pathways involving PI 3-kinase and GRB2. Thus, microinjection of GST-fusion proteins of either p85 or GRB2 inhibited IRS-1-dependent activation of mitogen-activated protein (MAP) and S6 kinases and oocyte maturation, although only the GST-SH2 of p85 reduced insulin-stimulated PI 3-kinase activation. Co-injection of a dominant negative Ras (S17N) with IRS-1 inhibited insulin-stimulated MAP and S6 kinase activation. Micro-injection of activated [Arg12,Thr59]Ras increased basal MAP and S6 kinase activities and sensitized the oocytes to insulin-stimulated maturation without altering insulin-stimulated PI 3-kinase. The Ras-enhanced oocyte maturation response, but not the elevated basal level of MAP and S6 kinase, was partially blocked by the SH2-p85, but not SH2-GRB2. These data strongly suggest that IRS-1 can mediate many of insulin's actions on cellular enzyme activation and cell cycle progression requires binding and activation of multiple different SH2-domain proteins.

Developmental Programming: Prenatal Testosterone Excess and Insulin Signaling Disruptions in Female Sheep.

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Lu, Chunxia; Cardoso, Rodolfo C; Puttabyatappa, Muraly; Padmanabhan, Vasantha

2016-05-01

Women with polycystic ovary syndrome often manifest insulin resistance. Using a sheep model of polycystic ovary syndrome-like phenotype, we explored the contribution of androgen and insulin in programming and maintaining disruptions in insulin signaling in metabolic tissues. Phosphorylation of AKT, ERK, GSK3beta, mTOR, and p70S6K was examined in the liver, muscle, and adipose tissue of control and prenatal testosterone (T)-, prenatal T plus androgen antagonist (flutamide)-, and prenatal T plus insulin sensitizer (rosiglitazone)-treated fetuses as well as 2-yr-old females. Insulin-stimulated phospho (p)-AKT was evaluated in control and prenatal T-, prenatal T plus postnatal flutamide-, and prenatal T plus postnatal rosiglitazone-treated females at 3 yr of age. GLUT4 expression was evaluated in the muscle at all time points. Prenatal T treatment increased mTOR, p-p70S6K, and p-GSK3beta levels in the fetal liver with both androgen antagonist and insulin sensitizer preventing the mTOR increase. Both interventions had partial effect in preventing the increase in p-GSK3beta. In the fetal muscle, prenatal T excess decreased p-GSK3beta and GLUT4. The decrease in muscle p-GSK3beta was partially prevented by insulin sensitizer cotreatment. Both interventions partially prevented the decrease in GLUT4. Prenatal T treatment had no effect on basal expression of any of the markers in 2-yr-old females. At 3 yr of age, prenatal T treatment prevented the insulin-stimulated increase in p-AKT in liver and muscle, but not in adipose tissue, and neither postnatal intervention restored p-AKT response to insulin stimulation. Our findings provide evidence that prenatal T excess changes insulin sensitivity in a tissue- and development-specific manner and that both androgens and insulin may be involved in the programming of these metabolic disruptions. © 2016 by the Society for the Study of Reproduction, Inc.

Fasting glucose, fasting insulin, and insulin resistance in the prediction of myocardial infarction and mortality at long-term follow-up

DEFF Research Database (Denmark)

Nielsen, M. L.; Pareek, M.; Leosdottir, M.

2015-01-01

Objective: To assess the additional prognostic value of fasting blood glucose (FBG), fasting plasma insulin (FPI), and homeostasis model assessment derived insulin resistance (HOMA-IR) for predicting incident myocardial infarction (MI) and all-cause mortality, independently of traditional...... measured at baseline. Subsequently, HOMA-IR was derived using the computerized HOMA calculator and ranked into quartiles due to the non-normal distribution and presumably non-linear biological effect of insulin resistance. Prognostic values of FBG, FPI, HOMA-IR, and traditional risk factors were tested.......1-48.3] years, whereas median [IQR] HOMA-IR was 0.9 [0.4-1.4]. Over a median follow-up time of 20 years, 1448 events occurred (11.3 per 1000 person-years). The simple prediction model, i.e. the model with traditional CV risk factors only, included age, gender, body mass index, systolic blood pressure, total...

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)....

Mid-gestational serum uric acid concentration effect on neonate birth weight and insulin resistance in pregnant women

OpenAIRE

Nasri, Khadijeh; Razavi, Maryamsadat; Rezvanfar, Mohammad Reza; Mashhadi, Esmat; Chehrei, Ali; Mohammadbeigi, Abolfazl

2015-01-01

Objective To investigate the relationship between mid-gestational serum uric acid and birth weight in diabetic pregnant women with or without insulin resistance. Methods: In a prospective cohort study, fasting uric acid, blood glucose, and serum insulin were measured in 247 pregnant women between 20-22 weeks of gestational period. Insulin resistance was estimated using the homeostasis model assessment-insulin resistance (HOMA-IR). Stratification analysis and independent t-test was used to ass...

Insulin and TOR signal in parallel through FOXO and S6K to promote epithelial wound healing

Science.gov (United States)

Kakanj, Parisa; Moussian, Bernard; Grönke, Sebastian; Bustos, Victor; Eming, Sabine A.; Partridge, Linda; Leptin, Maria

2016-01-01

The TOR and Insulin/IGF signalling (IIS) network controls growth, metabolism and ageing. Although reducing TOR or insulin signalling can be beneficial for ageing, it can be detrimental for wound healing, but the reasons for this difference are unknown. Here we show that IIS is activated in the cells surrounding an epidermal wound in Drosophila melanogaster larvae, resulting in PI3K activation and redistribution of the transcription factor FOXO. Insulin and TOR signalling are independently necessary for normal wound healing, with FOXO and S6K as their respective effectors. IIS is specifically required in cells surrounding the wound, and the effect is independent of glycogen metabolism. Insulin signalling is needed for the efficient assembly of an actomyosin cable around the wound, and constitutively active myosin II regulatory light chain suppresses the effects of reduced IIS. These findings may have implications for the role of insulin signalling and FOXO activation in diabetic wound healing. PMID:27713427

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...

Nitric oxide is required for the insulin sensitizing effects of contraction in mouse skeletal muscle.

Science.gov (United States)

Zhang, Xinmei; Hiam, Danielle; Hong, Yet-Hoi; Zulli, Anthony; Hayes, Alan; Rattigan, Stephen; McConell, Glenn K

2017-12-15

People with insulin resistance or type 2 diabetes can substantially increase their skeletal muscle glucose uptake during exercise and insulin sensitivity after exercise. Skeletal muscle nitric oxide (NO) is important for glucose uptake during exercise, although how prior exercise increases insulin sensitivity is unclear. In the present study, we examined whether NO is necessary for normal increases in skeletal muscle insulin sensitivity after contraction ex vivo in mouse muscle. The present study uncovers, for the first time, a novel role for NO in the insulin sensitizing effects of ex vivo contraction, which is independent of blood flow. The factors regulating the increase in skeletal muscle insulin sensitivity after exercise are unclear. We examined whether nitric oxide (NO) is required for the increase in insulin sensitivity after ex vivo contractions. Isolated C57BL/6J mouse EDL muscles were contracted for 10 min or remained at rest (basal) with or without the NO synthase (NOS) inhibition (N G -monomethyl-l-arginine; l-NMMA; 100 μm). Then, 3.5 h post contraction/basal, muscles were exposed to saline or insulin (120 μU ml -1 ) with or without l-NMMA during the last 30 min. l-NMMA had no effect on basal skeletal muscle glucose uptake. The increase in muscle glucose uptake with insulin (57%) was significantly (P contraction (140% increase). NOS inhibition during the contractions had no effect on this insulin-sensitizing effect of contraction, whereas NOS inhibition during insulin prevented the increase in skeletal muscle insulin sensitivity post-contraction. Soluble guanylate cyclase inhibition, protein kinase G (PKG) inhibition or cyclic nucleotide phosphodiesterase inhibition each had no effect on the insulin-sensitizing effect of prior contraction. In conclusion, NO is required for increases in insulin sensitivity several hours after contraction of mouse skeletal muscle via a cGMP/PKG independent pathway. © 2017 The Authors. The Journal of Physiology

The effect of N-stearoylethanolamine on liver phospholipid composition of rats with insulin resistance caused by alimentary obesity

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O. V. Onopchenko

2014-02-01

Full Text Available We used alimentary obesity-induced insulin resistance (IR model in rats to investigate the influence of N-stearoylethanolamine on the content of phospholipids and their fatty acid composition. Our results show that prolonged high-fat diet triggers considerable aberrations in the composition of main phospholipids in the liver and can be one of the causes of IR in rats. In particular, the increase of phosphatidylcholine, phosphatidylethanolamine and significant decrease of other phospholipids: lysophosphatidylcholine, lysophosphatidylethanolamine, sphingomyelin, phosphatidylinositol, phosphatidylserine and diphosphaglicerol were observed. The levels of monounsaturated (erucic, nervonic, oleic and polyunsaturated (eicosatrienoic, docosatrienoic, arachidonic fatty acids were increased; meanwhile the content of diunsaturated acids was decreased. The NSE administration (50 mg/kg of body weight caused restoration of the phospholipids content in the liver of rats with diet-induced IR that highly correlated with the decrease in plasma insulin level and the improvement of insulin sensitivity. Moreover, the effect of NSE was accompanied by the normalization of fatty acids composition of phospholipids that could be related to modulating influen­ce of NSE on the activity of the main fatty acid desaturases. It is known that the imbalance in phospholipid composition of the rat liver causes substantial metabolic alterations that are associated with the development of IR. Accordingly, the compensations of the imbalance by NSE can help to restore insulin sensitivity, inhibit the development of obesity, IR and type 2 diabetes.

Design, characterization and ex vivo evaluation of chitosan film integrating of insulin nanoparticles composed of thiolated chitosan derivative for buccal delivery of insulin.

Science.gov (United States)

Mortazavian, Elaheh; Dorkoosh, Farid Abedin; Rafiee-Tehrani, Morteza

2014-05-01

The purpose of this study is to optimize and characterize of chitosan buccal film for delivery of insulin nanoparticles that were prepared from thiolated dimethyl ethyl chitosan (DMEC-Cys). Insulin nanoparticles composed of chitosan and dimethyl ethyl chitosan (DMEC) were also prepared as control groups. The release of insulin from nanoparticles was studied in vitro in phosphate buffer solution (PBS) pH 7.4. Optimization of chitosan buccal films has been carried out by central composite design (CCD) response surface methodology. Independent variables were different amounts of chitosan and glycerol as mucoadhesive polymer and plasticizer, respectively. Tensile strength and bioadhesion force were considered as dependent variables. Ex vivo study was performed on excised rabbit buccal mucosa. Optimized insulin nanoparticles were obtained with acceptable physicochemical properties. In vitro release profile of insulin nanoparticles revealed that the highest solubility of nanoparticles in aqueous media is related to DMEC-Cys nanoparticles. CCD showed that optimized buccal film containing 4% chitosan and 10% glycerol has 5.81 kg/mm(2) tensile strength and 2.47 N bioadhesion forces. Results of ex vivo study demonstrated that permeation of insulin nanoparticles through rabbit buccal mucosa is 17.1, 67.89 and 97.18% for chitosan, DMEC and DMEC-Cys nanoparticles, respectively. Thus, this study suggests that DMEC-Cys can act as a potential enhancer for buccal delivery of insulin.

Dissociation of hepatic steatosis and insulin resistance in mice overexpressing DGAT in the liver.

Science.gov (United States)

Monetti, Mara; Levin, Malin C; Watt, Matthew J; Sajan, Mini P; Marmor, Stephen; Hubbard, Brian K; Stevens, Robert D; Bain, James R; Newgard, Christopher B; Farese, Robert V; Hevener, Andrea L; Farese, Robert V

2007-07-01

Hepatic steatosis, the accumulation of lipids in the liver, is widely believed to result in insulin resistance. To test the causal relationship between hepatic steatosis and insulin resistance, we generated mice that overexpress acyl-CoA:diacylglycerol acyltransferase 2 (DGAT2), which catalyzes the final step of triacylglycerol (TG) biosynthesis, in the liver (Liv-DGAT2 mice). Liv-DGAT2 mice developed hepatic steatosis, with increased amounts of TG, diacylglycerol, ceramides, and unsaturated long-chain fatty acyl-CoAs in the liver. However, they had no abnormalities in plasma glucose and insulin levels, glucose and insulin tolerance, rates of glucose infusion and hepatic glucose production during hyperinsulinemic-euglycemic clamp studies, or activities of insulin-stimulated signaling proteins in the liver. DGAT1 overexpression in the liver also failed to induce glucose or insulin intolerance. Our results indicate that DGAT-mediated lipid accumulation in the liver is insufficient to cause insulin resistance and show that hepatic steatosis can occur independently of insulin resistance.

Akt and Rac1 signalling are jointly required for insulin-stimulated glucose uptake in skeletal muscle and downregulated in insulin resistance

DEFF Research Database (Denmark)

Sylow, Lykke; Kleinert, Maximilian; Pehmøller, Christian

2014-01-01

Skeletal muscle plays a major role in regulating whole body glucose metabolism. Akt and Rac1 are important regulators of insulin-stimulated glucose uptake in skeletal muscle. However the relative role of each pathway and how they interact is not understood. Here we delineate how Akt and Rac1...... pathways signal to increase glucose transport independently of each other and are simultaneously downregulated in insulin resistant muscle. Pharmacological inhibition of Rac1 and Akt signalling was used to determine the contribution of each pathway to insulin-stimulated glucose uptake in mouse muscles....... The actin filament-depolymerizing agent LatrunculinB was combined with pharmacological inhibition of Rac1 or Akt, to examine whether either pathway mediates its effect via the actin cytoskeleton. Akt and Rac1 signalling were investigated under each condition, as well as upon Akt2 knockout and in ob/ob mice...

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

Science.gov (United States)

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.

Third Exposure to a Reduced Carbohydrate Meal Lowers Evening Postprandial Insulin and GIP Responses and HOMA-IR Estimate of Insulin Resistance.

Science.gov (United States)

Lin, Po-Ju; Borer, Katarina T

2016-01-01

30% compared to no such changes after three 60%-carbohydrate meals, an effect that was independent of pre-meal exercise. The parallel timing and magnitude of postprandial insulin and GIP changes suggest their dependence on a delayed intestinal adaptation to a low-carbohydrate diet. Pre-meal exercise exacerbated glucose intolerance with both diets most likely due to impairment of insulin signaling by pre-meal elevation of FFAs.

Effect of protocatechuic acid on insulin responsiveness and inflammation in visceral adipose tissue from obese individuals: possible role for PTP1B.

Science.gov (United States)

Ormazabal, Paulina; Scazzocchio, Beatrice; Varì, Rosaria; Santangelo, Carmela; D'Archivio, Massimo; Silecchia, Gianfranco; Iacovelli, Annunziata; Giovannini, Claudio; Masella, Roberta

2018-05-16

The occurrence of chronic inflammation in visceral adipose tissue (VAT) in obese subjects precipitates the development of insulin resistance and type 2 diabetes (T2D). Anthocyanins and their main metabolite protocatechuic acid (PCA) have been demonstrated to stimulate insulin signaling in human adipocytes. The aim of this study was to investigate whether PCA is able to modulate insulin responsiveness and inflammation in VAT from obese (OB) and normal weight (NW) subjects. VATs obtained from NW and OB subjects were incubated or not (control) with 100 μM PCA for 24 h. After incubation, tissues untreated and treated with PCA were acutely stimulated with insulin (20 nM, 20 min). PTP1B, p65 NF-κB, phospho-p65 NF-κB, IRS-1, IRβ, Akt, GLUT4 as well as basal and insulin-stimulated Tyr-IRS-1 and Ser-Akt phosphorylations were assessed by Western blotting in NW- and OB-VAT. Samples were assessed for PTP1B activity and adipocytokine secretion. PCA restored insulin-induced phosphorylation in OB-VAT by increasing phospho-Tyr-IRS-1 and phospho-Ser-Akt after insulin stimulation as observed in NW-VAT (p < 0.05). PTP1B activity was lower in OB-VAT treated with PCA with respect to untreated (p < 0.05). Compared to non-treated tissues, PCA reduced phospho-p65 NF-κB and IL-6 in OB-VAT, and IL-1β in NW-VAT (p < 0.05); and increased adiponectin secretion in NW-VAT (p < 0.05). PCA restores the insulin responsiveness of OB-VAT by increasing IRS-1 and Akt phosphorylation which could be related with the lower PTP1B activity found in PCA-treated OB-VAT. Furthermore, PCA diminishes inflammation in VAT. These results support the beneficial role of an anthocyanin-rich diet against inflammation and insulin resistance in obesity.

Time to insulin initiation can not be used in defining Latent Autoimmune Diabetes in Adults [LADA

DEFF Research Database (Denmark)

Brophy, S; Yderstræde, K; Mauricio, D

2007-01-01

and clinicians reported on criteria for initiating insulin. All patients were tested for glutamic acid decarboxylase autoantibodies (GADA) in a central laboratory. We examined time to insulin treatment for GADA positive patients in 6 participating centres. Results: There was inter-centre variation......Objective: Latent Autoimmune Diabetes in Adults [LADA] is type 1 diabetes presenting as non-insulin dependent diabetes. One feature of the selection criteria is time independent of insulin treatment. We examine the validity of this criterion. Methods: Patients were recruited in 9 European centres...

Berberine Protects against NEFA-Induced Impairment of Mitochondrial Respiratory Chain Function and Insulin Signaling in Bovine Hepatocytes

Directory of Open Access Journals (Sweden)

Zhen Shi

2018-06-01

Full Text Available Fatty liver is a major lipid metabolic disease in perinatal dairy cows and is characterized by high blood levels of non-esterified fatty acid (NEFA and insulin resistance. Berberine (BBR has been reported to improve insulin sensitivity in mice with hepatic steatosis. Mitochondrial dysfunction is considered a causal factor that induces insulin resistance. This study investigates the underlying mechanism and the beneficial effects of BBR on mitochondrial and insulin signaling in bovine hepatocytes. Revised quantitative insulin sensitivity check index (RQUICKI of cows with fatty liver was significantly lower than that of healthy cows. Importantly, the Akt and GSK3β phosphorylation levels, protein levels of PGC-1α and four of the five representative subunits of oxidative phosphorylation (OXPHOS were significantly decreased in cows with fatty liver using Western Blot analysis. In bovine hepatocytes, 1.2 mmol/L NEFA reduced insulin signaling and mitochondrial respiratory chain function, and 10 and 20 umol/L BBR restored these changes. Furthermore, activation of PGC-1α played the same beneficial effects of BBR on hepatocytes treated with NEFA. BBR treatment improves NEFA-impaired mitochondrial respiratory chain function and insulin signaling by increasing PGC-1α expression in hepatocytes, which provides a potential new strategy for the prevention and treatment of fatty liver in dairy cows.

[Changes in the secretion of somatotropin and insulin in hyperthyroidism].

Science.gov (United States)

Cavagnini, F; Peracchi, M; Panerai, A E; Pinto, M

1975-06-01

Twenty hyperthyroid patients were investigated for growth hormone (GH) and immunoreactive insulin (IRI) secretion in response to insulin hypoglycaemia, arginine infusion and glucose-induced hyperglycaemia. GH response to either insulin hypoglycaemia or arginine infusion was significantly reduced in these patients compared with 20 normal subjects. Thyrotoxic patients also displayed an abnormal GH pattern after a 100 g oral glucose load: in fact, serum GH underwent a paradoxical increase in spite of abnormally high levels attained by blood glucose. IRI secretion was also clearly reduced in response to arginine infusion and moderately blunted after oral glucose. In a group of patients re-evaluated under euthyroid conditions, a fair increase of GH response to the provocative stimuli jointly with the restoration of a normal suppressibility of serum GH by glucose were noted; by contrast, no significant change of IRI response to arginine or glucose took place. Likewise, the impairment of glucose tolerance was not improved. These findings indicate that an impairment of GH and IRI secretion is present in hyperthyroidism. The possibility that a potentiation of the catecholamine effects caused by the thyroid hormones is involved in this alteration deserves consideration.

Circadian hormone profiles and insulin sensitivity in patients with Addison's disease: a comparison of continuous subcutaneous hydrocortisone infusion with conventional glucocorticoid replacement therapy.

Science.gov (United States)

Björnsdottir, Sigridur; Øksnes, Marianne; Isaksson, Magnus; Methlie, Paal; Nilsen, Roy M; Hustad, Steinar; Kämpe, Olle; Hulting, Anna-Lena; Husebye, Eystein S; Løvås, Kristian; Nyström, Thomas; Bensing, Sophie

2015-07-01

Conventional glucocorticoid replacement therapy in patients with Addison's disease (AD) is unphysiological with possible adverse effects on mortality, morbidity and quality of life. The diurnal cortisol profile can likely be restored by continuous subcutaneous hydrocortisone infusion (CSHI). The aim of this study was to compare circadian hormone rhythms and insulin sensitivity in conventional thrice-daily regimen of glucocorticoid replacement therapy with CSHI treatment in patients with AD. An open, randomized, two-period, 12-week crossover multicentre trial in Norway and Sweden. Ten Norwegian patients were admitted for 24-h sampling of hormone profiles. Fifteen Swedish patients underwent euglycaemic-hyperinsulinaemic clamp. Thrice-daily regimen of oral hydrocortisone (OHC) and CSHI treatment. We measured the circadian rhythm of cortisol, adrenocorticotropic hormone (ACTH), growth hormone (GH), insulin-like growth factor-1, (IGF-1), IGF-binding protein-3 (IGFBP-3), glucose, insulin and triglycerides during OHC and CSHI treatment. Euglycaemic-hyperinsulinaemic clamp was used to assess insulin sensitivity. Continuous subcutaneous hydrocortisone infusion provided a more physiological circadian cortisol curve including a late-night cortisol surge. ACTH levels showed a near normal circadian variation for CSHI. CSHI prevented a continuous decrease in glucose during the night. No difference in insulin sensitivity was observed between the two treatment arms. Continuous subcutaneous hydrocortisone infusion replacement re-established a circadian cortisol rhythm and normalized the ACTH levels. Patients with CSHI replacement had a more stable night-time glucose level compared with OHC without compromising insulin sensitivity. Thus, restoring night-time cortisol levels might be advantageous for patients with AD. © 2015 John Wiley & Sons Ltd.

Influence of functional nutrients on insulin resistance in horses with equine metabolic syndrome

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Krzysztof Marycz, Eberhard Moll and Jakub Grzesiak

2014-04-01

Full Text Available The obesity is a rising health problem both in veterinary and human medicine. In equine medicine excessive body weight is frequently related to insulin resistance and laminitis as is defined as equine metabolic syndrome (EMS. The dietetic management is considered as the crucial part of treatment strategy in the course of EMS. The main feeding recommendation is to administer the low energy diet in order to restore insulin efficiency and to lower body weight. In this study 14 horses of different breed, both sexes and different ages with diagnosed equine metabolic syndrome were fed, concurrently, with oats (3g/kg bw, hay (15g/kg bw and experimental dietary supplement containing selected herbs, aminoacids, butyric acid derivative, biotin and selected dietetic plant like artichoke. The influence of above dietary protocol on body weight, insulin level, and adipose tissue morphometry was investigated in horses from group A. Horses from group B fed only with oats (3g/kg bw and hay (15g/kg bw served as a control. Results of the experiment indicated that tested supplement could improve insulin efficiency and reduce body mass in experimental horses group.

Deletion of glutamate dehydrogenase in beta-cells abolishes part of the insulin secretory response not required for glucose homeostasis

DEFF Research Database (Denmark)

Carobbio, Stefania; Frigerio, Francesca; Rubi, Blanca

2009-01-01

Insulin exocytosis is regulated in pancreatic ss-cells by a cascade of intracellular signals translating glucose levels into corresponding secretory responses. The mitochondrial enzyme glutamate dehydrogenase (GDH) is regarded as a major player in this process, although its abrogation has not been...... tested yet in animal models. Here, we generated transgenic mice, named betaGlud1(-/-), with ss-cell-specific GDH deletion. Our results show that GDH plays an essential role in the full development of the insulin secretory response. In situ pancreatic perfusion revealed that glucose-stimulated insulin...... secretion was reduced by 37% in betaGlud1(-/-). Furthermore, isolated islets with either constitutive or acute adenovirus-mediated knock-out of GDH showed a 49 and 38% reduction in glucose-induced insulin release, respectively. Adenovirus-mediated re-expression of GDH in betaGlud1(-/-) islets fully restored...

Independent signaling by Drosophila insulin receptor for axon guidance and growth

Directory of Open Access Journals (Sweden)

Caroline Rita Li

2014-01-01

Full Text Available The Drosophila insulin receptor (DInR regulates a diverse array of biological processes including growth, axon guidance, and sugar homeostasis. Growth regulation by DInR is mediated by Chico, the Drosophila homolog of vertebrate insulin-receptor-substrate proteins IRS1-4. In contrast, DInR regulation of photoreceptor axon guidance in the developing visual system is mediated by the SH2-SH3 domain adaptor protein Dreadlocks (Dock. In vitro studies by others identified five NPXY motifs, one in the juxtamembrane region and four in the signaling C-terminal tail (C-tail, important for interaction with Chico. Here we used yeast two-hybrid assays to identify regions in the DInR C-tail that interact with Dock. These Dock-binding sites were in separate portions of the C-tail from the previously identified Chico-binding sites. To test whether these sites are required for growth or axon guidance in whole animals, a panel of DInR proteins, in which the putative Chico and Dock interaction sites had been mutated individually or in combination, were tested for their ability to rescue viability, growth, and axon guidance defects of dinr mutant flies. Sites required for viability were identified. Unexpectedly, mutation of both putative Dock binding sites, either individually or in combination, did not lead to defects in photoreceptor axon guidance. Thus, either sites also required for viability are necessary for DInR function in axon guidance and/or there is redundancy built into the DInR/Dock interaction such that Dock is able to interact with multiple regions of DInR. We also found that simultaneous mutation of all 5 NPXY motifs implicated in Chico interaction drastically decreased growth in both male and female adult flies. Mutation of these 5 NPXY motifs did not affect photoreceptor axon guidance, showing that different sites within DInR control growth and axon guidance.

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

Glucose Induces Mouse β-Cell Proliferation via IRS2, MTOR, and Cyclin D2 but Not the Insulin Receptor

Science.gov (United States)

Stamateris, Rachel E.; Sharma, Rohit B.; Kong, Yahui; Ebrahimpour, Pantea; Panday, Deepika; Ranganath, Pavana; Zou, Baobo; Levitt, Helena; Parambil, Nisha Abraham; O’Donnell, Christopher P.; García-Ocaña, Adolfo

2016-01-01

An important goal in diabetes research is to understand the processes that trigger endogenous β-cell proliferation. Hyperglycemia induces β-cell replication, but the mechanism remains debated. A prime candidate is insulin, which acts locally through the insulin receptor. Having previously developed an in vivo mouse hyperglycemia model, we tested whether glucose induces β-cell proliferation through insulin signaling. By using mice lacking insulin signaling intermediate insulin receptor substrate 2 (IRS2), we confirmed that hyperglycemia-induced β-cell proliferation requires IRS2 both in vivo and ex vivo. Of note, insulin receptor activation was not required for glucose-induced proliferation, and insulin itself was not sufficient to drive replication. Glucose and insulin caused similar acute signaling in mouse islets, but chronic signaling differed markedly, with mammalian target of rapamycin (MTOR) and extracellular signal–related kinase (ERK) activation by glucose and AKT activation by insulin. MTOR but not ERK activation was required for glucose-induced proliferation. Cyclin D2 was necessary for glucose-induced β-cell proliferation. Cyclin D2 expression was reduced when either IRS2 or MTOR signaling was lost, and restoring cyclin D2 expression rescued the proliferation defect. Human islets shared many of these regulatory pathways. Taken together, these results support a model in which IRS2, MTOR, and cyclin D2, but not the insulin receptor, mediate glucose-induced proliferation. PMID:26740601

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

The Relationship between Serum 25-Hydroxyvitamin D Concentration, Cardiorespiratory Fitness, and Insulin Resistance in Japanese Men

Directory of Open Access Journals (Sweden)

Xiaomin Sun

2014-12-01

Full Text Available Here, we aim to investigate the independent and combined associations of serum 25-hydroxyvitamin D (25(OHD and cardiorespiratory fitness (CRF with glucose metabolism. Fasting blood samples of 107 men aged 40–79 years were analyzed for 25(OHD, glucose, insulin, glycated hemoglobin, and lipid profile. Homeostasis model assessment of insulin resistance index (HOMA-IR was calculated from the fasting concentrations of glucose and insulin. Visceral fat area (VFA was determined by magnetic resonance imaging and CRF by measuring maximal oxygen uptake. Median 25(OHD concentration was 36.3 nmol/L, while the prevalence of 25(OHD deficiency was 74.8%. Participants with high CRF had significantly lower HOMA-IR, glycated hemoglobin, and insulin values than participants with low CRF (p < 0.05. Higher 25(OHD concentration was strongly correlated with lower HOMA-IR and insulin values independent of VFA (p < 0.01 but significantly affected by CRF. In the high CRF group, participants with higher 25(OHD concentration had lower HOMA-IR values than participants with low 25(OHD concentration (p < 0.05. Higher 25(OHD and CRF are crucial for reducing insulin resistance regardless of abdominal fat. In addition, higher 25(OHD concentration may strengthen the effect of CRF on reducing insulin resistance in middle-aged and elderly Japanese men with high CRF.

Islet Oxygen Consumption Rate (OCR) Dose Predicts Insulin Independence in Clinical Islet Autotransplantation.

Science.gov (United States)

Papas, Klearchos K; Bellin, Melena D; Sutherland, David E R; Suszynski, Thomas M; Kitzmann, Jennifer P; Avgoustiniatos, Efstathios S; Gruessner, Angelika C; Mueller, Kathryn R; Beilman, Gregory J; Balamurugan, Appakalai N; Loganathan, Gopalakrishnan; Colton, Clark K; Koulmanda, Maria; Weir, Gordon C; Wilhelm, Josh J; Qian, Dajun; Niland, Joyce C; Hering, Bernhard J

2015-01-01

Reliable in vitro islet quality assessment assays that can be performed routinely, prospectively, and are able to predict clinical transplant outcomes are needed. In this paper we present data on the utility of an assay based on cellular oxygen consumption rate (OCR) in predicting clinical islet autotransplant (IAT) insulin independence (II). IAT is an attractive model for evaluating characterization assays regarding their utility in predicting II due to an absence of confounding factors such as immune rejection and immunosuppressant toxicity. Membrane integrity staining (FDA/PI), OCR normalized to DNA (OCR/DNA), islet equivalent (IE) and OCR (viable IE) normalized to recipient body weight (IE dose and OCR dose), and OCR/DNA normalized to islet size index (ISI) were used to characterize autoislet preparations (n = 35). Correlation between pre-IAT islet product characteristics and II was determined using receiver operating characteristic analysis. Preparations that resulted in II had significantly higher OCR dose and IE dose (p<0.001). These islet characterization methods were highly correlated with II at 6-12 months post-IAT (area-under-the-curve (AUC) = 0.94 for IE dose and 0.96 for OCR dose). FDA/PI (AUC = 0.49) and OCR/DNA (AUC = 0.58) did not correlate with II. OCR/DNA/ISI may have some utility in predicting outcome (AUC = 0.72). Commonly used assays to determine whether a clinical islet preparation is of high quality prior to transplantation are greatly lacking in sensitivity and specificity. While IE dose is highly predictive, it does not take into account islet cell quality. OCR dose, which takes into consideration both islet cell quality and quantity, may enable a more accurate and prospective evaluation of clinical islet preparations.

Islet Oxygen Consumption Rate (OCR Dose Predicts Insulin Independence in Clinical Islet Autotransplantation.

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Klearchos K Papas

Full Text Available Reliable in vitro islet quality assessment assays that can be performed routinely, prospectively, and are able to predict clinical transplant outcomes are needed. In this paper we present data on the utility of an assay based on cellular oxygen consumption rate (OCR in predicting clinical islet autotransplant (IAT insulin independence (II. IAT is an attractive model for evaluating characterization assays regarding their utility in predicting II due to an absence of confounding factors such as immune rejection and immunosuppressant toxicity.Membrane integrity staining (FDA/PI, OCR normalized to DNA (OCR/DNA, islet equivalent (IE and OCR (viable IE normalized to recipient body weight (IE dose and OCR dose, and OCR/DNA normalized to islet size index (ISI were used to characterize autoislet preparations (n = 35. Correlation between pre-IAT islet product characteristics and II was determined using receiver operating characteristic analysis.Preparations that resulted in II had significantly higher OCR dose and IE dose (p<0.001. These islet characterization methods were highly correlated with II at 6-12 months post-IAT (area-under-the-curve (AUC = 0.94 for IE dose and 0.96 for OCR dose. FDA/PI (AUC = 0.49 and OCR/DNA (AUC = 0.58 did not correlate with II. OCR/DNA/ISI may have some utility in predicting outcome (AUC = 0.72.Commonly used assays to determine whether a clinical islet preparation is of high quality prior to transplantation are greatly lacking in sensitivity and specificity. While IE dose is highly predictive, it does not take into account islet cell quality. OCR dose, which takes into consideration both islet cell quality and quantity, may enable a more accurate and prospective evaluation of clinical islet preparations.

Vitamin D intake is associated with insulin sensitivity in African American, but not European American, women

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Oster Robert A

2010-04-01

Full Text Available Abstract Background The prevalence of type 2 diabetes is higher among African Americans (AA vs European Americans (EA, independent of obesity and other known confounders. Although the reason for this disparity is not known, it is possible that relatively low levels of vitamin D among AA may contribute, as vitamin D has been positively associated with insulin sensitivity in some studies. The objective of this study was to test the hypothesis that dietary vitamin D would be associated with a robust measure of insulin sensitivity in AA and EA women. Methods Subjects were 115 African American (AA and 137 European American (EA healthy, premenopausal women. Dietary intake was determined with 4-day food records; the insulin sensitivity index (SI with a frequently-sampled intravenous glucose tolerance test and minimal modeling; the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR with fasting insulin and glucose; and body composition with dual-energy X-ray absorptiometry. Results Vitamin D intake was positively associated with SI (standardized β = 0.18, P = 0.05 and inversely associated with HOMA-IR (standardized β = -0.26, P = 0.007 in AA, and the relationships were independent of age, total body fat, energy intake, and % kcal from fat. Vitamin D intake was not significantly associated with indices of insulin sensitivity/resistance in EA (standardized β = 0.03, P = 0.74 and standardized β = 0.02, P = 0.85 for SI and HOMA-IR, respectively. Similar to vitamin D, dietary calcium was associated with SI and HOMA-IR among AA but not EA. Conclusions This study provides novel findings that dietary vitamin D and calcium were independently associated with insulin sensitivity in AA, but not EA. Promotion of these nutrients in the diet may reduce health disparities in type 2 diabetes risk among AA, although longitudinal and intervention studies are required.

Substrate Metabolism and Insulin Sensitivity During Fasting in Obese Human Subjects: Impact of GH Blockade.

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Pedersen, Morten Høgild; Svart, Mads Vandsted; Lebeck, Janne; Bidlingmaier, Martin; Stødkilde-Jørgensen, Hans; Pedersen, Steen Bønløkke; Møller, Niels; Jessen, Niels; Jørgensen, Jens O L

2017-04-01

Insulin resistance and metabolic inflexibility are features of obesity and are amplified by fasting. Growth hormone (GH) secretion increases during fasting and GH causes insulin resistance. To study the metabolic effects of GH blockade during fasting in obese subjects. Nine obese males were studied thrice in a randomized design: (1) after an overnight fast (control), (2) after 72 hour fasting (fasting), and (3) after 72 hour fasting with GH blockade (pegvisomant) [fasting plus GH antagonist (GHA)]. Each study day consisted of a 4-hour basal period followed by a 2-hour hyperinsulinemic, euglycemic clamp combined with indirect calorimetry, assessment of glucose and palmitate turnover, and muscle and fat biopsies. GH levels increased with fasting (P fasting-induced reduction of serum insulin-like growth factor I was enhanced by GHA (P Fasting increased lipolysis and lipid oxidation independent of GHA, but fasting plus GHA caused a more pronounced suppression of lipid intermediates in response to hyperinsulinemic, euglycemic clamp. Fasting-induced insulin resistance was abrogated by GHA (P Fasting plus GHA also caused elevated glycerol levels and reduced levels of counterregulatory hormones. Fasting significantly reduced the expression of antilipolytic signals in adipose tissue independent of GHA. Suppression of GH activity during fasting in obese subjects reverses insulin resistance and amplifies insulin-stimulated suppression of lipid intermediates, indicating that GH is an important regulator of substrate metabolism, insulin sensitivity, and metabolic flexibility also in obese subjects. Copyright © 2017 by the Endocrine Society

Developed beverage from roselle calyx and selected fruits modulates β-cell function, improves insulin sensitivity, and attenuates hyperlipidaemia in diabetic rats

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Ochuko L. Erukainure

2015-12-01

Full Text Available The aim of this study is to report the antidiabetic properties of a beverage developed from roselle calyx and selected fruits in male albino rats. The beverage was designed to contain 30% pawpaw (Carica papaya L., 10% grapefruit (Citrus paradisi, 20% guava leaves (Psidium guajava L. and 40% roselle calyx aqueous extracts. Four groups of five rats each were acclimatized on pelletized mouse chow for seven days, after which diabetes was induced by a single ip injection of alloxan in all groups except group 1, which served as control. Group 2 served as negative control while groups 3 and 4 were treated with the beverage at 2.5 and 5 ml/kg bw respectively. Food intake, body weight, and blood glucose levels were monitored. They were sacrificed by cervical dislocation after a 2 week treatment. Blood serum was analysed to evaluate insulin levels, β cell function, insulin resistance and lipid profile. Histological studies were carried out on pancreatic tissues. Treatment with both doses of the beverage led to a significant reduction (p < 0.05 in blood glucose, total cholesterol triglyceride, LDL and increased HDL levels. It also improved serum insulin levels, β cell function, reduced insulin resistance and restored pancreatic beta cells compared to the diabetic group. These antidiabetic properties may be as a consequence of modulation of the β-cell function, reduction of insulin resistance and preservation/restoration of β-cell integrity. However, treatment with the single dose showed signs of hyperinsulinaemia.

Pancreatic Islet Cell Transplantation

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Warnock, Garth L.; Rajotte, Ray V.

1992-01-01

Transplantation of insulin-producing tissue offers a physiologic approach to restoration of glycemic control. Whereas transplantation of vascularized pancreatic grafts has recently achieved encouraging results, pancreatic islet cell transplantation holds the promise of low morbidity and reduced requirements for agressive immunosuppression for recipients. Islet cell transplantation was recently demonstrated to induce euglycemia with insulin independence. Imagesp1656-a PMID:21221366

Microalbuminuria in insulin-dependent diabetes

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Niazy, S; Feldt-Rasmussen, B; Deckert, T

1987-01-01

Urinary albumin excretion in a representative sample of 679 patients with Type I (insulin-dependent) diabetes, 18 to 50 years of age, was investigated. Patients on antihypertensive therapy were excluded. Urinary albumin excretion was examined in one 24 hour urine sample using an ELISA technique....... Twenty-three per cent of the patients had microalbuminuria, i.e., 30-300 mg albumin/24 h. The prevalence of microalbuminuria was independent of sex, age, insulin dose and diabetes duration. In the majority of those cases in which microalbuminuria was found during the first 10 years of diabetes......, the concentrations were in the lower range, i.e., 30-50 mg/24 h. The prevalence of incipient nephropathy (urinary albumin excretion in a single urine sample of 51-300 mg/24 h) increased with diabetes duration. In patients with incipient nephropathy hemoglobin A1c tended to be, and blood pressure was, elevated...

Novel PLGA-based nanoparticles for the oral delivery of insulin

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Malathi S

2015-03-01

insulin-treated diabetic rats. The results show that the oral administration of ISTPPLG6 NPs is an effective method of reducing serum glucose level for a period of 24 hours. Histopathological studies reveal that ISTPPLG NPs could restore the damage caused by streptozotocin in the liver, kidneys, and pancreas, indicating its biocompatibility and regenerative effects.Conclusion: ISTPPLG6 NPs can act as potential drug carriers for the oral delivery of insulin. Keywords: drug delivery, polymer nanoparticles, poly(ethylene glycol, tocopherol poly(ethylene glycol 1000 succinate, hypoglycemic effect, histopathology

High intensity interval training improves liver and adipose tissue insulin sensitivity

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Katarina Marcinko

2015-12-01

Conclusions: These data indicate that HIIT lowers blood glucose levels by improving adipose and liver insulin sensitivity independently of changes in adiposity, adipose tissue inflammation, liver lipid content or AMPK phosphorylation of ACC.

Chemical stability of insulin. 1. Hydrolytic degradation during storage of pharmaceutical preparations.

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Brange, J; Langkjaer, L; Havelund, S; Vølund, A

1992-06-01

Hydrolysis of insulin has been studied during storage of various preparations at different temperatures. Insulin deteriorates rapidly in acid solutions due to extensive deamidation at residue AsnA21. In neutral formulations deamidation takes place at residue AsnB3 at a substantially reduced rate under formation of a mixture of isoAsp and Asp derivatives. The rate of hydrolysis at B3 is independent of the strength of the preparation, and in most cases the species of insulin, but varies with storage temperature and formulation. Total transformation at B3 is considerably reduced when insulin is in the crystalline as compared to the amorphous or soluble state, indicating that formation of the rate-limiting cyclic imide decreases when the flexibility of the tertiary structure is reduced. Neutral solutions containing phenol showed reduced deamidation probably because of a stabilizing effect of phenol on the tertiary structure (alpha-helix formation) around the deamidating residue, resulting in a reduced probability for formation of the intermediate imide. The ratio of isoAsp/Asp derivative was independent of time and temperature, suggesting a pathway involving only intermediate imide formation, without any direct side-chain hydrolysis. However, increasing formation of Asp relative to isoAsp derivative was observed with decreasing flexibility of the insulin three-dimensional structure in the formulation. In certain crystalline suspensions a cleavage of the peptide bond A8-A9 was observed. Formation of this split product is species dependent: bovine greater than porcine greater than human insulin. The hydrolytic cleavage of the peptide backbone takes place only in preparations containing rhombohedral crystals in addition to free zinc ions.

Dual Regulation of Gluconeogenesis by Insulin and Glucose in the Proximal Tubules of the Kidney.

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Sasaki, Motohiro; Sasako, Takayoshi; Kubota, Naoto; Sakurai, Yoshitaka; Takamoto, Iseki; Kubota, Tetsuya; Inagi, Reiko; Seki, George; Goto, Moritaka; Ueki, Kohjiro; Nangaku, Masaomi; Jomori, Takahito; Kadowaki, Takashi

2017-09-01

Growing attention has been focused on the roles of the proximal tubules (PTs) of the kidney in glucose metabolism, including the mechanism of regulation of gluconeogenesis. In this study, we found that PT-specific insulin receptor substrate 1/2 double-knockout mice, established by using the newly generated sodium-glucose cotransporter 2 (SGLT2)-Cre transgenic mice, exhibited impaired insulin signaling and upregulated gluconeogenic gene expression and renal gluconeogenesis, resulting in systemic insulin resistance. In contrast, in streptozotocin-treated mice, although insulin action was impaired in the PTs, the gluconeogenic gene expression was unexpectedly downregulated in the renal cortex, which was restored by administration of an SGLT1/2 inhibitor. In the HK-2 cells, the gluconeogenic gene expression was suppressed by insulin, accompanied by phosphorylation and inactivation of forkhead box transcription factor 1 (FoxO1). In contrast, glucose deacetylated peroxisome proliferator-activated receptor γ coactivator 1-α (PGC1α), a coactivator of FoxO1, via sirtuin 1, suppressing the gluconeogenic gene expression, which was reversed by inhibition of glucose reabsorption. These data suggest that both insulin signaling and glucose reabsorption suppress the gluconeogenic gene expression by inactivation of FoxO1 and PGC1α, respectively, providing insight into novel mechanisms underlying the regulation of gluconeogenesis in the PTs. © 2017 by the American Diabetes Association.

Oleanolic acid supplement attenuates liquid fructose-induced adipose tissue insulin resistance through the insulin receptor substrate-1/phosphatidylinositol 3-kinase/Akt signaling pathway in rats

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Li, Ying [Faculty of Basic Medical Sciences, Chongqing Medical University, Chongqing 400016 (China); Wang, Jianwei, E-mail: wangjianwei1968@gmail.com [Department of Traditional Chinese Medicine, Chongqing Medical University, Chongqing 400016 (China); Gu, Tieguang [Endocrinology and Metabolism Group, Sydney Institute of Health Sciences, Sydney, NSW 2000 Australia (Australia); Yamahara, Johji [Pharmafood Institute, Kyoto 602-8136 (Japan); Li, Yuhao, E-mail: yuhao@sitcm.edu.au [Endocrinology and Metabolism Group, Sydney Institute of Health Sciences, Sydney, NSW 2000 Australia (Australia)

2014-06-01

Oleanolic acid, a triterpenoid contained in more than 1620 plants including various fruits and foodstuffs, has numerous metabolic effects, such as hepatoprotection. However, its underlying mechanisms remain poorly understood. Adipose tissue insulin resistance (Adipo-IR) may contribute to the development and progress of metabolic abnormalities through release of excessive free fatty acids from adipose tissue. This study investigated the effect of oleanolic acid on Adipo-IR. The results showed that supplement with oleanolic acid (25 mg/kg, once daily, by oral gavage) over 10 weeks attenuated liquid fructose-induced increase in plasma insulin concentration and the homeostasis model assessment of insulin resistance (HOMA-IR) index in rats. Simultaneously, oleanolic acid reversed the increase in the Adipo-IR index and plasma non-esterified fatty acid concentrations during the oral glucose tolerance test assessment. In white adipose tissue, oleanolic acid enhanced mRNA expression of the genes encoding insulin receptor, insulin receptor substrate (IRS)-1 and phosphatidylinositol 3-kinase. At the protein level, oleanolic acid upregulated total IRS-1 expression, suppressed the increased phosphorylated IRS-1 at serine-307, and restored the increased phosphorylated IRS-1 to total IRS-1 ratio. In contrast, phosphorylated Akt to total Akt ratio was increased. Furthermore, oleanolic acid reversed fructose-induced decrease in phosphorylated-Akt/Akt protein to plasma insulin concentration ratio. However, oleanolic acid did not affect IRS-2 mRNA expression. Therefore, these results suggest that oleanolic acid supplement ameliorates fructose-induced Adipo-IR in rats via the IRS-1/phosphatidylinositol 3-kinase/Akt pathway. Our findings may provide new insights into the mechanisms of metabolic actions of oleanolic acid. - Highlights: • Adipose insulin resistance (Adipo-IR) contributes to metabolic abnormalities. • We investigated the effect of oleanolic acid (OA) on adipo-IR in

Oleanolic acid supplement attenuates liquid fructose-induced adipose tissue insulin resistance through the insulin receptor substrate-1/phosphatidylinositol 3-kinase/Akt signaling pathway in rats

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Li, Ying; Wang, Jianwei; Gu, Tieguang; Yamahara, Johji; Li, Yuhao

2014-01-01

Oleanolic acid, a triterpenoid contained in more than 1620 plants including various fruits and foodstuffs, has numerous metabolic effects, such as hepatoprotection. However, its underlying mechanisms remain poorly understood. Adipose tissue insulin resistance (Adipo-IR) may contribute to the development and progress of metabolic abnormalities through release of excessive free fatty acids from adipose tissue. This study investigated the effect of oleanolic acid on Adipo-IR. The results showed that supplement with oleanolic acid (25 mg/kg, once daily, by oral gavage) over 10 weeks attenuated liquid fructose-induced increase in plasma insulin concentration and the homeostasis model assessment of insulin resistance (HOMA-IR) index in rats. Simultaneously, oleanolic acid reversed the increase in the Adipo-IR index and plasma non-esterified fatty acid concentrations during the oral glucose tolerance test assessment. In white adipose tissue, oleanolic acid enhanced mRNA expression of the genes encoding insulin receptor, insulin receptor substrate (IRS)-1 and phosphatidylinositol 3-kinase. At the protein level, oleanolic acid upregulated total IRS-1 expression, suppressed the increased phosphorylated IRS-1 at serine-307, and restored the increased phosphorylated IRS-1 to total IRS-1 ratio. In contrast, phosphorylated Akt to total Akt ratio was increased. Furthermore, oleanolic acid reversed fructose-induced decrease in phosphorylated-Akt/Akt protein to plasma insulin concentration ratio. However, oleanolic acid did not affect IRS-2 mRNA expression. Therefore, these results suggest that oleanolic acid supplement ameliorates fructose-induced Adipo-IR in rats via the IRS-1/phosphatidylinositol 3-kinase/Akt pathway. Our findings may provide new insights into the mechanisms of metabolic actions of oleanolic acid. - Highlights: • Adipose insulin resistance (Adipo-IR) contributes to metabolic abnormalities. • We investigated the effect of oleanolic acid (OA) on adipo-IR in

Joint image restoration and location in visual navigation system

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Wu, Yuefeng; Sang, Nong; Lin, Wei; Shao, Yuanjie

2018-02-01

Image location methods are the key technologies of visual navigation, most previous image location methods simply assume the ideal inputs without taking into account the real-world degradations (e.g. low resolution and blur). In view of such degradations, the conventional image location methods first perform image restoration and then match the restored image on the reference image. However, the defective output of the image restoration can affect the result of localization, by dealing with the restoration and location separately. In this paper, we present a joint image restoration and location (JRL) method, which utilizes the sparse representation prior to handle the challenging problem of low-quality image location. The sparse representation prior states that the degraded input image, if correctly restored, will have a good sparse representation in terms of the dictionary constructed from the reference image. By iteratively solving the image restoration in pursuit of the sparest representation, our method can achieve simultaneous restoration and location. Based on such a sparse representation prior, we demonstrate that the image restoration task and the location task can benefit greatly from each other. Extensive experiments on real scene images with Gaussian blur are carried out and our joint model outperforms the conventional methods of treating the two tasks independently.

Obesity-induced DNA released from adipocytes stimulates chronic adipose tissue inflammation and insulin resistance.

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Nishimoto, Sachiko; Fukuda, Daiju; Higashikuni, Yasutomi; Tanaka, Kimie; Hirata, Yoichiro; Murata, Chie; Kim-Kaneyama, Joo-Ri; Sato, Fukiko; Bando, Masahiro; Yagi, Shusuke; Soeki, Takeshi; Hayashi, Tetsuya; Imoto, Issei; Sakaue, Hiroshi; Shimabukuro, Michio; Sata, Masataka

2016-03-01

Obesity stimulates chronic inflammation in adipose tissue, which is associated with insulin resistance, although the underlying mechanism remains largely unknown. Here we showed that obesity-related adipocyte degeneration causes release of cell-free DNA (cfDNA), which promotes macrophage accumulation in adipose tissue via Toll-like receptor 9 (TLR9), originally known as a sensor of exogenous DNA fragments. Fat-fed obese wild-type mice showed increased release of cfDNA, as determined by the concentrations of single-stranded DNA (ssDNA) and double-stranded DNA (dsDNA) in plasma. cfDNA released from degenerated adipocytes promoted monocyte chemoattractant protein-1 (MCP-1) expression in wild-type macrophages, but not in TLR9-deficient (Tlr9 (-/-) ) macrophages. Fat-fed Tlr9 (-/-) mice demonstrated reduced macrophage accumulation and inflammation in adipose tissue and better insulin sensitivity compared with wild-type mice, whereas bone marrow reconstitution with wild-type bone marrow restored the attenuation of insulin resistance observed in fat-fed Tlr9 (-/-) mice. Administration of a TLR9 inhibitory oligonucleotide to fat-fed wild-type mice reduced the accumulation of macrophages in adipose tissue and improved insulin resistance. Furthermore, in humans, plasma ssDNA level was significantly higher in patients with computed tomography-determined visceral obesity and was associated with homeostasis model assessment of insulin resistance (HOMA-IR), which is the index of insulin resistance. Our study may provide a novel mechanism for the development of sterile inflammation in adipose tissue and a potential therapeutic target for insulin resistance.

Early growth response-1 negative feedback regulates skeletal muscle postprandial insulin sensitivity via activating Ptp1b transcription.

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Wu, Jing; Tao, Wei-Wei; Chong, Dan-Yang; Lai, Shan-Shan; Wang, Chuang; Liu, Qi; Zhang, Tong-Yu; Xue, Bin; Li, Chao-Jun

2018-03-15

Postprandial insulin desensitization plays a critical role in maintaining whole-body glucose homeostasis by avoiding the excessive absorption of blood glucose; however, the detailed mechanisms that underlie how the major player, skeletal muscle, desensitizes insulin action remain to be elucidated. Herein, we report that early growth response gene-1 ( Egr-1) is activated by insulin in skeletal muscle and provides feedback inhibition that regulates insulin sensitivity after a meal. The inhibition of the transcriptional activity of Egr-1 enhanced the phosphorylation of the insulin receptor (InsR) and Akt, thus increasing glucose uptake in L6 myotubes after insulin stimulation, whereas overexpression of Egr-1 decreased insulin sensitivity. Furthermore, deletion of Egr-1 in the skeletal muscle improved systemic insulin sensitivity and glucose tolerance, which resulted in lower blood glucose levels after refeeding. Mechanistic analysis demonstrated that EGR-1 inhibited InsR phosphorylation and glucose uptake in skeletal muscle by binding to the proximal promoter region of protein tyrosine phosphatase-1B (PTP1B) and directly activating transcription. PTP1B knockdown largely restored insulin sensitivity and enhanced glucose uptake, even under conditions of EGR-1 overexpression. Our results indicate that EGR-1/PTP1B signaling negatively regulates postprandial insulin sensitivity and suggest a potential therapeutic target for the prevention and treatment of excessive glucose absorption.-Wu, J., Tao, W.-W., Chong, D.-Y., Lai, S.-S., Wang, C., Liu, Q., Zhang, T.-Y., Xue, B., Li, C.-J. Early growth response-1 negative feedback regulates skeletal muscle postprandial insulin sensitivity via activating Ptp1b transcription.

Bromocriptine and insulin sensitivity in lean and obese subjects

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L Bahler

2016-11-01

Full Text Available Bromocriptine is a glucose-lowering drug, which was shown to be effective in obese subjects with insulin resistance. It is usually administered in the morning. The exact working mechanism of bromocriptine still has to be elucidated. Therefore, in this open-label randomized prospective cross-over mechanistic study, we assessed whether the timing of bromocriptine administration (morning vs evening results in different effects and whether these effects differ between lean and obese subjects. We studied the effect of bromocriptine on insulin sensitivity in 8 lean and 8 overweight subjects using an oral glucose tolerance test. The subjects used bromocriptine in randomized cross-over order for 2 weeks in the morning and 2 weeks in the evening. We found that in lean subjects, bromocriptine administration in the evening resulted in a significantly higher post-prandial insulin sensitivity as compared with the pre-exposure visit (glucose area under the curve (AUC 742 mmol/L * 120 min (695–818 vs 641 (504–750, P = 0.036, AUC for insulin did not change, P = 0.575. In obese subjects, both morning and evening administration of bromocriptine resulted in a significantly higher insulin sensitivity: morning administration in obese: insulin AUC (55,900 mmol/L * 120 min (43,236–96,831 vs 36,448 (25,213–57,711, P = 0.012 and glucose AUC P = 0.069; evening administration in obese: glucose AUC (735 mmol/L * 120 min (614–988 vs 644 (568–829, P = 0.017 and insulin AUC, P = 0.208. In conclusion, bromocriptine increases insulin sensitivity in both lean and obese subjects. In lean subjects, this effect only occurred when bromocriptine was administrated in the evening, whereas in the obese, insulin sensitivity increased independent of the timing of bromocriptine administration.

alpha-hydroxybutyrate is an early biomarker of insulin resistance and glucose intolerance in a nondiabetic population.

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Walter E Gall

2010-05-01

Full Text Available Insulin resistance is a risk factor for type 2 diabetes and cardiovascular disease progression. Current diagnostic tests, such as glycemic indicators, have limitations in the early detection of insulin resistant individuals. We searched for novel biomarkers identifying these at-risk subjects.Using mass spectrometry, non-targeted biochemical profiling was conducted in a cohort of 399 nondiabetic subjects representing a broad spectrum of insulin sensitivity and glucose tolerance (based on the hyperinsulinemic euglycemic clamp and oral glucose tolerance testing, respectively.Random forest statistical analysis selected alpha-hydroxybutyrate (alpha-HB as the top-ranked biochemical for separating insulin resistant (lower third of the clamp-derived M(FFM = 33 [12] micromol x min(-1 x kg(FFM (-1, median [interquartile range], n = 140 from insulin sensitive subjects (M(FFM = 66 [23] micromol x min(-1 x kg(FFM (-1 with a 76% accuracy. By targeted isotope dilution assay, plasma alpha-HB concentrations were reciprocally related to M(FFM; and by partition analysis, an alpha-HB value of 5 microg/ml was found to best separate insulin resistant from insulin sensitive subjects. alpha-HB also separated subjects with normal glucose tolerance from those with impaired fasting glycemia or impaired glucose tolerance independently of, and in an additive fashion to, insulin resistance. These associations were also independent of sex, age and BMI. Other metabolites from this global analysis that significantly correlated to insulin sensitivity included certain organic acid, amino acid, lysophospholipid, acylcarnitine and fatty acid species. Several metabolites are intermediates related to alpha-HB metabolism and biosynthesis.alpha-hydroxybutyrate is an early marker for both insulin resistance and impaired glucose regulation. The underlying biochemical mechanisms may involve increased lipid oxidation and oxidative stress.

Chemical stability of insulin. 3. Influence of excipients, formulation, and pH.

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Brange, J; Langkjaer, L

1992-01-01

The influence of auxiliary substances and pH on the chemical transformations of insulin in pharmaceutical formulation, including various hydrolytic and intermolecular cross-linking reactions, was studied. Bacteriostatic agents had a profound stabilizing effect--phenol > m-cresol > methylparaben--on deamidation as well as on insulin intermolecular cross-linking reactions. Of the isotonicity substances, NaCl generally had a stabilizing effect whereas glycerol and glucose led to increased chemical deterioration. Phenol and sodium chloride exerted their stabilizing effect through independent mechanisms. Zinc ions, in concentrations that promote association of insulin into hexamers, increase the stability, whereas higher zinc content had no further influence. Protamine gave rise to additional formation of covalent protamine-insulin products which increased with increasing protamine concentration. The impact of excipients on the chemical processes seems to be dictated mainly via an influence on the three-dimensional insulin structure. The effect of the physical state of the insulin on the chemical stability was also complex, suggesting an intricate dependence of intermolecular proximity of involved functional groups. At pH values below five and above eight, insulin degrades relatively fast. At acid pH, deamidation at residue A21 and covalent insulin dimerization dominates, whereas disulfide reactions leading to covalent polymerization and formation of A- and B-chains prevailed in alkaline medium. Structure-reactivity relationship is proposed to be a main determinant for the chemical transformation of insulin.

[Comparison between basal insulin glargine and NPH insulin in patients with diabetes type 1 on conventional intensive insulin therapy].

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Pesić, Milica; Zivić, Sasa; Radenković, Sasa; Velojić, Milena; Dimić, Dragan; Antić, Slobodan

2007-04-01

Insulin glargine is a long-acting insulin analog that mimics normal basal insulin secretion without pronounced peaks. The aim of this study was to compare insulin glargine with isophane insulin (NPH insulin) for basal insulin supply in patients with type 1 diabetes. A total of 48 type 1 diabetics on long term conventional intensive insulin therapy (IT) were randomized to three different regimens of basal insulin substitution: 1. continuation of NPH insulin once daily at bedtime with more intensive selfmonitoring (n = 15); 2. NPH insulin twice daily (n = 15); 3. insulin glargine once daily (n = 18). Meal time insulin aspart was continued in all groups. Fasting blood glucose (FBG) was lower in the glargine group (7.30+/-0.98 mmol/1) than in the twice daily NPH group (7.47+/-1.06 mmol/1), but without significant difference. FBG was significantly higher in the once daily NPH group (8.44+/-0.85 mmol/l; p < 0.05). HbAlc after 3 months did not change in the once daily NPH group, but decreased in the glargine group (from 7.72+/-0.86% to 6.87+/-0.50%), as well as in the twice daily NPH group (from 7.80+/-0.83% to 7.01+/-0.63%). Total daily insulin doses were similar in all groups but only in the glargine group there was an increase of basal and decrease of meal related insulin doses. The frequency of mild hypoglycemia was significantly lower in the glargine group (6.56+/-2.09) than in both NPH groups (9.0+/-1.65 in twice daily NPH group and 8.13+/-1.30 in other NPH group) (episodes/patients-month, p < 0.05). Basal insulin supplementation in type 1 diabetes mellitus with either twice daily NPH insulin or glargine can result in similar glycemic control when combined with meal time insulin aspart. However, with glargine regimen FBG, HbAlc and frequency of hypoglycemic event are lower. These facts contribute to better patients satisfaction with insulin glargine versus NPH insulin in IIT in type 1 diabetics.

Beta Cell Mass Restoration in Alloxan-Diabetic Mice Treated with EGF and Gastrin.

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Imane Song

Full Text Available One week of treatment with EGF and gastrin (EGF/G was shown to restore normoglycemia and to induce islet regeneration in mice treated with the diabetogenic agent alloxan. The mechanisms underlying this regeneration are not fully understood. We performed genetic lineage tracing experiments to evaluate the contribution of beta cell neogenesis in this model. One day after alloxan administration, mice received EGF/G treatment for one week. The treatment could not prevent the initial alloxan-induced beta cell mass destruction, however it did reverse glycemia to control levels within one day, suggesting improved peripheral glucose uptake. In vitro experiments with C2C12 cell line showed that EGF could stimulate glucose uptake with an efficacy comparable to that of insulin. Subsequently, EGF/G treatment stimulated a 3-fold increase in beta cell mass, which was partially driven by neogenesis and beta cell proliferation as assessed by beta cell lineage tracing and BrdU-labeling experiments, respectively. Acinar cell lineage tracing failed to show an important contribution of acinar cells to the newly formed beta cells. No appearance of transitional cells co-expressing insulin and glucagon, a hallmark for alpha-to-beta cell conversion, was found, suggesting that alpha cells did not significantly contribute to the regeneration. An important fraction of the beta cells significantly lost insulin positivity after alloxan administration, which was restored to normal after one week of EGF/G treatment. Alloxan-only mice showed more pronounced beta cell neogenesis and proliferation, even though beta cell mass remained significantly depleted, suggesting ongoing beta cell death in that group. After one week, macrophage infiltration was significantly reduced in EGF/G-treated group compared to the alloxan-only group. Our results suggest that EGF/G-induced beta cell regeneration in alloxan-diabetic mice is driven by beta cell neogenesis, proliferation and recovery of

Insulin resistance and progression to type 1 diabetes in the European Nicotinamide Diabetes Intervention Trial (ENDIT)

DEFF Research Database (Denmark)

Bingley, Polly J; Mahon, Jeffrey L; Gale, Edwin A M

2008-01-01

OBJECTIVE: Insulin resistance can modulate progression to type 1 diabetes in individuals with ongoing islet autoimmunity. We wanted to see whether measures of insulin resistance improved risk assessment in islet cell antibody (ICA)-positive relatives when added to other immune and metabolic markers......-up was 4.21 years, and 105 individuals developed diabetes. Oral and intravenous glucose tolerance tests were performed at baseline; antibodies to GAD, IA-2, and insulin were determined by radioimmunoassay; and insulin resistance was estimated by homeostasis model assessment. Risk was assessed by Cox...... glucose tolerance test (P insulin resistance (HOMA2-IR) achieved only borderline significance (P = 0.06). HOMA2-IR was an independent determinant in participants with loss of FPIR (P = 0...

Vitamin D deficiency is associated with insulin resistance in nondiabetics and reduced insulin production in type 2 diabetics.

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Esteghamati, A; Aryan, Z; Esteghamati, Ar; Nakhjavani, M

2015-04-01

It is not known whether the association of serum 25-hydroxyvitamin D [25(OH)D] with glycemic measurements of individuals without diabetes is similar to those with diabetes or not. This study is aimed to investigate the association of serum 25(OH)D with glycemic markers of diabetics, nondiabetics, and prediabetics. A case-control study was conducted on age and sex matched 1,195 patients with type 2 DM, 121 prediabetics, and 209 healthy controls. Anthropometric variables, lipid profile, glycemic measurements, and serum 25(OH)D levels were recorded. Serum insulin and C-peptide levels were also measured. All glycemic measurements were compared between diabetics and nondiabetics and prediabetics at different vitamin D status. Patients with DM had lower serum 25(OH)D compared to prediabetics and healthy controls. Endogenous insulin production in response to food intake and in fasting was significantly lower in vitamin D deficient patients with DM compared to those with serum 25(OH)D>40 ng/ml. Diabetic women with serum 25(OH)D40 ng/ml. Healthy individuals with serum 25(OH)D<20 ng/ml had signs of insulin resistance as estimated by significant increase of HOMA-IR, HbA1c, and fasting plasma glucose (FPG). In addition, we found that serum 25(OH)D was inversely associated with insulin resistance. Vitamin D deficiency is associated with insulin resistance in nondiabetics, which is independent of obesity. Furthermore, vitamin D deficiency is associated with reduced insulin production in type 2 diabetics, which was mainly observed in men. Accordingly, a gender disparity also exists in association of serum 25(OH)D with glycemic measurements. © Georg Thieme Verlag KG Stuttgart · New York.

Divergent and convergent roles for insulin-like peptides in the worm, fly and mammalian nervous systems.

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Lau, Hiu E; Chalasani, Sreekanth H

2014-09-01

Insulin signaling plays a critical role in coupling external changes to animal physiology and behavior. Despite remarkable conservation in the insulin signaling pathway components across species, divergence in the mechanism and function of the signal is evident. Focusing on recent findings from C. elegans, D. melanogaster and mammals, we discuss the role of insulin signaling in regulating adult neuronal function and behavior. In particular, we describe the transcription-dependent and transcription-independent aspects of insulin signaling across these three species. Interestingly, we find evidence of diverse mechanisms underlying complex networks of peptide action in modulating nervous system function.

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

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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.

Proof of Concept: Matrix metalloproteinase inhibitor decreases inflammation and improves muscle insulin sensitivity in people with type 2 diabetes

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Frankwich Karen

2012-10-01

Full Text Available Abstract Background Obesity is a state of subclinical inflammation resulting in loss of function of insulin receptors and decreased insulin sensitivity. Inhibition of the inflammatory enzymes, matrix metalloproteinases (MMPs, for 6 months in rodent models restores insulin receptor function and insulin sensitivity. Methods This 12-week double-blind, randomized, placebo (PL-controlled proof-of-concept study was performed to determine if the MMP inhibitor (MMPI, doxycycline, decreased global markers of inflammation and enhanced muscle insulin sensitivity in obese people with type 2 diabetes (DM2. The study included non-DM2 controls (n = 15, and DM2 subjects randomized to PL (n = 13 or doxycycline 100 mg twice daily (MMPI; n = 11. All participants were evaluated on Day 1; MMPI and PL groups were also evaluated after 84 days of treatment. Results There was a significant decrease in inflammatory markers C-reactive protein (P  Conclusions This study demonstrated short term treatment of people with diabetes with an MMPI resulted in decreased inflammation and improved insulin sensitivity. Larger, longer studies are warranted to determine if doxycycline can improve glucose control in people with diabetes. Trial Registration Clinicaltrials.gov NCT01375491

Independent and Combined Association of Muscle Strength and Cardiorespiratory Fitness in Youth With Insulin Resistance and β-Cell Function in Young Adulthood

DEFF Research Database (Denmark)

Grøntved, Anders; Ried-Larsen, Mathias; Ekelund, Ulf

2013-01-01

ergometer test. Insulin resistance (homeostasis model assessment of insulin resistance [HOMA-IR]) and β-cell function (homeostasis model assessment of β-cell function [HOMA-B]) were estimated from fasting serum insulin and glucose that were obtained in youth and at follow-up in young adulthood.......RESULTSFor each 1-SD difference in isometric muscle strength (0.16 N/kg) in youth, fasting insulin, HOMA-IR, and HOMA-B in young adulthood changed with -11.3% (95% CI, -17.0 to -5.2), -12.2% (-18.2 to -5.7), and -8.9% (-14.4 to -3.0), respectively, in young adulthood after adjustment for CRF and personal...... lifestyle and demographic factors. Results for CRF were very similar in magnitude, and the magnitude of associations for both exposures was unchanged with additional adjustment for general or abdominal adiposity in youth. Combined associations of muscle strength and CRF with fasting insulin, HOMA-IR...

Independent signaling by Drosophila insulin receptor for axon guidance and growth.

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Li, Caroline R; Guo, Dongyu; Pick, Leslie

2013-01-01

The Drosophila insulin receptor (DInR) regulates a diverse array of biological processes including growth, axon guidance, and sugar homeostasis. Growth regulation by DInR is mediated by Chico, the Drosophila homolog of vertebrate insulin receptor substrate proteins IRS1-4. In contrast, DInR regulation of photoreceptor axon guidance in the developing visual system is mediated by the SH2-SH3 domain adaptor protein Dreadlocks (Dock). In vitro studies by others identified five NPXY motifs, one in the juxtamembrane region and four in the signaling C-terminal tail (C-tail), important for interaction with Chico. Here we used yeast two-hybrid assays to identify regions in the DInR C-tail that interact with Dock. These Dock binding sites were in separate portions of the C-tail from the previously identified Chico binding sites. To test whether these sites are required for growth or axon guidance in whole animals, a panel of DInR proteins, in which the putative Chico and Dock interaction sites had been mutated individually or in combination, were tested for their ability to rescue viability, growth and axon guidance defects of dinr mutant flies. Sites required for viability were identified. Unexpectedly, mutation of both putative Dock binding sites, either individually or in combination, did not lead to defects in photoreceptor axon guidance. Thus, either sites also required for viability are necessary for DInR function in axon guidance and/or there is redundancy built into the DInR/Dock interaction such that Dock is able to interact with multiple regions of DInR. We also found that simultaneous mutation of all five NPXY motifs implicated in Chico interaction drastically decreased growth in both male and female adult flies. These animals resembled chico mutants, supporting the notion that DInR interacts directly with Chico in vivo to control body size. Mutation of these five NPXY motifs did not affect photoreceptor axon guidance, segregating the roles of DInR in the

Subcutaneous insulin absorption explained by insulin's physicochemical properties. Evidence from absorption studies of soluble human insulin and insulin analogues in humans.

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Kang, S; Brange, J; Burch, A; Vølund, A; Owens, D R

1991-11-01

To study the influence of molecular aggregation on rates of subcutaneous insulin absorption and to attempt to elucidate the mechanism of absorption of conventional soluble human insulin in humans. Seven healthy male volunteers aged 22-43 yr and not receiving any drugs comprised the study. This study consisted of a single-blind randomized comparison of equimolar dosages of 125I-labeled forms of soluble hexameric 2 Zn2+ human insulin and human insulin analogues with differing association states at pharmaceutical concentrations (AspB10, dimeric; AspB28, mixture of monomers and dimers; AspB9, GluB27, monomeric). After an overnight fast and a basal period of 1 h, 0.6 nmol/kg of either 125I-labeled human soluble insulin (Actrapid HM U-100) or 125I-labeled analogue was injected subcutaneously on 4 separate days 1 wk apart. Absorption was assessed by measurement of residual radioactivity at the injection site by external gamma-counting. The mean +/- SE initial fractional disappearance rates for the four preparations were 20.7 +/- 1.9 (hexameric soluble human insulin), 44.4 +/- 2.5 (dimeric analogue AspB10), 50.6 +/- 3.9 (analogue AspB28), and 67.4 +/- 7.4%/h (monomeric analogue AspB9, GluB27). Absorption of the dimeric analogue was significantly faster than that of hexameric human insulin (P less than 0.001); absorption of monomeric insulin analogue AspB9, GluB27 was significantly faster than that of dimeric analogue AspB10 (P less than 0.01). There was an inverse linear correlation between association state and the initial fractional disappearance rates (r = -0.98, P less than 0.02). Analysis of the disappearance data on a log linear scale showed that only the monomeric analogue had a monoexponential course throughout. Two phases in the rates of absorption were identified for the dimer and three for hexameric human insulin. The fractional disappearance rates (%/h) calculated by log linear regression analysis were monomer 73.3 +/- 6.8; dimer 44.4 +/- 2.5 from 0 to 2 h and

Insulin receptor internalization defect in an insulin-resistant mouse melanoma cell line

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Androlewicz, M.J.; Straus, D.S.; Brandenburg, D.F.

1989-01-01

Previous studies from this laboratory demonstrated that the PG19 mouse melanoma cell line does not exhibit a biological response to insulin, whereas melanoma x mouse embryo fibroblast hybrids do respond to insulin. To investigate the molecular basis of the insulin resistance of the PG19 melanoma cells, insulin receptors from the insulin-resistant melanoma cells and insulin-sensitive fibroblast x melanoma hybrid cells were analyzed by the technique of photoaffinity labeling using the photoprobe 125 I-NAPA-DP-insulin. Photolabeled insulin receptors from the two cell types have identical molecular weights as determined by SDS gel electrophoresis under reducing and nonreducing conditions, indicating that the receptors on the two cell lines are structurally similar. Insulin receptor internalization studies revealed that the hybrid cells internalize receptors to a high degree at 37 degree C, whereas the melanoma cells internalize receptors to a very low degree or not at all. The correlation between ability to internalize insulin receptors and sensitivity to insulin action in this system suggests that uptake of the insulin-receptor complex may be required for insulin action in these cells. Insulin receptors from the two cell lines autophosphorylate in a similar insulin-dependent manner both in vitro and in intact cells, indicating that insulin receptors on the melanoma and hybrid cells have functional tyrosine protein kinase activity. Therefore, the block in insulin action in the PG19 melanoma cells appears to reside at a step beyond insulin-stimulated receptor autophosphorylation

Reduced Circulating Insulin Enhances Insulin Sensitivity in Old Mice and Extends Lifespan

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Nicole M. Templeman

2017-07-01

Full Text Available The causal relationships between insulin levels, insulin resistance, and longevity are not fully elucidated. Genetic downregulation of insulin/insulin-like growth factor 1 (Igf1 signaling components can extend invertebrate and mammalian lifespan, but insulin resistance, a natural form of decreased insulin signaling, is associated with greater risk of age-related disease in mammals. We compared Ins2+/− mice to Ins2+/+ littermate controls, on a genetically stable Ins1 null background. Proteomic and transcriptomic analyses of livers from 25-week-old mice suggested potential for healthier aging and altered insulin sensitivity in Ins2+/− mice. Halving Ins2 lowered circulating insulin by 25%–34% in aged female mice, without altering Igf1 or circulating Igf1. Remarkably, decreased insulin led to lower fasting glucose and improved insulin sensitivity in aged mice. Moreover, lowered insulin caused significant lifespan extension, observed across two diverse diets. Our study indicates that elevated insulin contributes to age-dependent insulin resistance and that limiting basal insulin levels can extend lifespan.

Reduced Circulating Insulin Enhances Insulin Sensitivity in Old Mice and Extends Lifespan.

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Templeman, Nicole M; Flibotte, Stephane; Chik, Jenny H L; Sinha, Sunita; Lim, Gareth E; Foster, Leonard J; Nislow, Corey; Johnson, James D

2017-07-11

The causal relationships between insulin levels, insulin resistance, and longevity are not fully elucidated. Genetic downregulation of insulin/insulin-like growth factor 1 (Igf1) signaling components can extend invertebrate and mammalian lifespan, but insulin resistance, a natural form of decreased insulin signaling, is associated with greater risk of age-related disease in mammals. We compared Ins2 +/- mice to Ins2 +/+ littermate controls, on a genetically stable Ins1 null background. Proteomic and transcriptomic analyses of livers from 25-week-old mice suggested potential for healthier aging and altered insulin sensitivity in Ins2 +/- mice. Halving Ins2 lowered circulating insulin by 25%-34% in aged female mice, without altering Igf1 or circulating Igf1. Remarkably, decreased insulin led to lower fasting glucose and improved insulin sensitivity in aged mice. Moreover, lowered insulin caused significant lifespan extension, observed across two diverse diets. Our study indicates that elevated insulin contributes to age-dependent insulin resistance and that limiting basal insulin levels can extend lifespan. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

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.

Effects of Ursodeoxycholic Acid and Insulin on Palmitate-Induced ROS Production and Down-Regulation of PI3K/Akt Signaling Activity.

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Yokoyama, Kunihiro; Tatsumi, Yasuaki; Hayashi, Kazuhiko; Goto, Hidemi; Ishikawa, Tetsuya; Wakusawa, Shinya

2017-01-01

In obese and diabetic patients, plasma free fatty acid (FFA) levels are often elevated and may play a causal role in insulin resistance and reactive oxygen species (ROS) production. We have previously shown that ursodeoxycholic acid (UDCA) has antioxidative activity through the phosphatidylinositol 3-kinase (PI3K)/Akt signaling-mediated glutathione production. In this study, we investigated the effects of UDCA on insulin response by analyzing intracellular ROS and the activation of the PI3K/Akt signaling pathway in HepG2 cells treated with palmitate. The level of ROS was quantified using 2',7'-dichlorodihydrofluorescein diacetate (H 2 DCFDA), and the activation of the PI3K/Akt signaling pathway was determined by Western blotting assay using appropriate antibodies. The intracellular ROS levels were increased by palmitate but were reduced by treatment with UDCA and insulin. Furthermore, insulin significantly stimulated the phosphorylation of Akt. When the cells were pre-treated with palmitate, insulin-induced Akt-phosphorylation was markedly inhibited. However, when the cells were treated with palmitate and UDCA, the effects of insulin were partially restored. UDCA may have protective effects against palmitate-induced decreases in responsiveness to insulin.

Myoinositol combined with alpha-lipoic acid may improve the clinical and endocrine features of polycystic ovary syndrome through an insulin-independent action.

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De Cicco, Simona; Immediata, Valentina; Romualdi, Daniela; Policola, Caterina; Tropea, Anna; Di Florio, Christian; Tagliaferri, Valeria; Scarinci, Elisa; Della Casa, Silvia; Lanzone, Antonio; Apa, Rosanna

2017-09-01

The aim of our study was to investigate the effects of a combined treatment with alpha-lipoic acid (ALA) and myoinositol (MYO) on clinical, endocrine and metabolic features of women affected by polycystic ovary syndrome (PCOS). In this pilot cohort study, forty women with PCOS were enrolled and clinical, hormonal and metabolic parameters were evaluated before and after a six-months combined treatment with ALA and MYO daily. Studied patients experienced a significant increase in the number of cycles in six months (p < 0.01). The free androgen index (FAI), the mean androstenedione and DHEAS levels significantly decreased after treatment (p < 0.05). Mean SHBG levels significantly raised (p < 0.01). A significant improvement in mean Ferriman-Gallwey (F-G) score (p < 0.01) and a significant reduction of BMI (p < 0.01) were also observed. A significant reduction of AMH levels, ovarian volume and total antral follicular count were observed in our studied women (p< 0.05). No significant changes occurred in gluco-insulinaemic and lipid parameters after treatment. The combined treatment of ALA and MYO is able to restore the menstrual pattern and to improve the hormonal milieu of PCOS women, even in the absence of apparent changes in insulin metabolism.

Mangiferin ameliorates insulin resistance by inhibiting inflammation and regulatiing adipokine expression in adipocytes under hypoxic condition.

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Yang, Chao-Qiang; Xu, Jing-Hua; Yan, Dan-Dan; Liu, Bao-Lin; Liu, Kang; Huang, Fang

2017-09-01

Adipose tissue hypoxia has been recognized as the initiation of insulin resistance syndromes. The aim of the present study was to investigate the effects of mangiferin on the insulin signaling pathway and explore whether mangiferin could ameliorate insulin resistance caused by hypoxia in adipose tissue. Differentiated 3T3-L1 adipocytes were incubated under normal and hypoxic conditions, respectively. Protein expressions were analyzed by Western blotting. Inflammatory cytokines and HIF-1-dependent genes were tested by ELISA and q-PCR, respectively. The glucose uptake was detected by fluorescence microscopy. HIF-1α was abundantly expressed during 8 h of hypoxic incubation. Inflammatory reaction was activated by up-regulated NF-κB phosphorylation and released cytokines like IL-6 and TNF-α. Glucose uptake was inhibited and insulin signaling pathway was damaged as well. Mangiferin substantially inhibited the expression of HIF-1α. Lactate acid and lipolysis, products released by glycometabolism and lipolysis, were also inhibited. The expression of inflammatory cytokines was significantly reduced and the damaged insulin signaling pathway was restored to proper functional level. The glucose uptake of hypoxic adipocytes was promoted and the dysfunction of adipocytes was relieved. These results showed that mangiferin could not only improve the damaged insulin signaling pathway in hypoxic adipocytes, but also ameliorate inflammatory reaction and insulin resistance caused by hypoxia. Copyright © 2017 China Pharmaceutical University. Published by Elsevier B.V. All rights reserved.

Kaempferol alleviates insulin resistance via hepatic IKK/NF-κB signal in type 2 diabetic rats.

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Luo, Cheng; Yang, Hui; Tang, Chengyong; Yao, Gaoqiong; Kong, Lingxi; He, Haixia; Zhou, Yuanda

2015-09-01

Recent studies show that inflammation underlies the metabolic disorders of insulin resistance and type 2 diabetes mellitus. Since kaempferol, a naturally occurring flavonoid, has been described to have potent anti-inflammatory properties, we investigated whether kaempferol could ameliorate insulin resistance through inhibiting inflammatory responses. The model of diabetic rat was induced by 6-week high-fat diet plus streptozotocin. Animals were orally treated with kaempferol (50 or 150 mg/kg) and aspirin (100mg/kg) for 10 weeks. The results showed that kaempferol ameliorated blood lipids and insulin in an dose-dependent manner. Kaempferol effectively restored insulin resistance induced alteration of glucose disposal by using an insulin tolerance test and the euglycemic-hyperinsulinemic clamp method. Western blotting results showed that KPF inhibited the phosphorylation of insulin receptor substrate-1 (IRS-1), IkB kinase α (IKKα) and IkB kinase β (IKKβ). These effects were accompanied with reduction in nucleic and cytosol levels of nuclear factor kappa-β (NF-κB), and further tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) levels. Aspirin had similar effects. These results provide in vivo evidence that kaempferol-mediated down-regulation of IKK and subsequent inhibition of NF-κB pathway activation may be associated with the reduction of hepatic inflammatory lesions, which is contributing to the improvement of insulin signaling defect in diabetes. Copyright © 2015 Elsevier B.V. All rights reserved.

Comparison between basal insulin glargine and NPH insulin in patients with diabetes type 1 on conventional intensive insulin therapy

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Pešić Milica

2007-01-01

Full Text Available Background/Aim. Insulin glargine is a long-acting insulin analog that mimics normal basal insulin secretion without pronounced peaks. The aim of this study was to compare insulin glargine with isophane insulin (NPH insulin for basal insulin supply in patients with type 1 diabetes. Methods. A total of 48 type 1 diabetics on long term conventional intensive insulin therapy (IIT were randomized to three different regimens of basal insulin substitution: 1. continuation of NPH insulin once daily at bedtime with more intensive selfmonitoring (n = 15; 2. NPH insulin twice daily (n = 15; 3. insulin glargine once daily (n = 18. Meal time insulin aspart was continued in all groups. Results. Fasting blood glucose (FBG was lower in the glargine group (7.30±0.98 mmol/l than in the twice daily NPH group (7.47±1.06 mmol/l, but without significant difference. FBG was significantly higher in the once daily NPH group (8.44±0.85 mmol/l; p < 0.05. HbA1c after 3 months did not change in the once daily NPH group, but decreased in the glargine group (from 7.72±0.86% to 6.87±0.50%, as well as in the twice daily NPH group (from 7.80±0.83% to 7.01±0.63%. Total daily insulin doses were similar in all groups but only in the glargine group there was an increase of basal and decrease of meal related insulin doses. The frequency of mild hypoglycemia was significantly lower in the glargine group (6.56±2.09 than in both NPH groups (9.0±1.65 in twice daily NPH group and 8.13±1.30 in other NPH group (episodes/patients-month, p < 0.05. Conclusion. Basal insulin supplementation in type 1 diabetes mellitus with either twice daily NPH insulin or glargine can result in similar glycemic control when combined with meal time insulin aspart. However, with glargine regimen FBG, HbA1c and frequency of hypoglycemic event are lower. These facts contribute to better patients satisfaction with insulin glargine versus NPH insulin in IIT in type 1 diabetics.

Insulin signaling misregulation underlies circadian and cognitive deficits in a Drosophila fragile X model.

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Monyak, R E; Emerson, D; Schoenfeld, B P; Zheng, X; Chambers, D B; Rosenfelt, C; Langer, S; Hinchey, P; Choi, C H; McDonald, T V; Bolduc, F V; Sehgal, A; McBride, S M J; Jongens, T A

2017-08-01

Fragile X syndrome (FXS) is an undertreated neurodevelopmental disorder characterized by low intelligence quotent and a wide range of other symptoms including disordered sleep and autism. Although FXS is the most prevalent inherited cause of intellectual disability, its mechanistic underpinnings are not well understood. Using Drosophila as a model of FXS, we showed that select expression of dfmr1 in the insulin-producing cells (IPCs) of the brain was sufficient to restore normal circadian behavior and to rescue the memory deficits in the fragile X mutant fly. Examination of the insulin signaling (IS) pathway revealed elevated levels of Drosophila insulin-like peptide 2 (Dilp2) in the IPCs and elevated IS in the dfmr1 mutant brain. Consistent with a causal role for elevated IS in dfmr1 mutant phenotypes, the expression of dfmr1 specifically in the IPCs reduced IS, and genetic reduction of the insulin pathway also led to amelioration of circadian and memory defects. Furthermore, we showed that treatment with the FDA-approved drug metformin also rescued memory. Finally, we showed that reduction of IS is required at different time points to rescue circadian behavior and memory. Our results indicate that insulin misregulation underlies the circadian and cognitive phenotypes displayed by the Drosophila fragile X model, and thus reveal a metabolic pathway that can be targeted by new and already approved drugs to treat fragile X patients.

Liver-derived systemic factors drive β-cell hyperplasia in insulin resistant states

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El Ouaamari, Abdelfattah; Kawamori, Dan; Dirice, Ercument; Liew, Chong Wee; Shadrach, Jennifer L.; Hu, Jiang; Katsuta, Hitoshi; Hollister-Lock, Jennifer; Qian, Weijun; Wagers, Amy J.; Kulkarni, Rohit N.

2013-02-21

Integrative organ cross-talk regulates key aspects of energy homeostasis and its dysregulation may underlie metabolic disorders such as obesity and diabetes. To test the hypothesis that cross-talk between the liver and pancreatic islets modulates β-cell growth in response to insulin resistance, we used the Liver-specific Insulin Receptor Knockout (LIRKO) mouse, a unique model that exhibits dramatic islet hyperplasia. Using complementary in vivo parabiosis and transplantation assays, and in vitro islet culture approaches, we demonstrate that humoral, non-neural, non-cell autonomous factor(s) induce β-cell proliferation in LIRKO mice. Furthermore, we report that a hepatocyte-derived factor(s) stimulates mouse and human β-cell proliferation in ex vivo assays, independent of ambient glucose and insulin levels. These data implicate the liver as a critical source of β-cell growth factors in insulin resistant states.

A model of insulin fibrils derived from the x-ray crystal structure of a monomeric insulin (despentapeptide insulin).

Science.gov (United States)

Brange, J; Dodson, G G; Edwards, D J; Holden, P H; Whittingham, J L

1997-04-01

The crystal structure of despentapeptide insulin, a monomeric insulin, has been refined at 1.3 A spacing and subsequently used to predict and model the organization in the insulin fibril. The model makes use of the contacts in the densely packed despentapeptide insulin crystal, and takes into account other experimental evidence, including binding studies with Congo red. The dimensions of this model fibril correspond well with those measured experimentally, and the monomer-monomer contacts within the fibril are in accordance with the known physical chemistry of insulin fibrils. Using this model, it may be possible to predict mutations in insulin that might alleviate problems associated with fibril formation during insulin therapy.

High-Fat Diet Augments VPAC1 Receptor-Mediated PACAP Action on the Liver, Inducing LAR Expression and Insulin Resistance

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Masanori Nakata

2016-01-01

Full Text Available Pituitary adenylate cyclase-activating polypeptide (PACAP acts on multiple processes of glucose and energy metabolism. PACAP potentiates insulin action in adipocytes and insulin release from pancreatic β-cells, thereby enhancing glucose tolerance. Contrary to these effects at organ levels, PACAP null mice exhibit hypersensitivity to insulin. However, this apparent discrepancy remains to be solved. We aimed to clarify the mechanism underlying the antidiabetic phenotype of PACAP null mice. Feeding with high-fat diet (HFD impaired insulin sensitivity and glucose tolerance in wild type mice, whereas these changes were prevented in PACAP null mice. HFD also impaired insulin-induced Akt phosphorylation in the liver in wild type mice, but not in PACAP null mice. Using GeneFishing method, HFD increased the leukocyte common antigen-related (LAR protein tyrosine phosphatase in the liver in wild type mice. Silencing of LAR restored the insulin signaling in the liver of HFD mice. Moreover, the increased LAR expression by HFD was prevented in PACAP null mice. HFD increased the expression of VPAC1 receptor (VPAC1-R, one of three PACAP receptors, in the liver of wild type mice. These data indicate that PACAP-VPAC1-R signaling induces LAR expression and insulin resistance in the liver of HFD mice. Antagonism of VPAC1-R may prevent progression of HFD-induced insulin resistance in the liver, providing a novel antidiabetic strategy.

Metformin Ameliorates Dysfunctional Traits of Glibenclamide- and Glucose-Induced Insulin Secretion by Suppression of Imposed Overactivity of the Islet Nitric Oxide Synthase-NO System.

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Ingmar Lundquist

Full Text Available Metformin lowers diabetic blood glucose primarily by reducing hepatic gluconeogenesis and increasing peripheral glucose uptake. However, possible effects by metformin on beta-cell function are incompletely understood. We speculated that metformin might positively influence insulin secretion through impacting the beta-cell nitric oxide synthase (NOS-NO system, a negative modulator of glucose-stimulated insulin release. In short-time incubations with isolated murine islets either glibenclamide or high glucose augmented insulin release associated with increased NO production from both neural and inducible NOS. Metformin addition suppressed the augmented NO generation coinciding with amplified insulin release. Islet culturing with glibenclamide or high glucose revealed pronounced fluorescence of inducible NOS in the beta-cells being abolished by metformin co-culturing. These findings were reflected in medium nitrite-nitrate levels. A glucose challenge following islet culturing with glibenclamide or high glucose revealed markedly impaired insulin response. Metformin co-culturing restored this response. Culturing murine islets and human islets from controls and type 2 diabetics with high glucose or high glucose + glibenclamide induced a pronounced decrease of cell viability being remarkably restored by metformin co-culturing. We show here, that imposed overactivity of the beta-cell NOS-NO system by glibenclamide or high glucose leads to insulin secretory dysfunction and reduced cell viability and also, importantly, that these effects are relieved by metformin inhibiting beta-cell NO overproduction from both neural and inducible NOS thus ameliorating a concealed negative influence by NO induced by sulfonylurea treatment and/or high glucose levels. This double-edged effect of glibenclamide on the beta-cellsuggests sulfonylurea monotherapy in type 2 diabetes being avoided.

Tau hyperphosphorylation induces oligomeric insulin accumulation and insulin resistance in neurons.

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Rodriguez-Rodriguez, Patricia; Sandebring-Matton, Anna; Merino-Serrais, Paula; Parrado-Fernandez, Cristina; Rabano, Alberto; Winblad, Bengt; Ávila, Jesús; Ferrer, Isidre; Cedazo-Minguez, Angel

2017-12-01

Insulin signalling deficiencies and insulin resistance have been directly linked to the progression of neurodegenerative disorders like Alzheimer's disease. However, to date little is known about the underlying molecular mechanisms or insulin state and distribution in the brain under pathological conditions. Here, we report that insulin is accumulated and retained as oligomers in hyperphosphorylated tau-bearing neurons in Alzheimer's disease and in several of the most prevalent human tauopathies. The intraneuronal accumulation of insulin is directly dependent on tau hyperphosphorylation, and follows the tauopathy progression. Furthermore, cells accumulating insulin show signs of insulin resistance and decreased insulin receptor levels. These results suggest that insulin retention in hyperphosphorylated tau-bearing neurons is a causative factor for the insulin resistance observed in tauopathies, and describe a novel neuropathological concept with important therapeutic implications. © The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Statin Intake Is Associated With Decreased Insulin Sensitivity During Cardiac Surgery

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Sato, Hiroaki; Carvalho, George; Sato, Tamaki; Hatzakorzian, Roupen; Lattermann, Ralph; Codere-Maruyama, Takumi; Matsukawa, Takashi; Schricker, Thomas

2012-01-01

OBJECTIVE Surgical trauma impairs intraoperative insulin sensitivity and is associated with postoperative adverse events. Recently, preprocedural statin therapy is recommended for patients with coronary artery disease. However, statin therapy is reported to increase insulin resistance and the risk of new-onset diabetes. Thus, we investigated the association between preoperative statin therapy and intraoperative insulin sensitivity in nondiabetic, dyslipidemic patients undergoing coronary artery bypass grafting. RESEARCH DESIGN AND METHODS In this prospective, nonrandomized trial, patients taking lipophilic statins were assigned to the statin group and hypercholesterolemic patients not receiving any statins were allocated to the control group. Insulin sensitivity was assessed by the hyperinsulinemic-normoglycemic clamp technique during surgery. The mean, SD of blood glucose, and the coefficient of variation (CV) after surgery were calculated for each patient. The association between statin use and intraoperative insulin sensitivity was tested by multiple regression analysis. RESULTS We studied 120 patients. In both groups, insulin sensitivity gradually decreased during surgery with values being on average ∼20% lower in the statin than in the control group. In the statin group, the mean blood glucose in the intensive care unit was higher than in the control group (153 ± 20 vs. 140 ± 20 mg/dL; P statin group (SD, P statin use was independently associated with intraoperative insulin sensitivity (β = −0.16; P = 0.03). CONCLUSIONS Preoperative use of lipophilic statins is associated with increased insulin resistance during cardiac surgery in nondiabetic, dyslipidemic patients. PMID:22829524

Insulin resistance in polycystic ovary syndrome

OpenAIRE

Hutchison, Samantha Kate

2017-01-01

Polycystic ovary syndrome (PCOS) affects 8-18% of women, presenting a major public health and economic burden. Women with PCOS have insulin resistance (IR) independent of obesity. IR has an integral aetiological role in the reproductive and metabolic consequences of PCOS including obesity, type 2 diabetes (diabetes) and cardiovascular risk factors. Excess weight exacerbates IR and increases PCOS severity. PCOS combined with obesity presents a useful model to study IR before confounding hyperg...

Exenatide augments first- and second-phase insulin secretion in response to intravenous glucose in subjects with type 2 diabetes

DEFF Research Database (Denmark)

Fehse, Frauke; Trautmann, Michael; Holst, Jens Juul

2005-01-01

CONTEXT: First-phase insulin secretion (within 10 min after a sudden rise in plasma glucose) is reduced in type 2 diabetes mellitus (DM2). The incretin mimetic exenatide has glucoregulatory activities in DM2, including glucose-dependent enhancement of insulin secretion. OBJECTIVE: The objective...... of the study was to determine whether exenatide can restore a more normal pattern of insulin secretion in subjects with DM2. DESIGN: Fasted subjects received iv insulin infusion to reach plasma glucose 4.4-5.6 mmol/liter. Subjects received iv exenatide (DM2) or saline (DM2 and healthy volunteers), followed...... by iv glucose challenge. PATIENTS: Thirteen evaluable DM2 subjects were included in the study: 11 males, two females; age, 56 +/- 7 yr; body mass index, 31.7 +/- 2.4 kg/m2; hemoglobin A1c, 6.6 +/- 0.7% (mean +/- sd) treated with diet/exercise (n = 1), metformin (n = 10), or acarbose (n = 2). Controls...

Massive weight loss restores 24-hour growth hormone release profiles and serum insulin-like growth factor-I levels in obese subjects

DEFF Research Database (Denmark)

Rasmussen, M H; Hvidberg, A; Juul, A

1995-01-01

levels of insulin-like growth factor-I (IGF-I), IGF-binding protein-3 (IGFBP-3), as well as insulin in obese subjects before and after a massive weight loss. We studied 18 obese subjects (age, 26 +/- 1 yr; body mass index, 40.9 +/- 1.1 kg/m2); 18 normal age-, and sex-matched control subjects; and 9...... using anthropometric measurements and dual energy x-ray absorptiometry scanning (DXA). In the obese subjects, 24-h spontaneous GH release profiles and the GH responses to insulin-induced hypoglycemia and L-arginine as well as basal IGF-I levels and the IGF-I/IGFBP-3 molar ratio were decreased, whereas...

Fractional filling with the microdepot technique as an alternative to bolus hyaluronic acid injections in facial volume restoration.

Science.gov (United States)

Lim, Adrian C; Lowe, Patricia M

2011-05-01

For volume restoration of the face, hyaluronic acid is conventionally injected through long, large-bore, 18-gauge needles because of the higher viscosity subtypes required. These hyaluronic acids are either more highly cross-linked or larger in particle size than the less-viscous subtypes. The microdepot injection technique involves using the 31-gauge BD insulin syringe (Becton-Dickinson, North Ryde, NSW Australia) to deposit small amounts of filler (0.05-0.1 mL) throughout the area of volume loss. The procedure is extremely well tolerated, requiring only topical and ice anaesthesia. Using this method, volume restoration can be achieved naturally and progressively over a period of time. Fractional filling every 3-4 months is continued until the desired level of volume correction is attained. Patients undergoing fractional filling followed over a 12-month period did not indicate any observable compromise in filler longevity, even when highly viscous hyaluronic acid fillers were injected through small-bore, 31-gauge insulin syringes. © 2011 The Authors. Australasian Journal of Dermatology © 2011 The Australasian College of Dermatologists.

Crown color match of implant-supported zirconia and Porcelain-Fused-to-Metal restorations:

DEFF Research Database (Denmark)

Peng, Min; Fei, Wei; Hosseini, Mandana

2014-01-01

ShadeTM, Micro Dental) in CIEL¿a¿b¿ coordinates. Subjective crown color match scores were evaluated. Independent sample t test of SPSS17.0 was used to compare the difference between zirconia restoration and PFM restoration. Spearman correlation was used to analyze the relationship between the spectrophotometric...

Anti-insulin antibody test

Science.gov (United States)

Insulin antibodies - serum; Insulin Ab test; Insulin resistance - insulin antibodies; Diabetes - insulin antibodies ... Normally, there are no antibodies against insulin in your blood. ... different laboratories. Some labs use different measurements or ...

Cerebral insulin, insulin signaling pathway, and brain angiogenesis.

Science.gov (United States)

Zeng, Yi; Zhang, Le; Hu, Zhiping

2016-01-01

Insulin performs unique non-metabolic functions within the brain. Broadly speaking, two major areas of these functions are those related to brain endothelial cells and the blood-brain barrier (BBB) function, and those related to behavioral effects, like cognition in disease states (Alzheimer's disease, AD) and in health. Recent studies showed that both these functions are associated with brain angiogenesis. These findings raise interesting questions such as how they are linked to each other and whether modifying brain angiogenesis by targeting certain insulin signaling pathways could be an effective strategy to treat dementia as in AD, or even to help secure healthy longevity. The two canonical downstream pathways involved in mediating the insulin signaling pathway, the phosphoinositide-3 kinase (PI3K), and mitogen-activated protein kinase (MAPK) cascades, in the brain are supposed to be similar to those in the periphery. PI3K and MAPK pathways play important roles in angiogenesis. Both are involved in stimulating hypoxia inducible factor (HIF) in angiogenesis and could be activated by the insulin signaling pathway. This suggests that PI3K and MAPK pathways might act as cross-talk between the insulin signaling pathway and the angiogenesis pathway in brain. But the cerebral insulin, insulin signaling pathway, and the detailed mechanism in the connection of insulin signaling pathway, brain angiogenesis pathway, and healthy aging or dementias are still mostly not clear and need further studies.

Insulin resistance in obesity can be reliably identified from fasting plasma insulin.

Science.gov (United States)

ter Horst, K W; Gilijamse, P W; Koopman, K E; de Weijer, B A; Brands, M; Kootte, R S; Romijn, J A; Ackermans, M T; Nieuwdorp, M; Soeters, M R; Serlie, M J

2015-12-01

Insulin resistance is the major contributor to cardiometabolic complications of obesity. We aimed to (1) establish cutoff points for insulin resistance from euglycemic hyperinsulinemic clamps (EHCs), (2) identify insulin-resistant obese subjects and (3) predict insulin resistance from routinely measured variables. We assembled data from non-obese (n=112) and obese (n=100) men who underwent two-step EHCs using [6,6-(2)H2]glucose as tracer (insulin infusion dose 20 and 60 mU m(-2) min(-1), respectively). Reference ranges for hepatic and peripheral insulin sensitivity were calculated from healthy non-obese men. Based on these reference values, obese men with preserved insulin sensitivity or insulin resistance were identified. Cutoff points for insulin-mediated suppression of endogenous glucose production (EGP) and insulin-stimulated glucose disappearance rate (Rd) were 46.5% and 37.3 μmol kg(-)(1) min(-)(1), respectively. Most obese men (78%) had EGP suppression within the reference range, whereas only 12% of obese men had Rd within the reference range. Obese men with Rd obese men in age, body mass index (BMI), body composition, fasting glucose or cholesterol, but did have higher fasting insulin (110±49 vs 63±29 pmol l(-1), Pobese men could be identified with good sensitivity (80%) and specificity (75%) from fasting insulin >74 pmol l(-1). Most obese men have hepatic insulin sensitivity within the range of non-obese controls, but below-normal peripheral insulin sensitivity, that is, insulin resistance. Fasting insulin (>74 pmol l(-1) with current insulin immunoassay) may be used for identification of insulin-resistant (or metabolically unhealthy) obese men in research and clinical settings.

Leptin rapidly improves glucose homeostasis in obese mice by increasing hypothalamic insulin sensitivity.

Science.gov (United States)

Koch, Christiane; Augustine, Rachael A; Steger, Juliane; Ganjam, Goutham K; Benzler, Jonas; Pracht, Corinna; Lowe, Chrishanthi; Schwartz, Michael W; Shepherd, Peter R; Anderson, Greg M; Grattan, David R; Tups, Alexander

2010-12-01

Obesity is associated with resistance to the actions of both leptin and insulin via mechanisms that remain incompletely understood. To investigate whether leptin resistance per se contributes to insulin resistance and impaired glucose homeostasis, we investigated the effect of acute leptin administration on glucose homeostasis in normal as well as leptin- or leptin receptor-deficient mice. In hyperglycemic, leptin-deficient Lep(ob/ob) mice, leptin acutely and potently improved glucose metabolism, before any change of body fat mass, via a mechanism involving the p110α and β isoforms of phosphatidylinositol-3-kinase (PI3K). Unlike insulin, however, the anti-diabetic effect of leptin occurred independently of phospho-AKT, a major downstream target of PI3K, and instead involved enhanced sensitivity of the hypothalamus to insulin action upstream of PI3K, through modulation of IRS1 (insulin receptor substrate 1) phosphorylation. These data suggest that leptin resistance, as occurs in obesity, reduces the hypothalamic response to insulin and thereby impairs peripheral glucose homeostasis, contributing to the development of type 2 diabetes.

Science Roles and Interactions in Adaptive Management of Large River Restoration Projects, Midwest United States

Science.gov (United States)

Jacobson, R. B.; Galat, D. L.; Smith, C. B.

2010-12-01

Most large-river restoration projects include formal or informal implementations of adaptive management strategies which acknowledge uncertainty and use scientific inquiry to learn and refine management options. Although the central role of science in reducing uncertainty is acknowledged in such projects, specific roles and interactions can vary widely, including how science relates to decision-making within the governance of these projects. Our objective is to present some structured generalizations about science roles and interactions as developed from the authors’ experiences in adaptive management of large river restoration in the Midwest United States. Scientific information may be introduced into decision making by scientists acting in any of the three roles common to adaptive management -- action agency representative, stakeholder, or science provider. We have observed that confusion and gridlock can arise when it is unclear if a scientist is acting as an advocate for a stakeholder or management position, or instead as an independent, “honest broker” of science. Although both advocacy and independence are proper and expected in public decision making, it is useful when scientists unambiguously identify their role. While complete scientific independence may be illusory, transparency and peer review can promote the ideal. Transparency comes from setting clear directions and objectives at the decision-making level and defining at the outset how learning will help assess progress and inform decisions. Independent peer reviews of proposals, study plans, and publications serve as a powerful tool to advance scientific independence, even if funding sources present a potential conflict of interest. Selection of experts for scientific advice and review often requires consideration of the balance between benefits of the “outside” expert (independent, knowledgeable but with little specific understanding of the river system), compared to those provided by the �

Role of altered insulin signaling pathways in the pathogenesis of podocyte malfunction and microalbuminuria

Science.gov (United States)

Jauregui, Alexandra; Mintz, Daniel H; Mundel, Peter; Fornoni, Alessia

2010-01-01

Purpose of review In diabetic nephropathy (DN), insulin resistance and hyperinsulinemia correlate with the development of albuminuria. The possibility that altered insulin signaling in glomerular cells and particularly podocytes contributes to the development of DN will be discussed. Recent findings While normal podocytes uptake glucose in response to insulin, diabetic podocytes become insulin resistant in experimental DN prior to the development of significant albuminuria. Both clinical and experimental data suggest that insulin sensitizers may be renoprotective independently of their systemic effects on the metabolic control of diabetes. Summary We will review the clinical and experimental evidence that altered insulin signaling correlates with the development of DN in both type 1 and type 2 diabetes, and that insulin sensitizers may be superior to other hypoglycemic agents in the prevention of DN. We will then review potential mechanisms by which altered podocyte insulin signaling may contribute to the development of DN. Understanding the role of podocyte in glucose metabolism is important because it may lead to the discovery of novel pathogenetic mechanisms of DN, it may affect current strategies for prevention and treatment of DN, and it may allow for the identification of novel therapeutic targets. PMID:19724224

Swimming training induces liver adaptations to oxidative stress and insulin sensitivity in rats submitted to high-fat diet.

Science.gov (United States)

Zacarias, Aline Cruz; Barbosa, Maria Andrea; Guerra-Sá, Renata; De Castro, Uberdan Guilherme Mendes; Bezerra, Frank Silva; de Lima, Wanderson Geraldo; Cardoso, Leonardo M; Santos, Robson Augusto Souza Dos; Campagnole-Santos, Maria José; Alzamora, Andréia Carvalho

2017-11-01

Oxidative stress, physical inactivity and high-fat (FAT) diets are associated with hepatic disorders such as metabolic syndrome (MS). The therapeutic effects of physical training (PT) were evaluated in rats with MS induced by FAT diet for 13 weeks, on oxidative stress and insulin signaling in the liver, during the last 6 weeks. FAT-sedentary (SED) rats increased body mass, retroperitoneal fat, mean arterial pressure (MAP) and heart rate (HR), and total cholesterol, serum alanine aminotransferase, glucose and insulin. Livers of FAT-SED rats increased superoxide dismutase activity, thiobarbituric acid-reactive substances, protein carbonyl and oxidized glutathione (GSSG); and decreased catalase activity, reduced glutathione/GSSG ratio, and the mRNA expression of insulin receptor substrate 1 (IRS-1) and serine/threonine kinase 2. FAT-PT rats improved in fitness and reduced their body mass, retroperitoneal fat, and glucose, insulin, total cholesterol, MAP and HR; and their livers increased superoxide dismutase and catalase activities, the reduced glutathione/GSSG ratio and the expression of peroxisome proliferator-activated receptor gamma and insulin receptor compared to FAT-SED rats. These findings indicated adaptive responses to PT by restoring the oxidative balance and insulin signaling in the liver and certain biometric and biochemical parameters as well as MAP in MS rats.

Absence of down-regulation of the insulin receptor by insulin. A possible mechanism of insulin resistance in the rat.

OpenAIRE

Walker, A P; Flint, D J

1983-01-01

Insulin resistance occurs in rat adipocytes during pregnancy and lactation despite increased or normal insulin binding respectively; this suggests that a post-receptor defect exists. The possibility has been examined that, although insulin binding occurs normally, internalization of insulin or its receptor may be impaired in these states. Insulin produced a dose-dependent reduction in the number of insulin receptors on adipocytes from virgin rats maintained in culture medium, probably due to ...

Regulation of the pituitary tumor transforming gene by insulin-like-growth factor-I and insulin differs between malignant and non-neoplastic astrocytes

International Nuclear Information System (INIS)

Chamaon, Kathrin; Kirches, Elmar; Kanakis, Dimitrios; Braeuninger, Stefan; Dietzmann, Knut; Mawrin, Christian

2005-01-01

The reasons for overexpression of the oncogene pituitary tumor transforming gene (PTTG) in tumors are still not fully understood. A possible influence of the insulin-like growth factor I (Igf-I) may be of interest, since enhanced Igf-I signalling was reported in various human tumors. We examined the influence of Igf-I and insulin on PTTG expression in human astrocytoma cells in comparison to proliferating non-neoplastic rat embryonal astrocytes. PTTG mRNA expression and protein levels were increased in malignant astrocytes treated with Igf-I or insulin, whereas in rat embryonic astrocytes PTTG expression and protein levels increased only when cells were exposed to Igf-I. Enhanced transcription did not occur after treatment with inhibitors of phosphoinositol-3-kinase (PI3K) and mitogen-activated protein kinase (MAPK), blocking the two basic signalling pathways of Igf-I and insulin. In addition to this transcriptional regulation, both kinases directly bind to PTTG, suggesting a second regulatory route by phosphorylation. However, the interaction of endogenous PTTG with MAPK and PI3K, as well as PTTG phosphorylation were independent from Igf-I or insulin. The latter results were also found in human testis, which contains high PTTG levels as well as in nonneoplastic astrocytes. This suggest, that PI3K and MAPK signalling is involved in PTTG regulation not only in malignant astrocytomas but also in non-tumorous cells

Peripheral Blood Transcriptomic Signatures of Fasting Glucose and Insulin Concentrations

Science.gov (United States)

Chen, Brian H.; Hivert, Marie-France; Peters, Marjolein J.; Pilling, Luke C.; Hogan, John D.; Pham, Lisa M.; Harries, Lorna W.; Fox, Caroline S.; Bandinelli, Stefania; Dehghan, Abbas; Hernandez, Dena G.; Hofman, Albert; Hong, Jaeyoung; Joehanes, Roby; Johnson, Andrew D.; Munson, Peter J.; Rybin, Denis V.; Singleton, Andrew B.; Uitterlinden, André G.; Ying, Saixia; Melzer, David; Levy, Daniel; van Meurs, Joyce B.J.; Ferrucci, Luigi; Florez, Jose C.; Dupuis, Josée

2016-01-01

Genome-wide association studies (GWAS) have successfully identified genetic loci associated with glycemic traits. However, characterizing the functional significance of these loci has proven challenging. We sought to gain insights into the regulation of fasting insulin and fasting glucose through the use of gene expression microarray data from peripheral blood samples of participants without diabetes in the Framingham Heart Study (FHS) (n = 5,056), the Rotterdam Study (RS) (n = 723), and the InCHIANTI Study (Invecchiare in Chianti) (n = 595). Using a false discovery rate q fasting glucose and 433 transcripts associated with fasting insulin levels after adjusting for age, sex, technical covariates, and complete blood cell counts. Among the findings, circulating IGF2BP2 transcript levels were positively associated with fasting insulin in both the FHS and RS. Using 1000 Genomes–imputed genotype data, we identified 47,587 cis-expression quantitative trait loci (eQTL) and 6,695 trans-eQTL associated with the 433 significant insulin-associated transcripts. Of note, we identified a trans-eQTL (rs592423), where the A allele was associated with higher IGF2BP2 levels and with fasting insulin in an independent genetic meta-analysis comprised of 50,823 individuals. We conclude that integration of genomic and transcriptomic data implicate circulating IGF2BP2 mRNA levels associated with glucose and insulin homeostasis. PMID:27625022

Weight-loss changes PPAR expression, reduces atherosclerosis and improves cardiovascular function in obese insulin-resistant mice

Energy Technology Data Exchange (ETDEWEB)

Verreth, Wim; Verhamme, Peter; Pelat, Michael; Ganame, Javier; Bielicki, John K.; Mertens, Ann; Quarck, Rozenn; Benhabiles, Nora; Marguerie, Gerard; Mackness, Bharti; Mackness, Mike; Ninio, Ewa; Herregods, Marie-Christine; Balligand, Jean-Luc; Holvoet, Paul

2003-09-01

Weight-loss in obese insulin-resistant, but not in insulin-sensitive, persons reduces CHD risk. It is not known to what extent changes in the adipose gene expression profile are important for reducing CHD risk. We studied the effect of diet restriction-induced weight-loss on gene expression in adipose tissue, atherosclerosis and cardiovascular function in mice with combined leptin and LDL-receptor deficiency. Obesity, hypertriglyceridemia and insulin-resistance are associated with hypertension, impaired left ventricle function and accelerated atherosclerosis in those mice. Diet restriction during 12 weeks caused a 45% weight-loss and changes in the gene expression in adipose tissue of PPARa and PPAR? and of key genes regulating glucose transport and insulin sensitivity, lipid metabolism, oxidative stress and inflammation, most of which are under the transcriptional control of PPARs. These changes were associated with increased insulin-sensitivity, decreased hypertriglyceridemia, reduced mean 24-hour blood pressure and heart rate, restored circadian variations of blood pressure and heart rate, increased ejection fraction, and reduced atherosclerosis. Thus, induction of PPARa and PPAR? in adipose tissue is a key mechanism for reducing atherosclerosis and improving cardiovascular function resulting from weight-loss. Our observations point to the critical role of PPARs in the pathogenesis of cardiovascular features of the metabolic syndrome.

Clinical use of the co-formulation of insulin degludec and insulin aspart

DEFF Research Database (Denmark)

Kumar, A; Awata, T; Bain, S C

2016-01-01

(HbA1c ) to current modern insulins, but with lower risk of nocturnal hypoglycaemia. In prior insulin users, glycaemic control was achieved with lower or equal insulin doses vs. other basal+meal-time or premix insulin regimens. In insulin-naïve patients with T2DM, IDegAsp can be started once or twice...... a simpler insulin regimen than other available basal-bolus or premix-based insulin regimens, with stable daytime basal coverage, a lower rate of hypoglycaemia and some flexibility in injection timing compared with premix insulins....

Effects of intranasal insulin on endogenous glucose production in insulin-resistant men.

Science.gov (United States)

Xiao, Changting; Dash, Satya; Stahel, Priska; Lewis, Gary F

2018-03-14

The effects of intranasal insulin on the regulation of endogenous glucose production (EGP) in individuals with insulin resistance were assessed in a single-blind, crossover study. Overweight or obese insulin-resistant men (n = 7; body mass index 35.4 ± 4.4 kg/m 2 , homeostatic model assessment of insulin resistance 5.6 ± 1.6) received intranasal spray of either 40 IU insulin lispro or placebo in 2 randomized visits. Acute systemic spillover of intranasal insulin into the circulation was matched with a 30-minute intravenous infusion of insulin lispro in the nasal placebo arm. EGP was assessed under conditions of a pancreatic clamp with a primed, constant infusion of glucose tracer. Under these experimental conditions, compared with placebo, intranasal administration of insulin did not significantly affect plasma glucose concentrations, EGP or glucose disposal in overweight/obese, insulin-resistant men, in contrast to our previous study, in which an equivalent dose of intranasal insulin significantly suppressed EGP in lean, insulin-sensitive men. Insulin resistance is probably associated with impairment in centrally mediated insulin suppression of EGP. © 2018 John Wiley & Sons Ltd.

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

DEFF Research Database (Denmark)

Højlund, Kurt

2014-01-01

. These metabolic disorders are all characterized by reduced plasma adiponectin and insulin resistance in peripheral tissues. Quantitatively skeletal muscle is the major site of insulin resistance. Both low plasma adiponectin and insulin resistance contribute to an increased risk of type 2 diabetes...... described a novel syndrome characterized by postprandial hyperinsulinemic hypoglycemia and insulin resistance. This syndrome is caused by a mutation in the tyrosine kinase domain of the insulin receptor gene (INSR). We have studied individuals with this mutation as a model of inherited insulin resistance....... Type 2 diabetes, obesity and PCOS are characterized by pronounced defects in the insulin-stimulated glucose uptake, in particular glycogen synthesis and to a lesser extent glucose oxidation, and the ability of insulin to suppress lipid oxidation. In inherited insulin resistance, however, only insulin...

Psychological insulin resistance in type 2 diabetes patients regarding oral antidiabetes treatment, subcutaneous insulin injections, or inhaled insulin.

Science.gov (United States)

Petrak, Frank; Herpertz, Stephan; Stridde, Elmar; Pfützner, Andreas

2013-08-01

"Psychological insulin resistance" (PIR) is an obstacle to insulin treatment in type 2 diabetes, and patients' expectations regarding alternative ways of insulin delivery are poorly understood. PIR and beliefs regarding treatment alternatives were analyzed in patients with type 2 diabetes (n=532; mean glycated hemoglobin, 68±12 mmol/mol [8.34±1.5%]) comparing oral antidiabetes treatment, subcutaneous insulin injections, or inhaled insulin. Questionnaires were used to assess barriers to insulin treatment (BIT), generic and diabetes-specific quality of life (Short Form 36 and Problem Areas in Diabetes, German version), diabetes knowledge, locus of control (Questionnaire for the Assessment of Diabetes-Specific Locus of Control, in German), coping styles (Freiburg Questionnaire of Illness Coping, 15-Items Short Form), self-esteem (Rosenberg Self-Esteem Scale, German version), and mental disorders (Patient Health Questionnaire, German version). Patients discussed treatment optimization options with a physician and were asked to make a choice about future diabetes therapy options in a two-step treatment choice scenario. Step 1 included oral antidiabetes drugs or subcutaneous insulin injection (SCI). Step 2 included an additional treatment alternative of inhaled insulin (INH). Subgroups were analyzed according to their treatment choice. Most patients perceived their own diabetes-related behavior as active, problem-focused, internally controlled, and oriented toward their doctors' recommendations, although their diabetes knowledge was limited. In Step 1, rejection of the recommended insulin was 82%, and in Step 2, it was 57%. Fear of hypoglycemia was the most important barrier to insulin treatment. Patients choosing INH (versus SCI) scored higher regarding fear of injection, expected hardship from insulin therapy, and BIT-Sumscore. The acceptance of insulin is very low in type 2 diabetes patients. The option to inhale insulin increases the acceptability for some but

Osteocalcin improves insulin resistance and inflammation in obese mice: Participation of white adipose tissue and bone.

Science.gov (United States)

Guedes, J A C; Esteves, J V; Morais, M R; Zorn, T M; Furuya, D T

2017-11-26

The discovery of osteocalcin, a protein synthetized by osteoblasts, as a hormone that has positive effects on insulin resistance, contributed to support the concept of bone as an endocrine organ. However, very little is known about the molecular pathways involved in osteocalcin improved-insulin resistance. The present study aimed to investigate the mechanisms of action of osteocalcin on insulin resistance and inflammation in obese mice and 3T3-L1 adipocytes. Lean control, saline-treated obese and uncarboxylated osteocalcin (uOC)-treated obese mice were subjected to insulin tolerance test in vivo. Blood was collect for biochemical/metabolic profile analysis; and, skeletal muscle, white adipose tissue (WAT) and bone were collected for protein (Western blotting) and mRNA (RT-qPCR) analysis. uOC effects on insulin resistance and inflammation were also investigated in 3T3-L1 adipocytes challenged with tumor necrosis factor. Osteocalcin treatment improved in vivo insulin resistance in obese mice. In WAT, osteocalcin had positive effects such as (1) WAT weight reduction; (2) upregulation of glucose transporter (GLUT) 4 protein and its mRNA (Slc2a4); (3) improved insulin-induced AKT phosphorylation; (4) downregulation of several genes involved in inflammation and inflammassome transcriptional machinery, and (5) reduction of the density of macrophage in crown-like structures (histomorphometrical analysis). Notably, in 3T3-L1 adipocytes, osteocalcin restored Slc2a4/GLUT4 content and reduced the expression of inflammatory genes after TNF-a challenge; moreover, osteocalcin treatment increased AKT phosphorylation induced by insulin. Finally, it was observed that in bone, osteocalcin improves insulin resistance by increasing insulin-induced AKT phosphorylation and reducing the expression of genes involved in bone insulin resistance, resulting in increased secretion of uncarboxylated osteocalcin in circulation. We provided some mechanisms of action for osteocalcin in the

Postreceptor defects causing insulin resistance in normoinsulinemic non-insulin-dependent diabetes mellitus

International Nuclear Information System (INIS)

Bolinder, J.; Ostman, J.; Arner, P.

1982-01-01

The mechanisms of the diminished hypoglycemic response to insulin in non-insulin-dependent diabetes mellitus (NIDDM) with normal levels of circulating plasma insulin were investigated. Specific binding of mono- 125 I (Tyr A14)-insulin to isolated adipocytes and effects of insulin (5--10,000 microunits/ml) on glucose oxidation and lipolysis were determined simultaneously in subcutaneous adipose tissue of seven healthy subjects of normal weight and seven untreated NIDDM patients with normal plasma insulin levels. The two groups were matched for age, sex, and body weight. Insulin binding, measured in terms of receptor number and affinity, was normal in NIDDM, the total number of receptors averaging 350,000 per cell. Neither sensitivity nor the maximum antilipolytic effect of insulin was altered in NIDDM patients as compared with control subjects; the insulin concentration producing half the maximum effect (ED50) was 10 microunits/ml. As regards the effect of insulin on glucose oxidation, for the control subjects ED50 was 30 microunits/ml, whereas in NIDDM patients, insulin exerted no stimulatory effect. The results obtained suggest that the effect of insulin on glucose utilization in normoinsulinemic NIDDM may be diminished in spite of normal insulin binding to receptors. The resistance may be due solely to postreceptor defects, and does not involve antilipolysis

Serum Insulin, Glucose, Indices of Insulin Resistance, and Risk of Lung Cancer.

Science.gov (United States)

Argirion, Ilona; Weinstein, Stephanie J; Männistö, Satu; Albanes, Demetrius; Mondul, Alison M

2017-10-01

Background: Although insulin may increase the risk of some cancers, few studies have examined fasting serum insulin and lung cancer risk. Methods: We examined serum insulin, glucose, and indices of insulin resistance [insulin:glucose molar ratio and homeostasis model assessment of insulin resistance (HOMA-IR)] and lung cancer risk using a case-cohort study within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study of Finnish men. A total of 196 cases and 395 subcohort members were included. Insulin and glucose were measured in fasting serum collected 5 to 12 years before diagnosis. Cox proportional hazards models were utilized to estimate the relative risk of lung cancer. Results: The average time between blood collection and lung cancer was 9.6 years. Fasting serum insulin levels were 8.7% higher in subcohort members than cases. After multivariable adjustment, men in the fourth quartile of insulin had a significantly higher risk of lung cancer than those in the first quartile [HR = 2.10; 95% confidence interval (CI), 1.12-3.94]. A similar relationship was seen with HOMA-IR (HR = 1.83; 95% CI, 0.99-3.38). Risk was not strongly associated with glucose or the insulin:glucose molar ratio ( P trend = 0.55 and P trend = 0.27, respectively). Conclusions: Higher fasting serum insulin concentrations, as well as the presence of insulin resistance, appear to be associated with an elevated risk of lung cancer development. Impact: Although insulin is hypothesized to increase risk of some cancers, insulin and lung cancer remain understudied. Higher insulin levels and insulin resistance were associated with increased lung cancer risk. Although smoking cessation is the best method of lung cancer prevention, other lifestyle changes that affect insulin concentrations and sensitivity may reduce lung cancer risk. Cancer Epidemiol Biomarkers Prev; 26(10); 1519-24. ©2017 AACR . ©2017 American Association for Cancer Research.

Differential effects of insulin injections and insulin infusions on levels ...

African Journals Online (AJOL)

Studies have shown that while injections of insulin cause an increase in fat mass, infusions of insulin increase fat mass. The aim of this paper was to test the hypothesis that if an increase in glycogen is an indicator of an impending increase in adipose mass, then insulin infusions should not increase glycogen, while insulin ...

Light regulation of the insulin receptor in the retina.

Science.gov (United States)

Rajala, Raju V S; Anderson, Robert E

2003-10-01

The peptide hormone insulin binds its cognate cell-surface receptors to activate a coordinated biochemical-signaling network and to induce intracellular events. The retina is an integral part of the central nervous system and is known to contain insulin receptors, although their function is unknown. This article, describes recent studies that link the photobleaching of rhodopsin to tyrosine phosphorylation of the insulin receptor and subsequent activation of phosphoinositide 3- kinase (PI3K). We recently found a light-dependent increase in tyrosine phosphorylation of the insulin receptor-beta-subunit (IR beta) and an increase in PI3K enzyme activity in isolated rod outer segments (ROS) and in anti-phosphotyrosine (PY) and anti-IR beta immunoprecipitates of retinal homogenates. The light effect, which was localized to photoreceptor neurons, is independent of insulin secretion. Our results suggest that light induces tyrosine phosphorylation of IR beta in outer-segment membranes, which leads to the binding of p85 through its N-terminal SH2 domain and the generation of PI-3,4,5-P3. We suggest that the physiological role of this process may be to provide neuroprotection of the retina against light damage by activating proteins that protect against stress-induced apoptosis. The studies linking PI3K activation through tyrosine phosphorylation of IR beta now provide physiological relevance for the presence of these receptors in the retina.

Rates of insulin secretion in INS-1 cells are enhanced by coupling to anaplerosis and Kreb’s cycle flux independent of ATP synthesis

International Nuclear Information System (INIS)

Cline, Gary W.; Pongratz, Rebecca L.; Zhao, Xiaojian; Papas, Klearchos K.

2011-01-01

Highlights: ► We studied media effects on mechanisms of insulin secretion of INS-1 cells. ► Insulin secretion was higher in DMEM than KRB despite identical ATP synthesis rates. ► Insulin secretion rates correlated with rates of anaplerosis and TCA cycle. ► Mitochondria metabolism and substrate cycles augment secretion signal of ATP. -- Abstract: Mechanistic models of glucose stimulated insulin secretion (GSIS) established in minimal media in vitro, may not accurately describe the complexity of coupling metabolism with insulin secretion that occurs in vivo. As a first approximation, we have evaluated metabolic pathways in a typical growth media, DMEM as a surrogate in vivo medium, for comparison to metabolic fluxes observed under the typical experimental conditions using the simple salt-buffer of KRB. Changes in metabolism in response to glucose and amino acids and coupling to insulin secretion were measured in INS-1 832/13 cells. Media effects on mitochondrial function and the coupling efficiency of oxidative phosphorylation were determined by fluorometrically measured oxygen consumption rates (OCRs) combined with 31 P NMR measured rates of ATP synthesis. Substrate preferences and pathways into the TCA cycle, and the synthesis of mitochondrial 2nd messengers by anaplerosis were determined by 13 C NMR isotopomer analysis of the fate of [U- 13 C] glucose metabolism. Despite similar incremental increases in insulin secretion, the changes of OCR in response to increasing glucose from 2.5 to 15 mM were blunted in DMEM relative to KRB. Basal and stimulated rates of insulin secretion rates were consistently higher in DMEM, while ATP synthesis rates were identical in both DMEM and KRB, suggesting greater mitochondrial uncoupling in DMEM. The relative rates of anaplerosis, and hence synthesis and export of 2nd messengers from the mitochondria were found to be similar in DMEM to those in KRB. And, the correlation of total PC flux with insulin secretion rates in DMEM

Economic benefits of improved insulin stability in insulin pumps.

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Weiss, Richard C; van Amerongen, Derek; Bazalo, Gary; Aagren, Mark; Bouchard, Jonathan R

2011-05-01

Insulin pump users discard unused medication and infusion sets according to labeling and manufacturer's instructions. The stability labeling for insulin aspart (rDNA origin] (Novolog) was increased from two days to six. The associated savings was modeled from the perspective of a hypothetical one-million member health plan and the total United States population. The discarded insulin volume and the number of infusion sets used under a two-day stability scenario versus six were modeled. A mix of insulin pumps of various reservoir capacities with a range of daily insulin dosages was used. Average daily insulin dose was 65 units ranging from 10 to 150 units. Costs of discarded insulin aspart [rDNA origin] were calculated using WAC (Average Wholesale Price minus 16.67%). The cost of pump supplies was computed for the two-day scenario assuming a complete infusion set change, including reservoirs, every two days. Under the six-day scenario complete infusion sets were discarded every six days while cannulas at the insertion site were changed midway between complete changes. AWP of least expensive supplies was used to compute their costs. For the hypothetical health plan (1,182 pump users) the annual reduction in discarded insulin volume between scenarios was 19.8 million units. The corresponding cost reduction for the plan due to drug and supply savings was $3.4 million. From the U.S. population perspective, savings of over $1 billion were estimated. Using insulin that is stable for six days in pump reservoirs can yield substantial savings to health plans and other payers, including patients.

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

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Højlund, Kurt

2014-07-01

Type 2 diabetes, obesity and polycystic ovary syndrome (PCOS) are common metabolic disorders which are observed with increasing prevalences, and which are caused by a complex interplay between genetic and environmental factors, including increased calorie intake and physical inactivity. These metabolic disorders are all characterized by reduced plasma adiponectin and insulin resistance in peripheral tissues. Quantitatively skeletal muscle is the major site of insulin resistance. Both low plasma adiponectin and insulin resistance contribute to an increased risk of type 2 diabetes and cardiovascular disease. In several studies, we have investigated insulin action on glucose and lipid metabolism, and at the molecular level, insulin signaling to glucose transport and glycogen synthesis in skeletal muscle from healthy individuals and in obesity, PCOS and type 2 diabetes. Moreover, we have described a novel syndrome characterized by postprandial hyperinsulinemic hypoglycemia and insulin resistance. This syndrome is caused by a mutation in the tyrosine kinase domain of the insulin receptor gene (INSR). We have studied individuals with this mutation as a model of inherited insulin resistance. Type 2 diabetes, obesity and PCOS are characterized by pronounced defects in the insulin-stimulated glucose uptake, in particular glycogen synthesis and to a lesser extent glucose oxidation, and the ability of insulin to suppress lipid oxidation. In inherited insulin resistance, however, only insulin action on glucose uptake and glycogen synthesis is impaired. This suggests that the defects in glucose and lipid oxidation in the common metabolic disorders are secondary to other factors. In young women with PCOS, the degree of insulin resistance was similar to that seen in middle-aged patients with type 2 diabetes. This supports the hypothesis of an unique pathogenesis of insulin resistance in PCOS. Insulin in physiological concentrations stimulates glucose uptake in human skeletal

Insulin resistance is associated with the aggressiveness of pancreatic ductal carcinoma.

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Dugnani, Erica; Balzano, Gianpaolo; Pasquale, Valentina; Scavini, Marina; Aleotti, Francesca; Liberati, Daniela; Di Terlizzi, Gaetano; Gandolfi, Alessandra; Petrella, Giovanna; Reni, Michele; Doglioni, Claudio; Bosi, Emanuele; Falconi, Massimo; Piemonti, Lorenzo

2016-12-01

To study whether insulin resistance accelerates the development and/or the progression of pancreatic adenocarcinoma (PDAC), we hypothesized that patients with insulin resistance, compared with those without insulin resistance, show: (1) a younger age and more advanced PDAC stage at diagnosis and (2) a shorter disease-free and overall survival after PDAC diagnosis. Prospective observational study of patients admitted to a referral center for pancreatic disease. Insulin resistance was defined as a HOMA-IR value greater than the 66th percentile value of the patients included in this study. Survival was estimated according to Kaplan-Meier and by Cox regression. Of 296 patients with PDAC, 99 (33 %) met criteria for being classified as insulin resistant at diagnosis. Median follow-up time after diagnosis was 5.27 ± 0.23 years. Patients with insulin resistance received a diagnosis of PDAC at a similar age compared to patients without insulin resistance (67.1 ± 9 vs. 66.8 ± 10 years, p = 0.68), but were more likely to have a cancer stage ≥3 (23.2 vs. 14.2 %, p = 0.053) and a residual disease after surgery (R1 56.4 vs. 38 %; p = 0.007). The median overall survival was 1.3 ± 0.14 and 1.79 ± 0.11 years for the patients with and without insulin resistance, respectively (p = 0.016). Results did not change when patients with diabetes at PDAC diagnosis were excluded from the analysis. Multivariate analysis showed that insulin resistance was independently associated with overall survival. Insulin resistance is associated with the aggressiveness of PDAC.

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.

IGF-I, IGF-II, and Insulin Stimulate Different Gene Expression Responses through Binding to the IGF-I Receptor

DEFF Research Database (Denmark)

Versteyhe, Soetkin; Klaproth, Birgit; Borup, Rehannah

2013-01-01

Insulin and the insulin-like growth factors (IGF)-I and -II are closely related peptides important for regulation of metabolism, growth, differentiation, and development. The IGFs exert their main effects through the IGF-I receptor. Although the insulin receptor is the main physiological receptor...... for insulin, this peptide hormone can also bind at higher concentrations to the IGF-I receptor and exert effects through it. We used microarray gene expression profiling to investigate the gene expression regulated by IGF-I, IGF-II, and insulin after stimulation of the IGF-I receptor. Fibroblasts from mice......, knockout for IGF-II and the IGF-II/cation-independent mannose-6-phosphate receptor, and expressing functional IGF-I but no insulin receptors, were stimulated for 4 h with equipotent saturating concentrations of insulin, IGF-I, and IGF-II. Each ligand specifically regulated a group of transcripts...

Mid-gestational serum uric acid concentration effect on neonate birth weight and insulin resistance in pregnant women.

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Nasri, Khadijeh; Razavi, Maryamsadat; Rezvanfar, Mohammad Reza; Mashhadi, Esmat; Chehrei, Ali; Mohammadbeigi, Abolfazl

2015-01-01

To investigate the relationship between mid-gestational serum uric acid and birth weight in diabetic pregnant women with or without insulin resistance. In a prospective cohort study, fasting uric acid, blood glucose, and serum insulin were measured in 247 pregnant women between 20-22 weeks of gestational period. Insulin resistance was estimated using the homeostasis model assessment-insulin resistance (HOMA-IR). Stratification analysis and independent t-test was used to assess the association between uric acid and birth weights regarding to insulin resistance. The means of the mid-gestational serum uric acid concentrations were not significantly different in women with and without insulin resistance. But stratification analysis showed that there was a significant difference between uric acid concentration and macrosomic birth in diabetic women without insulin resistance. Higher mid - gestation serum uric acid concentration, even if it does not exceed the normal range, is accompanied by lower birth weight only in non-insulin resistance women. Insulin resistance could have a negative confounding effect on hyperuriemia and birth weight.

ROLE OF INSULIN SENSITIZERS ON CARDIOVASCULAR RISK FACTORS IN POLYCYSTIC OVARIAN SYNDROME: A META-ANALYSIS.

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Thethi, Tina K; Katalenich, Bonnie; Nagireddy, Prathima; Chabbra, Pankdeep; Kuhadiya, Nitesh; Fonseca, Vivian

2015-06-01

Polycystic ovarian syndrome (PCOS) is associated with an increase in cardiovascular (CV) risk factors such as insulin resistance, with accompanying hyperinsulinemia and hyperlipidemia, which are predisposing factors for type 2 diabetes mellitus and CV disease. The aim of this meta-analysis is to examine the effect of insulin sensitizers on clinical and biochemical features of PCOS and risk factors for CV disease. A systematic literature review was conducted, and randomized controlled clinical trials were identified by a search of bibliographic databases: Medline database (from 1966 forward), EMBASE (January 1985 forward), and Cochrane Central Register of Controlled Trials. Reviews of reference lists further identified candidate trials. Data was independently abstracted in duplicate by 2 investigators using a standardized data-collection form. Articles without a comparison group and randomization allocation were excluded. Reviewers worked independently and in duplicate to determine the methodological quality of trials, then collected data on patient characteristics, interventions, and outcomes. Of 455 studies, 44 trials were eligible. A random effects model was used. Significant unadjusted results favoring treatment with insulin sensitizers were obtained for body mass index (BMI) (effect size [ES] of 0.58), waist to hip ratio (WHR) (ES of 0.02), low-density-lipoprotein cholesterol (LDL-C) (ES of 0.11), fasting insulin (ES of 2.82), fasting glucose (ES of 0.10), free testosterone (ES of 1.88), and androstenedione level (ES of 0.76). Treatment with insulin sensitizers in women with PCOS results in improvement in CV factors such as BMI, WHR, LDL-C, fasting insulin, glucose, free testosterone, and androstenedione.

Objectively measured time spent sedentary is associated with insulin resistance independent of overall and central body fat in 9- to 10-year-old Portuguese children

DEFF Research Database (Denmark)

Sardinha, Luis B; Andersen, Lars Bo; Anderssen, Sigmund A

2007-01-01

OBJECTIVE: We examined the independent relationships between objectively measured physical activity and insulin resistance in Portuguese children. RESEARCH DESIGN AND METHODS: This is a school-based, cross-sectional study in 147 randomly selected girls (aged 9.8 +/- 0.3 years; 27.8 +/- 9.3% body...... fat) and 161 boys (aged 9.8 +/- 0.3 years; 22.0 +/- 9.2% body fat). Physical activity was assessed by the Actigraph accelerometer for 4 days and summarized as time spent sedentary (accelerometer counts ... (beta-coefficient = 0.001 [95% CI 0.0002-0.002]; P = 0.013). Time spent in moderate- and vigorous-intensity physical activity (-0.002 [-0.003 to -0.001]; P = 0.0009) and overall physical activity (-0.001 [-0.008 to 0.003]; P

Correction of Diabetic Hyperglycemia and Amelioration of Metabolic Anomalies by Minicircle DNA Mediated Glucose-Dependent Hepatic Insulin Production.

Directory of Open Access Journals (Sweden)

Tausif Alam

Full Text Available Type 1 diabetes mellitus (T1DM is caused by immune destruction of insulin-producing pancreatic β-cells. Commonly used insulin injection therapy does not provide a dynamic blood glucose control to prevent long-term systemic T1DM-associated damages. Donor shortage and the limited long-term success of islet transplants have stimulated the development of novel therapies for T1DM. Gene therapy-based glucose-regulated hepatic insulin production is a promising strategy to treat T1DM. We have developed gene constructs which cause glucose-concentration-dependent human insulin production in liver cells. A novel set of human insulin expression constructs containing a combination of elements to improve gene transcription, mRNA processing, and translation efficiency were generated as minicircle DNA preparations that lack bacterial and viral DNA. Hepatocytes transduced with the new constructs, ex vivo, produced large amounts of glucose-inducible human insulin. In vivo, insulin minicircle DNA (TA1m treated streptozotocin (STZ-diabetic rats demonstrated euglycemia when fasted or fed, ad libitum. Weight loss due to uncontrolled hyperglycemia was reversed in insulin gene treated diabetic rats to normal rate of weight gain, lasting ∼1 month. Intraperitoneal glucose tolerance test (IPGT demonstrated in vivo glucose-responsive changes in insulin levels to correct hyperglycemia within 45 minutes. A single TA1m treatment raised serum albumin levels in diabetic rats to normal and significantly reduced hypertriglyceridemia and hypercholesterolemia. Elevated serum levels of aspartate transaminase, alanine aminotransferase, and alkaline phosphatase were restored to normal or greatly reduced in treated rats, indicating normalization of liver function. Non-viral insulin minicircle DNA-based TA1m mediated glucose-dependent insulin production in liver may represent a safe and promising approach to treat T1DM.

Lipid-induced insulin resistance does not impair insulin access to skeletal muscle

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Richey, Joyce M.; Castro, Ana Valeria B.; Broussard, Josiane L.; Ionut, Viorica; Bergman, Richard N.

2015-01-01

Elevated plasma free fatty acids (FFA) induce insulin resistance in skeletal muscle. Previously, we have shown that experimental insulin resistance induced by lipid infusion prevents the dispersion of insulin through the muscle, and we hypothesized that this would lead to an impairment of insulin moving from the plasma to the muscle interstitium. Thus, we infused lipid into our anesthetized canine model and measured the appearance of insulin in the lymph as a means to sample muscle interstitium under hyperinsulinemic euglycemic clamp conditions. Although lipid infusion lowered the glucose infusion rate and induced both peripheral and hepatic insulin resistance, we were unable to detect an impairment of insulin access to the lymph. Interestingly, despite a significant, 10-fold increase in plasma FFA, we detected little to no increase in free fatty acids or triglycerides in the lymph after lipid infusion. Thus, we conclude that experimental insulin resistance induced by lipid infusion does not reduce insulin access to skeletal muscle under clamp conditions. This would suggest that the peripheral insulin resistance is likely due to reduced cellular sensitivity to insulin in this model, and yet we did not detect a change in the tissue microenvironment that could contribute to cellular insulin resistance. PMID:25852002

Comparative Study of Serum Leptin and Insulin Resistance Levels Between Korean Postmenopausal Vegetarian and Non-vegetarian Women.

Science.gov (United States)

Kim, Mi-Hyun; Bae, Yun-Jung

2015-07-01

The present study was conducted to compare serum leptin and insulin resistance levels between Korean postmenopausal long-term semi-vegetarians and non-vegetarians. Subjects of this study belonged to either a group of postmenopausal vegetarian women (n = 54), who maintained a semi-vegetarian diet for over 20 years or a group of non-vegetarian controls. Anthropometric characteristics, serum leptin, serum glucose, serum insulin, insulin resistance (HOMA-IR; Homeostasis Model Assessment of Insulin Resistance), and nutrient intake were compared between the two groups. The vegetarians showed significantly lower body weight (p vegetarians. The HOMA-IR of the vegetarians was significantly lower than that of the non-vegetarians (p vegetarian diet might be related to lower insulin resistance independent of the % of body fat in postmenopausal women.

Alternative translation initiation of Caveolin-2 desensitizes insulin signaling through dephosphorylation of insulin receptor by PTP1B and causes insulin resistance.

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Kwon, Hayeong; Jang, Donghwan; Choi, Moonjeong; Lee, Jaewoong; Jeong, Kyuho; Pak, Yunbae

2018-06-01

Insulin resistance, defined as attenuated sensitivity responding to insulin, impairs insulin action. Direct causes and molecular mechanisms of insulin resistance have thus far remained elusive. Here we show that alternative translation initiation (ATI) of Caveolin-2 (Cav-2) regulates insulin sensitivity. Cav-2β isoform yielded by ATI desensitizes insulin receptor (IR) via dephosphorylation by protein-tyrosine phosphatase 1B (PTP1B), and subsequent endocytosis and lysosomal degradation of IR, causing insulin resistance. Blockage of Cav-2 ATI protects against insulin resistance by preventing Cav-2β-PTP1B-directed IR desensitization, thereby normalizing insulin sensitivity and glucose uptake. Our findings show that Cav-2β is a negative regulator of IR signaling, and identify a mechanism causing insulin resistance through control of insulin sensitivity via Cav-2 ATI. Copyright © 2018 Elsevier B.V. All rights reserved.

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

Conversion from insulin glargine U-100 to insulin glargine U-300 or insulin degludec and the impact on dosage requirements.

Science.gov (United States)

Pearson, Scott M; Trujillo, Jennifer M

2018-04-01

We wanted to determine whether basal insulin requirements change when patients transition from insulin glargine U-100 (Gla-100) to insulin glargine U-300 (Gla-300) or insulin degludec. This study involved subjects seen in the University of Colorado Health Endocrine Clinic who were transitioned from Gla-100 to either Gla-300 ( n = 95) or insulin degludec ( n = 39). The primary outcome was the difference between baseline Gla-100 dose and dose of Gla-300 or insulin degludec prescribed after first follow-up visit within 1-12 months. Secondary outcomes included changes in glycemic control and empiric dose conversion from Gla-100 to Gla-300 or insulin degludec on the day of transition. Wilcoxon rank sum tests evaluated changes in insulin doses, and paired t tests assessed changes in glycemic control using GraphPad statistical software. Median daily basal insulin dose increased for individuals transitioned from Gla-100 to Gla-300 from 30 [19-60 interquartile range (IQR)] units at baseline to 34.5 (19-70 IQR) units after follow up ( p = 0.01). For patients transitioned to insulin degludec, dose changes from baseline to follow up were not significantly different ( p = 0.56). At the time of transition, the prescribed dose of Gla-300 or insulin degludec did not significantly differ from the previous dose of Gla-100 ( p = 0.73 and 0.28, respectively), indicating that empiric dose adjustments were not routinely prescribed. Patients who transitioned from Gla-100 to Gla-300 had increased basal insulin requirements between visits, while basal insulin requirements for those transitioned from Gla-100 to insulin degludec were not significantly different.

Branched Chain Amino Acids Are Associated with Insulin Resistance Independent of Leptin and Adiponectin in Subjects with Varying Degrees of Glucose Tolerance.

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Connelly, Margery A; Wolak-Dinsmore, Justyna; Dullaart, Robin P F

2017-05-01

Branched chain amino acids (BCAA) may be involved in the pathogenesis of insulin resistance and are associated with type 2 diabetes mellitus (T2DM) development. Adipokines such as leptin and adiponectin influence insulin resistance and reflect adipocyte dysfunction. We examined the extent to which the association of BCAA with insulin resistance is attributable to altered leptin and adiponectin levels in individuals with varying degrees of glucose tolerance. BCAA were measured by nuclear magnetic resonance, whereas leptin and adiponectin were measured by immunoassay, in subjects with normal fasting glucose (n = 30), impaired fasting glucose (n = 25), and T2DM (n = 15). Insulin resistance was estimated by homeostasis model assessment (HOMAir). BCAA were higher in men than in women (P BCAA were correlated with HOMAir (r = 0.46; P  0.05). Multivariable linear regression analysis, adjusting for age, sex, T2DM, and body mass index (BMI), demonstrated that BCAA were positively associated with HOMAir (β = 0.242, P = 0.023). When BCAA, leptin, and adiponectin were included together, the positive relationship of HOMAir with BCAA (β = 0.275, P = 0.012) remained significant. Insulin resistance was associated with BCAA. This association remained after adjusting for age, sex, T2DM, BMI, as well as leptin and adiponectin. It is unlikely that the relationship of insulin resistance with BCAA is to a major extent attributable to effects of leptin and adiponectin.

Independent technical review, handbook

International Nuclear Information System (INIS)

1994-02-01

Purpose Provide an independent engineering review of the major projects being funded by the Department of Energy, Office of Environmental Restoration and Waste Management. The independent engineering review will address questions of whether the engineering practice is sufficiently developed to a point where a major project can be executed without significant technical problems. The independent review will focus on questions related to: (1) Adequacy of development of the technical base of understanding; (2) Status of development and availability of technology among the various alternatives; (3) Status and availability of the industrial infrastructure to support project design, equipment fabrication, facility construction, and process and program/project operation; (4) Adequacy of the design effort to provide a sound foundation to support execution of project; (5) Ability of the organization to fully integrate the system, and direct, manage, and control the execution of a complex major project

Independent technical review, handbook

Energy Technology Data Exchange (ETDEWEB)

1994-02-01

Purpose Provide an independent engineering review of the major projects being funded by the Department of Energy, Office of Environmental Restoration and Waste Management. The independent engineering review will address questions of whether the engineering practice is sufficiently developed to a point where a major project can be executed without significant technical problems. The independent review will focus on questions related to: (1) Adequacy of development of the technical base of understanding; (2) Status of development and availability of technology among the various alternatives; (3) Status and availability of the industrial infrastructure to support project design, equipment fabrication, facility construction, and process and program/project operation; (4) Adequacy of the design effort to provide a sound foundation to support execution of project; (5) Ability of the organization to fully integrate the system, and direct, manage, and control the execution of a complex major project.

Lipoprotein(a) is not related to markers of insulin resistance in pregnancy.

Science.gov (United States)

Todoric, Jelena; Handisurya, Ammon; Leitner, Karoline; Harreiter, Juergen; Hoermann, Gregor; Kautzky-Willer, Alexandra

2013-10-01

Dyslipidemia, a major risk factor for cardiovascular disease is a common finding in patients with type 2 diabetes and among women with gestational diabetes. Elevated levels of lipoprotein(a) [Lp(a)] are linked to increased risk of cardiovascular disease. However, its relationship with insulin resistance, type 2 diabetes and gestational diabetes is controversial and unproven. Here we aimed to clarify whether Lp(a) levels are associated with insulin sensitivity in pregnancy. Sixty-four women with gestational diabetes and 165 with normal glucose tolerance were enrolled in the study. Fasting Lp(a) serum levels were measured in all women at 24-28 weeks of gestation. In pregnancy, there was no significant difference in serum Lp(a) concentrations between the two groups. Its level did not correlate with markers of insulin resistance (HOMA-IR), insulin sensitivity (HOMA-S%), pancreatic beta-cell function (HOMA-B%) and insulin sensitivity in dynamic conditions (OGIS). In addition, fasting glucose and insulin levels and those throughout an oral glucose tolerance test were independent of Lp(a) concentrations in our study group. Lp(a) levels in pregnant women do not differ with respect to the presence or absence of gestational diabetes. Although influenced by some components of the lipid profile, such as triglycerides and HDL-C, insulin resistance in pregnancy is not affected by Lp(a).

Impaired translocation of GLUT4 results in insulin resistance of atrophic soleus muscle.

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Xu, Peng-Tao; Song, Zhen; Zhang, Wen-Cheng; Jiao, Bo; Yu, Zhi-Bin

2015-01-01

Whether or not the atrophic skeletal muscle induces insulin resistance and its mechanisms are not resolved now. The antigravity soleus muscle showed a progressive atrophy in 1-week, 2-week, and 4-week tail-suspended rats. Hyperinsulinemic-euglycemic clamp showed that the steady-state glucose infusion rate was lower in 4-week tail-suspended rats than that in the control rats. The glucose uptake rates under insulin- or contraction-stimulation were significantly decreased in 4-week unloaded soleus muscle. The key protein expressions of IRS-1, PI3K, and Akt on the insulin-dependent pathway and of AMPK, ERK, and p38 on the insulin-independent pathway were unchanged in unloaded soleus muscle. The unchanged phosphorylation of Akt and p38 suggested that the activity of two signal pathways was not altered in unloaded soleus muscle. The AS160 and GLUT4 expression on the common downstream pathway also was not changed in unloaded soleus muscle. But the GLUT4 translocation to sarcolemma was inhibited during insulin stimulation in unloaded soleus muscle. The above results suggest that hindlimb unloading in tail-suspended rat induces atrophy in antigravity soleus muscle. The impaired GLUT4 translocation to sarcolemma under insulin stimulation may mediate insulin resistance in unloaded soleus muscle and further affect the insulin sensitivity of whole body in tail-suspended rats.

Impaired Translocation of GLUT4 Results in Insulin Resistance of Atrophic Soleus Muscle

Directory of Open Access Journals (Sweden)

Peng-Tao Xu

2015-01-01

Full Text Available Whether or not the atrophic skeletal muscle induces insulin resistance and its mechanisms are not resolved now. The antigravity soleus muscle showed a progressive atrophy in 1-week, 2-week, and 4-week tail-suspended rats. Hyperinsulinemic-euglycemic clamp showed that the steady-state glucose infusion rate was lower in 4-week tail-suspended rats than that in the control rats. The glucose uptake rates under insulin- or contraction-stimulation were significantly decreased in 4-week unloaded soleus muscle. The key protein expressions of IRS-1, PI3K, and Akt on the insulin-dependent pathway and of AMPK, ERK, and p38 on the insulin-independent pathway were unchanged in unloaded soleus muscle. The unchanged phosphorylation of Akt and p38 suggested that the activity of two signal pathways was not altered in unloaded soleus muscle. The AS160 and GLUT4 expression on the common downstream pathway also was not changed in unloaded soleus muscle. But the GLUT4 translocation to sarcolemma was inhibited during insulin stimulation in unloaded soleus muscle. The above results suggest that hindlimb unloading in tail-suspended rat induces atrophy in antigravity soleus muscle. The impaired GLUT4 translocation to sarcolemma under insulin stimulation may mediate insulin resistance in unloaded soleus muscle and further affect the insulin sensitivity of whole body in tail-suspended rats.

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.

Moringa olifeira Lam. Stimulates Activation of the Insulin-Dependent Akt Pathway. Antidiabetic Effect in a Diet-Induced Obesity (DIO) Mouse Model.

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Attakpa, E S; Sangaré, M M; Béhanzin, G J; Ategbo, J-M; Seri, B; Khan, N A

2017-01-01

We investigated the antidiabetic effect of Moringa olifeira Lam. in a diet-induced obesity (DIO) mouse model. Six mice were randomly selected as normal controls. Moringa olifeira Lam. leaf extract at a dose of 200, 400 or 600 mg/kg body weight, glibenclamide (Glib) at the dose of 10 mg/kg (positive control) and distilled water at 10 ml/kg (control group) were administered orally by gastric intubation, and each group consisted of six mice. Insulinsensitive tissues (liver, skeletal muscle) were collected to investigate antidiabetic effects and examine the plant's molecular mechanisms. Moringa olifeira Lam. leaf extract prevented weight gain. It also reduced blood glucose in DIO mice. Glib and Moringa olifeira Lam. leaf extract, 400 mg/kg, treatments restored insulin levels towards normal values (P < 0.05 versus diabetic control group). Western immunoblot analysis of different tissues, collected at the end of the study, demonstrated that Moringa olifeira Lam. stimulated activation of the insulin-dependent Akt pathway and increased the protein content of Glut 4 in skeletal muscle. The improvement of hepatic steatosis observed in DIO-treated mice was associated with a decrease in the hepatic content of SREBP-1, a transcription factor involved in de novo lipogenesis. The hepatic PPARα protein content in the plant extract- treated mice remained significantly higher than those of the control group (P < 0.05). In conclusion, this study provides the first evidence for direct action of Moringa olifeira Lam. on pancreatic β-cells, enhancing glucose-stimulated insulin secretion. This correlated with hypoglycaemic effects in diabetic mice associated with restored levels of plasma insulin.

Hyperosmotic stress inhibits insulin receptor substrate-1 function by distinct mechanisms in 3T3-L1 adipocytes

DEFF Research Database (Denmark)

Gual, Philippe; Gonzalez, Teresa; Grémeaux, Thierry

2003-01-01

. Furthermore, the mammalian target of rapamycin (mTOR) inhibitor rapamycin prevented the osmotic shock-induced phosphorylation of IRS-1 on Ser307. The inhibition of mTOR completely reversed the inhibitory effect of hyperosmotic stress on insulin-induced IRS-1 tyrosine phosphorylation and PI 3-kinase activation......In 3T3-L1 adipocytes, hyperosmotic stress was found to inhibit insulin signaling, leading to an insulin-resistant state. We show here that, despite normal activation of insulin receptor, hyperosmotic stress inhibits both tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) and IRS-1....... In addition, prolonged osmotic stress enhanced the degradation of IRS proteins through a rapamycin-insensitive pathway and a proteasome-independent process. These data support evidence of new mechanisms involved in osmotic stress-induced cellular insulin resistance. Short-term osmotic stress induces...

Estimating Rate of Insulin Resistance in Patients with Preeclampsia Using HOMA-IR Index and Comparison with Nonpreeclampsia Pregnant Women

OpenAIRE

Abhari, Farideh Rezaei; Ghanbari Andarieh, Maryam; Farokhfar, Asadollah; Ahmady, Soleiman

2014-01-01

Women with preeclampsia, independent of obesity and glucose intolerance, exhibit insulin resistance during pregnancy. The purpose of the present study is to determine whether early diagnosis of insulin resistance during pregnancy can predict preeclampsia. Through a case-control study, 675 pregnant women were selected and their first trimester blood was taken. Their fasting blood glucose and insulin were also measured after diagnosis of preeclampsia by 20 weeks of pregnancy. Based on the exper...

Ordovas-Oxidized LDL is associated with metabolic syndrome traits independently of central obesity and insulin resistance

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This study assesses whether oxidative stress, using oxidized LDL (ox-LDL) as a proxy, is associated with metabolic syndrome (MS), whether ox-LDL mediates the association between central obesity and MS, and whether insulin resistance mediates the association between ox-LDL and MS. We examined baselin...

The association of cysteine with obesity, inflammatory cytokines and insulin resistance in Hispanic children and adolescents.

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Amany K Elshorbagy

Full Text Available Plasma total cysteine (tCys independently relates to fat mass in adults. Dietary cyst(eine promotes adiposity and decreases glucose tolerance in some rodent models, but alleviates insulin resistance in others.To investigate whether the association of tCys with body fat extends to children at particular risk of obesity, and whether tCys is associated with insulin resistance and obesity-associated inflammation.We explored the cross-sectional relations of fasting plasma tCys and related metabolites with body composition measured by dual-energy X-ray absorptiometry in 984 Hispanic children and adolescents aged 4-19 years from the Viva La Familia Study. Linear and logistic regression and dose-response curves were used to evaluate relations of tCys with obesity, insulin resistance and inflammatory markers including interleukin-6 (IL-6, tumor necrosis factor-alpha (TNF-α, monocyte chemoattractant protein-1 (MCP-1 and C-reactive protein (CRP.tCys, methionine and total homocysteine (tHcy increased with age. Upper tCys quartile was independently associated with a 5-fold increased risk of obesity (95% CI 3.5-8.0, P<0.001, and 2-fold risk of insulin resistance (95% CI: 1.6-5.0, P<0.001; adjusted for body fat%. Within the overweight/obese subgroup, but not in normal-weight children, tCys accounted for 9% of the variability in body fat% (partial r = 0.30, P<0.001; adjusted for age and gender. tCys correlated positively with serum non-esterified fatty acids and leptin, partly independent of body fat, but was not associated with serum IL-6, TNF-α or MCP-1. A positive correlation with CRP disappeared after adjustment for BMI.tCys is independently associated with obesity and insulin resistance in Hispanic children and adolescents, highlighting a previously underappreciated link between the sulfur amino acid metabolic pathway and obesity and cardiometabolic risk.

Comparison of metformin and insulin versus insulin alone for type 2 diabetes: systematic review of randomised clinical trials with meta-analyses and trial sequential analyses.

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Hemmingsen, Bianca; Christensen, Louise Lundby; Wetterslev, Jørn; Vaag, Allan; Gluud, Christian; Lund, Søren S; Almdal, Thomas

2012-04-19

To compare the benefits and harms of metformin and insulin versus insulin alone as reported in randomised clinical trials of patients with type 2 diabetes. Systematic review of randomised clinical trials with meta-analyses and trial sequential analyses. The Cochrane Library, Medline, Embase, Science Citation Index Expanded, Latin American Caribbean Health Sciences Literature, and Cumulative Index to Nursing and Allied Health Literature until March 2011. We also searched abstracts presented at the American Diabetes Association and European Association for the Study of Diabetes Congresses, contacted relevant trial authors and pharmaceutical companies, hand searched reference lists of included trials, and searched the US Food and Drug Administration website. Two authors independently screened titles and abstracts for randomised clinical trials comparing metformin and insulin versus insulin alone (with or without placebo) in patients with type 2 diabetes, older than 18 years, and with an intervention period of at least 12 weeks. We included trials irrespective of language, publication status, predefined outcomes, antidiabetic interventions used before randomisation, and reported outcomes. We included 26 randomised trials with 2286 participants, of which 23 trials with 2117 participants could provide data. All trials had high risk of bias. Data were sparse for outcomes relevant to patients. Metformin and insulin versus insulin alone did not significantly affect all cause mortality (relative risk 1.30, 95% confidence interval 0.57 to 2.99) or cardiovascular mortality (1.70, 0.35 to 8.30). Trial sequential analyses showed that more trials were needed before reliable conclusions could be drawn regarding these outcomes. In a fixed effect model, but not in a random effects model, severe hypoglycaemia was significantly more frequent with metformin and insulin than with insulin alone (2.83, 1.17 to 6.86). In a random effects model, metformin and insulin resulted in reduced Hb

Heterozygous deficiency of endoglin decreases insulin and hepatic triglyceride levels during high fat diet.

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Daniel Beiroa

Full Text Available Endoglin is a transmembrane auxiliary receptor for transforming growth factor-beta (TGF-beta that is predominantly expressed on proliferating endothelial cells. It plays a wide range of physiological roles but its importance on energy balance or insulin sensitivity has been unexplored. Endoglin deficient mice die during midgestation due to cardiovascular defects. Here we report for first time that heterozygous endoglin deficiency in mice decreases high fat diet-induced hepatic triglyceride content and insulin levels. Importantly, these effects are independent of changes in body weight or adiposity. At molecular level, we failed to detect relevant changes in the insulin signalling pathway at basal levels in liver, muscle or adipose tissues that could explain the insulin-dependent effect. However, we found decreased triglyceride content in the liver of endoglin heterozygous mice fed a high fat diet in comparison to their wild type littermates. Overall, our findings indicate that endoglin is a potentially important physiological mediator of insulin levels and hepatic lipid metabolism.

Restoring proximal caries lesions conservatively with tunnel restorations.

Science.gov (United States)

Chu, Chun-Hung; Mei, May L; Cheung, Chloe; Nalliah, Romesh P

2013-07-30

The tunnel restoration has been suggested as a conservative alternative to the conventional box preparation for treating proximal caries. The main advantage of tunnel restoration over the conventional box or slot preparation includes being more conservative and increasing tooth integrity and strength by preserving the marginal ridge. However, tunnel restoration is technique-sensitive and can be particularly challenging for inexperienced restorative dentists. Recent advances in technology, such as the contemporary design of dental handpieces with advanced light-emitting diode (LED) and handheld comfort, offer operative dentists better vision, illumination, and maneuverability. The use of magnifying loupes also enhances the visibility of the preparation. The advent of digital radiographic imaging has improved dental imaging and reduced radiation. The new generation of restorative materials has improved mechanical properties. Tunnel restoration can be an option to restore proximal caries if the dentist performs proper case selection and pays attention to the details of the restorative procedures. This paper describes the clinical technique of tunnel restoration and reviews the studies of tunnel restorations.

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

Mammary tumors that become independent of the type I insulin-like growth factor receptor express elevated levels of platelet-derived growth factor receptors

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Campbell Craig I

2011-11-01

Full Text Available Abstract Background Targeted therapies are becoming an essential part of breast cancer treatment and agents targeting the type I insulin-like growth factor receptor (IGF-IR are currently being investigated in clinical trials. One of the limitations of targeted therapies is the development of resistant variants and these variants typically present with unique gene expression patterns and characteristics compared to the original tumor. Results MTB-IGFIR transgenic mice, with inducible overexpression of the IGF-IR were used to model mammary tumors that develop resistance to IGF-IR targeting agents. IGF-IR independent mammary tumors, previously shown to possess characteristics associated with EMT, were found to express elevated levels of PDGFRα and PDGFRβ. Furthermore, these receptors were shown to be inversely expressed with the IGF-IR in this model. Using cell lines derived from IGF-IR-independent mammary tumors (from MTB-IGFIR mice, it was demonstrated that PDGFRα and to a lesser extent PDGFRβ was important for cell migration and invasion as RNAi knockdown of PDGFRα alone or PDGFRα and PDGFRβ in combination, significantly decreased tumor cell migration in Boyden chamber assays and suppressed cell migration in scratch wound assays. Somewhat surprisingly, concomitant knockdown of PDGFRα and PDGFRβ resulted in a modest increase in cell proliferation and a decrease in apoptosis. Conclusion During IGF-IR independence, PDGFRs are upregulated and function to enhance tumor cell motility. These results demonstrate a novel interaction between the IGF-IR and PDGFRs and highlight an important, therapeutically relevant pathway, for tumor cell migration and invasion.

Novel covalently linked insulin dimer engineered to investigate the function of insulin dimerization

DEFF Research Database (Denmark)

Vinther, Tine N.; Norrman, Mathias; Strauss, Holger M.

2012-01-01

An ingenious system evolved to facilitate insulin binding to the insulin receptor as a monomer and at the same time ensure sufficient stability of insulin during storage. Insulin dimer is the cornerstone of this system. Insulin dimer is relatively weak, which ensures dissociation into monomers...... in the circulation, and it is stabilized by hexamer formation in the presence of zinc ions during storage in the pancreatic ß-cell. Due to the transient nature of insulin dimer, direct investigation of this important form is inherently difficult. To address the relationship between insulin oligomerization...... and insulin stability and function, we engineered a covalently linked insulin dimer in which two monomers were linked by a disulfide bond. The structure of this covalent dimer was identical to the self-association dimer of human insulin. Importantly, this covalent dimer was capable of further oligomerization...

Mathematical model of glucose-insulin homeostasis in healthy rats.

Science.gov (United States)

Lombarte, Mercedes; Lupo, Maela; Campetelli, German; Basualdo, Marta; Rigalli, Alfredo

2013-10-01

According to the World Health Organization there are over 220 million people in the world with diabetes and 3.4 million people died in 2004 as a consequence of this pathology. Development of an artificial pancreas would allow to restore control of blood glucose by coupling an infusion pump to a continuous glucose sensor in the blood. The design of such a device requires the development and application of mathematical models which represent the gluco-regulatory system. Models developed by other research groups describe very well the gluco-regulatory system but have a large number of mathematical equations and require complex methodologies for the estimation of its parameters. In this work we propose a mathematical model to study the homeostasis of glucose and insulin in healthy rats. The proposed model consists of three differential equations and 8 parameters that describe the variation of: blood glucose concentration, blood insulin concentration and amount of glucose in the intestine. All parameters were obtained by setting functions to the values of glucose and insulin in blood obtained after oral glucose administration. In vivo and in silico validations were performed. Additionally, a qualitative analysis has been done to verify the aforementioned model. We have shown that this model has a single, biologically consistent equilibrium point. This model is a first step in the development of a mathematical model for the type I diabetic rat. Copyright © 2013 Elsevier Inc. All rights reserved.

Insulin analogues: have they changed insulin treatment and improved glycaemic control?

DEFF Research Database (Denmark)

Madsbad, Sten

2002-01-01

To improve insulin therapy, new insulin analogues have been developed. Two fast-acting analogues with a more rapid onset of effect and a shorter duration of action combined with a low day-to-day variation in absorption rate are now available. Despite this favourable time-action profile most studies....... This is probably the main explanation for the absence of improvement in overall glycaemic control when compared with regular human insulin. A tendency to a reduction in hypoglycaemic events during treatment with fast-acting analogues has been observed in most studies. Recent studies have indicated that NPH insulin...... administered several times daily at mealtimes can improve glycaemic control without increasing the risk of hypoglycaemia. The fast-acting analogues are now also available as insulin mixed with NPH. Insulin glargine is a new long-acting insulin which is soluble and precipitates after injection, resulting...

Insulin structure and stability.

Science.gov (United States)

Brange, J; Langkjoer, L

1993-01-01

Insulin is composed of 51 amino acids in two peptide chains (A and B) linked by two disulfide bonds. The three-dimensional structure of the insulin molecule (insulin monomer), essentially the same in solution and in solid phase, exists in two main conformations. These differ in the extent of helix in the B chain which is governed by the presence of phenol or its derivatives. In acid and neutral solutions, in concentrations relevant for pharmaceutical formulation, the insulin monomer assembles to dimers and at neutral pH, in the presence of zinc ions, further to hexamers. Many crystalline modifications of insulin have been identified but only those with the hexamer as the basic unit are utilized in preparations for therapy. The insulin hexamer forms a relatively stable unit but some flexibility remains within the individual molecules. The intrinsic flexibility at the ends of the B chain plays an important role in governing the physical and chemical stability of insulin. A variety of chemical changes of the primary structure (yielding insulin derivatives), and physical modifications of the secondary to quaternary structures (resulting in "denaturation," aggregation, and precipitation) are known to affect insulin and insulin preparations during storage and use (Fig. 8). The tendency of insulin to undergo structural transformation resulting in aggregation and formation of insoluble insulin fibrils has been one of the most intriguing and widely studied phenomena in relation to insulin stability. Although the exact mechanism of fibril formation is still obscure, it is now clear that the initial step is an exposure of certain hydrophobic residues, normally buried in the three-dimensional structure, to the surface of the insulin monomer. This requires displacement of the COOH-terminal B-chain residues from their normal position which can only be accomplished via monomerization of the insulin. Therefore, most methods stabilizing insulin against fibrillation share the

Serum acylated ghrelin is negatively correlated with the insulin resistance in the CODING study.

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Peyvand Amini

Full Text Available Ghrelin is a 28-amino acid orexigenic peptide synthesized mainly in the stomach. Acute administration of ghrelin has been found to decrease insulin secretion. However, little data is available regarding whether ghrelin contributes to the long-term regulation of insulin resistance at the population level. The aim of this study is to investigate the association between circulating ghrelin and insulin resistance in a large population based study.A total of 2082 CODING study (Complex Diseases in the Newfoundland population: Environment and Genetics subjects were assessed. Subjects were of at least third generation Newfoundland descent, between the ages of 20 and 79 years, and had no serious metabolic, cardiovascular, or endocrine diseases. Ghrelin was measured with an Enzyme Immunoassay method. Insulin and fasting glucose were measured by Immulite 2500 autoanalyzer and Lx20 clinical chemistry analyzer, respectively. Homeostatic Model Assessment of β cell function (HOMA-β and Insulin Resistance (HOMA-IR and Quantitative Insulin-sensitivity Check Index (QUICKI were used for measurement of insulin resistance.Partial correlation analyses showed a significant negative correlation between circulating ghrelin and insulin level and insulin resistance in the entire cohort and also in men and women separately. The aforementioned correlation was independent of age, percentage of trunk fat and HDL-cholesterol. According to menopausal status, only pre-menopausal women revealed negative correlations.Our results suggest that except for postmenopausal women, high circulating ghrelin level is associated with lower insulin resistance in the general population.

Branched Chain Amino Acids Are Associated with Insulin Resistance Independent of Leptin and Adiponectin in Subjects with Varying Degrees of Glucose Tolerance

NARCIS (Netherlands)

Connelly, Margery A.; Wolak-Dinsmore, Justyna; Dullaart, Robin P. F.

Background: Branched chain amino acids (BCAA) may be involved in the pathogenesis of insulin resistance and are associated with type 2 diabetes mellitus (T2DM) development. Adipokines such as leptin and adiponectin influence insulin resistance and reflect adipocyte dysfunction. We examined the

Alteration in insulin action

DEFF Research Database (Denmark)

Tanti, J F; Gual, P; Grémeaux, T

2004-01-01

Insulin resistance, when combined with impaired insulin secretion, contributes to the development of type 2 diabetes. Insulin resistance is characterised by a decrease in insulin effect on glucose transport in muscle and adipose tIssue. Tyrosine phosphorylation of insulin receptor substrate 1 (IRS......-1) and its binding to phosphatidylinositol 3-kinase (PI 3-kinase) are critical events in the insulin signalling cascade leading to insulin-stimulated glucose transport. Modification of IRS-1 by serine phosphorylation could be one of the mechanisms leading to a decrease in IRS-1 tyrosine...... to phosphorylate these serine residues have been identified. These exciting results suggest that serine phosphorylation of IRS-1 is a possible hallmark of insulin resistance in biologically insulin responsive cells or tIssues. Identifying the pathways by which "diabetogenic" factors activate IRS-1 kinases...

Relationship between serum insulin level and age and sex in 980 patients with essential hypertension

International Nuclear Information System (INIS)

Cai Jianlin; Ji Naijun; Mei Yubin; Wang Chengyao; Fan Bifu; Chen Donghai; Guan Li; Tong Lijun; Li Fuyuan; Gao Meiying

2004-01-01

Objective: To investigate the change of serum insulin level in essential hypertension patients and its relationship with age and sex. Methods: The levels of serum insulin were determined with radioimmunoassay in 980 essential hypertension patients and 120 controls. Results: The levels of serum insulin in the essential hypertension patients were significantly higher than those in the controls (t=4.280, P<0.01). However, there were no significant differences among the levels in different sex and age groups. The same held true for women before and after menopause as well as different stages of hypertension. Conclusion: The average serum insulin level in EH patients was significantly higher than the level in controls, and had positive correlation to mean arterial pressure. But no significant differences were found among different sex and age groups, so serum insulin could be a new independent risk factor of essential hypertension

Mitochondrial GTP Regulates Glucose-Induced Insulin Secretion

OpenAIRE

Kibbey, Richard G.; Pongratz, Rebecca L.; Romanelli, Anthony J.; Wollheim, Claes B.; Cline, Gary W.; Shulman, Gerald I.

2007-01-01

Substrate-level mitochondrial GTP (mtGTP) and ATP (mtATP) synthesis occurs by nucleotide-specific isoforms of the tricarboxylic acid (TCA) cycle enzyme succinyl CoA synthetase (SCS). Unlike mtATP, each molecule of glucose metabolized produces approximately one mtGTP in pancreatic β-cells independent of coupling with oxidative phosphorylation making mtGTP a potentially important fuel signal. siRNA suppression of the GTP-producing pathway (ΔSCS-GTP) reduced glucose-stimulated insulin secretion ...

Intake of vinegar beverage is associated with restoration of ovulatory function in women with polycystic ovary syndrome.

Science.gov (United States)

Wu, Di; Kimura, Fuminori; Takashima, Akiko; Shimizu, Yoshihiko; Takebayashi, Akie; Kita, Nobuyuki; Zhang, Guangmei; Murakami, Takashi

2013-05-01

Polycystic ovary syndrome (PCOS) is one of major causes of irregular menstruation. It is defined as a condition involving the combination of hyperandrogenism and chronic oligomenorrhea or anovulation, and is thought to have a variety of etiologies. Insulin resistance (impaired insulin sensitivity) has been suggested to be one of the etiologies of PCOS. PCOS patients often need to take medication to treat anovulation and infertility. Therefore, it would be beneficial to patients if simple non-pharmacological treatments can be developed. Recently the efficacy of vinegar to improve insulin resistance has been reported. To study the effect of vinegar on metabolic and hormonal indices and ovulatory function in PCOS, seven patients seeking a non-pharmacological treatment for PCOS took a beverage containing 15 g of apple vinegar daily for 90 to 110 days. Ovulation, the menstrual interval, fasting serum glucose level, fasting serum insulin level, luteinizing hormone (LH), follicle stimulating hormone (FSH), and testosterone were compared before and after intake of the vinegar beverage. Intake of the vinegar beverage resulted in a decrease of the homeostasis model assessment insulin resistance index (HOMA-R) in six patients, as well as a decrease of the LH/FSH ratio in five of seven patients. Ovulatory menstruation was observed within 40 day in four of seven patients. These findings suggest the possibility of vinegar to restore ovulatory function through improving insulin sensitivity in PCOS patients, thus, avoiding pharmacological treatment. Intake of vinegar might reduce medical cost and treatment time for insulin resistance, anovulation, and infertility in patients with PCOS.

In nondiabetic, human immunodeficiency virus-infected patients with lipodystrophy, hepatic insulin extraction and posthepatic insulin clearance rate are decreased in proportion to insulin resistance

DEFF Research Database (Denmark)

Haugaard, Steen B; Andersen, Ove; Hansen, Birgitte R

2005-01-01

In healthy, nondiabetic individuals with insulin resistance, fasting insulin is inversely correlated to the posthepatic insulin clearance rate (MCRi) and the hepatic insulin extraction (HEXi). We investigated whether similar early mechanisms to facilitate glucose homeostasis exist in nondiabetic...... endogenous insulin secretion, which was estimated by deconvolution of C-peptide concentrations. Hepatic extraction of insulin was calculated as 1 minus the ratio of fasting posthepatic insulin delivery rate to fasting endogenous insulin secretion rate. Compared with controls, LIPO displayed increased fasting...... insulin (130%, P Hepatic extraction of insulin was similar between groups (LIPO, 55%; controls, 57%; P > .8). In LIPO, HEXi and MCRi correlated inversely with fasting insulin (r = -0.56, P

Robustness Area Technique Developing Guidelines for Power System Restoration

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Paulo Murinelli Pesoti

2017-01-01

Full Text Available This paper proposes a novel energy based technique called the Robustness Area (RA technique that measures power system robustness levels, as a helper for planning Power System Restorations (PSRs. The motivation is on account of the latest blackouts in Brazil, where the local Independent System Operator (ISO encountered difficulties related to circuit disconnections during the restoration. The technique identifies vulnerable and robust buses, pointing out system areas that should be firstly reinforced during PSR, in order to enhance system stability. A Brazilian power system restoration area is used to compare the guidelines adopted by the ISO with a more suitable new plan indicated by the RA tool. Active power and reactive power load margin and standing phase angle show the method efficiency as a result of a well balanced system configuration, enhancing the restoration performance. Time domain simulations for loop closures and severe events also show the positive impact that the proposed tool brings to PSRs.

Insulin-releasing action of the novel antidiabetic agent BTS 67 582.

Science.gov (United States)

McClenaghan, N H; Flatt, P R; Bailey, C J

1998-02-01

1. BTS 67582 (1,1-dimethyl-2-(2-morpholinophenyl)guanidine fumarate) is a novel antidiabetic agent with a short-acting insulin-releasing effect. This study examined its mode of action in the clonal B-cell line BRIN-BD11. 2. BTS 67582 increased insulin release from BRIN-BD11 cells in a concentration-dependent manner (10[-8] to 10[-4] M) at both non-stimulating (1.1 mM) and stimulating (16.7 mM) concentrations of glucose. 3. BTS 67582 (10[-4] M) potentiated the insulin-releasing effect of a depolarizing concentration of K+ (30 mM), whereas the K+ channel openers pinacidil (400 microM) and diazoxide (300 microM) inhibited BTS 67582-induced release. 4. Suppression of Ca+ channel activity with verapamil (20 microM) reduced the insulin-releasing effect of BTS 67582 (10[-4] M). 5. BTS 67582 (10[-4] M) potentiated insulin release induced by amino acids (10 mM), and enhanced the combined stimulant effects of glucose plus either the fatty acid palmitate (10 mM), or agents which raise intracellular cyclic AMP concentrations (25 microM forskolin and 1 mM isobutylmethylxanthine), or the cholinoceptor agonist carbachol (100 microM). 6. Inhibition of glucose-stimulated insulin release by adrenaline or noradrenaline (10 microM) was partially reversed by BTS 67582 (10[-4] M). 7. These data suggest that the insulin-releasing effect of BTS 67582 involves regulation of ATP-sensitive K+ channel activity and Ca2+ influx, and that the drug augments the stimulant effects of nutrient insulin secretagogues and agents which enhance adenylate cyclase and phospholipase C. BTS 67582 may also exert insulin-releasing effects independently of ATP-sensitive K+ channel activity.

Novel covalently linked insulin dimer engineered to investigate the function of insulin dimerization.

Directory of Open Access Journals (Sweden)

Tine N Vinther

Full Text Available An ingenious system evolved to facilitate insulin binding to the insulin receptor as a monomer and at the same time ensure sufficient stability of insulin during storage. Insulin dimer is the cornerstone of this system. Insulin dimer is relatively weak, which ensures dissociation into monomers in the circulation, and it is stabilized by hexamer formation in the presence of zinc ions during storage in the pancreatic β-cell. Due to the transient nature of insulin dimer, direct investigation of this important form is inherently difficult. To address the relationship between insulin oligomerization and insulin stability and function, we engineered a covalently linked insulin dimer in which two monomers were linked by a disulfide bond. The structure of this covalent dimer was identical to the self-association dimer of human insulin. Importantly, this covalent dimer was capable of further oligomerization to form the structural equivalent of the classical hexamer. The covalently linked dimer neither bound to the insulin receptor, nor induced a metabolic response in vitro. However, it was extremely thermodynamically stable and did not form amyloid fibrils when subjected to mechanical stress, underlining the importance of oligomerization for insulin stability.

Acute systemic insulin intolerance does not alter the response of the Akt/GSK-3 pathway to environmental hypoxia in human skeletal muscle

DEFF Research Database (Denmark)

D'Hulst, Gommaar; Sylow, Lykke; Hespel, Peter

2015-01-01

PURPOSE: To investigate how acute environmental hypoxia regulates blood glucose and downstream intramuscular insulin signaling after a meal in healthy humans. METHODS: Fifteen subjects were exposed for 4 h to normoxia (NOR) or to normobaric hypoxia (HYP, FiO2 = 0.11) in a randomized order 40 min ...... insulin intolerance developed independently of defects in conventional insulin signaling in skeletal muscle....

Insulin resistance in obesity can be reliably identified from fasting plasma insulin

NARCIS (Netherlands)

ter Horst, K. W.; Gilijamse, P. W.; Koopman, K. E.; de Weijer, B. A.; Brands, M.; Kootte, R. S.; Romijn, J. A.; Ackermans, M. T.; Nieuwdorp, M.; Soeters, M. R.; Serlie, M. J.

2015-01-01

Insulin resistance is the major contributor to cardiometabolic complications of obesity. We aimed to (1) establish cutoff points for insulin resistance from euglycemic hyperinsulinemic clamps (EHCs), (2) identify insulin-resistant obese subjects and (3) predict insulin resistance from routinely

Evidence for altered transport of insulin across the blood-brain barrier in insulin-resistant humans.

Science.gov (United States)

Heni, Martin; Schöpfer, Patricia; Peter, Andreas; Sartorius, Tina; Fritsche, Andreas; Synofzik, Matthis; Häring, Hans-Ulrich; Maetzler, Walter; Hennige, Anita M

2014-08-01

Eating behavior, body weight regulation, peripheral glucose metabolism, and cognitive function depend on adequate insulin action in the brain, and recent studies in humans suggested that impaired insulin action in the brain emerges upon fat intake, obesity, and genetic variants. As insulin enters into the brain in a receptor-mediated fashion, we hypothesized that whole-body insulin sensitivity might affect the transport of insulin into the brain and contribute to the aversive effect of insulin resistance in the central nervous system. In this study, we aimed to determine the ratio of insulin in the cerebrospinal fluid and serum to whole-body insulin sensitivity. Healthy human subjects participated in an oral glucose tolerance test to determine whole-body insulin sensitivity and underwent lumbar puncture. Blood and CSF concentrations of insulin were significantly correlated. The CSF/serum ratio for insulin was significantly associated with whole body insulin sensitivity with reduced insulin transported into the CSF in insulin-resistant subjects. Together, our data suggest that transport of insulin into the CSF relates to peripheral insulin sensitivity and impairs insulin action in the brain. This underlines the need for sensitizing measures in insulin-resistant subjects.

Total body fat, pro-inflammatory cytokines and insulin resistance in Indian subjects

Energy Technology Data Exchange (ETDEWEB)

Yajnik, C S [Diabetes Unit, KEM Hospital Research Centre, Pune (India); Yudkin, J S [Whittington Hospital, University College of London, London (United Kingdom); Shetty, P S [London School of Hygiene and Tropical Medicine, London (United Kingdom); Kurpad, A [St. John' s Medical College, Bangalore (India)

1999-07-01

There is a growing epidemic of insulin resistance syndrome (IRS) in Indians. We postulate that increased susceptibility of the urban Indians to insulin resistance is a result of a tendency to increased fat deposition from the time of intrauterine life (thrifty phenotype), exaggerated in the urban environment by a positive energy balance. The pro-inflammatory cytokines secreted by the inflammatory cells as well by the adipose tissue could aggravate insulin resistance and endothelial damage and therefore, increase the susceptibility to type 2 diabetes and coronary heart disease (CHD) independent of the previously proposed glucose fatty acid cycle mechanism. In a preliminary study, we propose to make detailed measurements of the proposed mechanisms in a selected population from 3 geographical locations in and near the city of Pune, India and also validate simple 'epidemiologic' measurements of body composition with 'reference' measurements. One hundred men (30 to 50y) each from the three geographical locations (rural, urban slum-dwellers and urban middle class in Pune) will be studied for: (i) Body composition: Anthropometric and bioimpedance measurement of total body fat (to be calibrated against deuterated water in 30 subjects from each location), and muscle mass by anthropometry and urinary creatinine excretion; (ii) Body fat distribution by subscapular- triceps ratio, waist-hip ratio; (iii) Metabolic: Glucose tolerance and insulin resistance variables (insulin, lipids, NEFA) and leptin; (iv) Endothelial markers: e-Selectin and von Willebrand Factor (vWF); (v) Inflammatory markers and pro-inflammatory cytokines: C-reactive protein (CRP), Interleukin-6 (IL-6) and tumour necrosis factor (TNF- {alpha}); (vi) Energy Balance: Assessment of nutritional intake (calories, carbohydrates, proteins and fats, n3 and n6 fatty acids) and physical activity by a questionnaire. Insulin resistance variables, endothelial markers, cytokines and obesity parameters will be compared in

Total body fat, pro-inflammatory cytokines and insulin resistance in Indian subjects

International Nuclear Information System (INIS)

Yajnik, C.S.; Yudkin, J.S.; Shetty, P.S.; Kurpad, A.

1999-01-01

There is a growing epidemic of insulin resistance syndrome (IRS) in Indians. We postulate that increased susceptibility of the urban Indians to insulin resistance is a result of a tendency to increased fat deposition from the time of intrauterine life (thrifty phenotype), exaggerated in the urban environment by a positive energy balance. The pro-inflammatory cytokines secreted by the inflammatory cells as well by the adipose tissue could aggravate insulin resistance and endothelial damage and therefore, increase the susceptibility to type 2 diabetes and coronary heart disease (CHD) independent of the previously proposed glucose fatty acid cycle mechanism. In a preliminary study, we propose to make detailed measurements of the proposed mechanisms in a selected population from 3 geographical locations in and near the city of Pune, India and also validate simple 'epidemiologic' measurements of body composition with 'reference' measurements. One hundred men (30 to 50y) each from the three geographical locations (rural, urban slum-dwellers and urban middle class in Pune) will be studied for: (i) Body composition: Anthropometric and bioimpedance measurement of total body fat (to be calibrated against deuterated water in 30 subjects from each location), and muscle mass by anthropometry and urinary creatinine excretion; (ii) Body fat distribution by subscapular- triceps ratio, waist-hip ratio; (iii) Metabolic: Glucose tolerance and insulin resistance variables (insulin, lipids, NEFA) and leptin; (iv) Endothelial markers: e-Selectin and von Willebrand Factor (vWF); (v) Inflammatory markers and pro-inflammatory cytokines: C-reactive protein (CRP), Interleukin-6 (IL-6) and tumour necrosis factor (TNF- α); (vi) Energy Balance: Assessment of nutritional intake (calories, carbohydrates, proteins and fats, n3 and n6 fatty acids) and physical activity by a questionnaire. Insulin resistance variables, endothelial markers, cytokines and obesity parameters will be compared in the 3

Comparison of a soluble co-formulation of insulin degludec/insulin aspart vs biphasic insulin aspart 30 in type 2 diabetes

DEFF Research Database (Denmark)

Niskanen, Leo; Leiter, Lawrence A; Franek, Edward

2012-01-01

Insulin degludec/insulin aspart (IDegAsp) is a soluble co-formulation of insulin degludec (70%) and insulin aspart (IAsp: 30%). Here, we compare the efficacy and safety of IDegAsp, an alternative IDegAsp formulation (AF: containing 45% IAsp), and biphasic IAsp 30 (BIAsp 30)....

Molecular Mechanisms of Insulin Secretion and Insulin Action.

Science.gov (United States)

Flatt, Peter R.; Bailey, Clifford J.

1991-01-01

Information and current ideas on the factors regulating insulin secretion, the mechanisms underlying the secretion and biological actions of insulin, and the main characteristics of diabetes mellitus are presented. (Author)

Reversal of hyperglycemia in mice by using human expandable insulin-producing cells differentiated from fetal liver progenitor cells

Science.gov (United States)

Zalzman, Michal; Gupta, Sanjeev; Giri, Ranjit K.; Berkovich, Irina; Sappal, Baljit S.; Karnieli, Ohad; Zern, Mark A.; Fleischer, Norman; Efrat, Shimon

2003-06-01

Beta-cell replacement is considered to be the most promising approach for treatment of type 1 diabetes. Its application on a large scale is hindered by a shortage of cells for transplantation. Activation of insulin expression, storage, and regulated secretion in stem/progenitor cells offers novel ways to overcome this shortage. We explored whether fetal human progenitor liver cells (FH) could be induced to differentiate into insulin-producing cells after expression of the pancreatic duodenal homeobox 1 (Pdx1) gene, which is a key regulator of pancreatic development and insulin expression in beta cells. FH cells possess a considerable replication capacity, and this was further extended by introduction of the gene for the catalytic subunit of human telomerase. Immortalized FH cells expressing Pdx1 activated multiple beta-cell genes, produced and stored considerable amounts of insulin, and released insulin in a regulated manner in response to glucose. When transplanted into hyperglycemic immunodeficient mice, the cells restored and maintained euglycemia for prolonged periods. Quantitation of human C-peptide in the mouse serum confirmed that the glycemia was normalized by the transplanted human cells. This approach offers the potential of a novel source of cells for transplantation into patients with type 1 diabetes.

Restoring proximal caries lesions conservatively with tunnel restorations

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Chu CH

2013-07-01

Full Text Available Chun-Hung Chu1, May L Mei,1 Chloe Cheung,1 Romesh P Nalliah2 1Faculty of Dentistry, The University of Hong Kong, Hong Kong, People's Republic of China; 2Department of Restorative Dentistry and Biomaterials Sciences, Harvard School of Dental Medicine, Boston, MA, USA Abstract: The tunnel restoration has been suggested as a conservative alternative to the conventional box preparation for treating proximal caries. The main advantage of tunnel restoration over the conventional box or slot preparation includes being more conservative and increasing tooth integrity and strength by preserving the marginal ridge. However, tunnel restoration is technique-sensitive and can be particularly challenging for inexperienced restorative dentists. Recent advances in technology, such as the contemporary design of dental handpieces with advanced light-emitting diode (LED and handheld comfort, offer operative dentists better vision, illumination, and maneuverability. The use of magnifying loupes also enhances the visibility of the preparation. The advent of digital radiographic imaging has improved dental imaging and reduced radiation. The new generation of restorative materials has improved mechanical properties. Tunnel restoration can be an option to restore proximal caries if the dentist performs proper case selection and pays attention to the details of the restorative procedures. This paper describes the clinical technique of tunnel restoration and reviews the studies of tunnel restorations. Keywords: operative, practice, tunnel preparation, composite, amalgam, glass ionomer

Body fat related to daily physical activity and insulin concentrations in non-diabetic children

DEFF Research Database (Denmark)

Dencker, Magnus; Thorsson, Ola; Karlsson, Magnus K

2007-01-01

This study explored the associations between body fat versus daily physical activity and insulin concentrations in non-diabetic young children in a cross-sectional study of 172 children (93 boys and 79 girls) aged 8-11 years. Blood samples were analysed for serum insulin and daily physical activity......%). Body fat distribution was calculated as AFM/TBF. Body fat distribution was independently linked to both insulin concentrations and physical activity. In contrast, TBF, AFM, and BF% were linked to physical activity only and not to insulin concentrations. In conclusion in this population of non-diabetic...... was measured by accelerometers. Time spent performing vigorous activity was estimated from accelerometer data by using established cut-off points. Dual-energy x-ray absorptiometry (DXA) was used to quantify abdominal fat mass (AFM) and total body fat (TBF), also calculated as percentage of body weight (BF...

Rates of insulin secretion in INS-1 cells are enhanced by coupling to anaplerosis and Kreb's cycle flux independent of ATP synthesis

Energy Technology Data Exchange (ETDEWEB)

Cline, Gary W., E-mail: gary.cline@yale.edu [The Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520 (United States); Department of Surgery, University of Minnesota-Twin Cities, Minneapolis, MN 55455 (United States); Pongratz, Rebecca L.; Zhao, Xiaojian [The Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520 (United States); Papas, Klearchos K. [Department of Surgery, University of Minnesota-Twin Cities, Minneapolis, MN 55455 (United States)

2011-11-11

Highlights: Black-Right-Pointing-Pointer We studied media effects on mechanisms of insulin secretion of INS-1 cells. Black-Right-Pointing-Pointer Insulin secretion was higher in DMEM than KRB despite identical ATP synthesis rates. Black-Right-Pointing-Pointer Insulin secretion rates correlated with rates of anaplerosis and TCA cycle. Black-Right-Pointing-Pointer Mitochondria metabolism and substrate cycles augment secretion signal of ATP. -- Abstract: Mechanistic models of glucose stimulated insulin secretion (GSIS) established in minimal media in vitro, may not accurately describe the complexity of coupling metabolism with insulin secretion that occurs in vivo. As a first approximation, we have evaluated metabolic pathways in a typical growth media, DMEM as a surrogate in vivo medium, for comparison to metabolic fluxes observed under the typical experimental conditions using the simple salt-buffer of KRB. Changes in metabolism in response to glucose and amino acids and coupling to insulin secretion were measured in INS-1 832/13 cells. Media effects on mitochondrial function and the coupling efficiency of oxidative phosphorylation were determined by fluorometrically measured oxygen consumption rates (OCRs) combined with {sup 31}P NMR measured rates of ATP synthesis. Substrate preferences and pathways into the TCA cycle, and the synthesis of mitochondrial 2nd messengers by anaplerosis were determined by {sup 13}C NMR isotopomer analysis of the fate of [U-{sup 13}C] glucose metabolism. Despite similar incremental increases in insulin secretion, the changes of OCR in response to increasing glucose from 2.5 to 15 mM were blunted in DMEM relative to KRB. Basal and stimulated rates of insulin secretion rates were consistently higher in DMEM, while ATP synthesis rates were identical in both DMEM and KRB, suggesting greater mitochondrial uncoupling in DMEM. The relative rates of anaplerosis, and hence synthesis and export of 2nd messengers from the mitochondria were found

Insulin Biosynthetic Interaction Network Component, TMEM24, Facilitates Insulin Reserve Pool Release

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Anita Pottekat

2013-09-01

Full Text Available Insulin homeostasis in pancreatic β cells is now recognized as a critical element in the progression of obesity and type II diabetes (T2D. Proteins that interact with insulin to direct its sequential synthesis, folding, trafficking, and packaging into reserve granules in order to manage release in response to elevated glucose remain largely unknown. Using a conformation-based approach combined with mass spectrometry, we have generated the insulin biosynthetic interaction network (insulin BIN, a proteomic roadmap in the β cell that describes the sequential interacting partners of insulin along the secretory axis. The insulin BIN revealed an abundant C2 domain-containing transmembrane protein 24 (TMEM24 that manages glucose-stimulated insulin secretion from a reserve pool of granules, a critical event impaired in patients with T2D. The identification of TMEM24 in the context of a comprehensive set of sequential insulin-binding partners provides a molecular description of the insulin secretory pathway in β cells.

Identification of residues in the insulin molecule important for binding to insulin-degrading enzyme

Energy Technology Data Exchange (ETDEWEB)

Affholter, J.A.; Roth, R.A. (Stanford Univ. School of Medicine, CA (USA)); Cascieri, M.A.; Bayne, M.L. (Merck Sharp and Dohme Research Labs., Rahway, NJ (USA)); Brange, J. (Novo Research Institute, Bagsvaerd (Denmark)); Casaretto, M. (Deutsches Wollforschungsinstitut an der Technischen, Aachen (West Germany))

1990-08-21

Insulin-degrading enzyme (IDE) hydrolyzes insulin at a limited number of sites. Although the positions of these cleavages are known, the residues of insulin important in its binding to IDE have not been defined. To this end, the authors have studied the binding of a variety of insulin analogues to the protease in a solid-phase binding assay using immunoimmobilized IDE. Since IDE binds insulin with 600-fold greater affinity than it does insulin-like growth factor, the first set of analogues studied were hybrid molecules of insulin and IGF I. Removal of the eight amino acid D-chain region of IGF I (which has been predicted to interfere with binding to the 23-25 region) results in a 25-fold increase in affinity for IDE, confirming the importance of residues 23-25 in the high-affinity recognition of IDE. A similar role for the corresponding (B24-26) residues of insulin is supported by the use of site-directed mutant and semisynthetic insulin analogues. Insulin mutants (B25-Asp)insulin and (B25-His)insulin display 16- and 20-fold decreases in IDE affinity versus wild-type insulin. Similar decreases in affinity are observed with the C-terminal truncation mutants (B1-24-His{sup 25}-NH{sub 2})insulin and (B1-24-Leu{sup 25}-NH{sub 2})insulin, but not (B1-24-Trp{sup 25}-NH{sub 2})insulin and (B1-24-Tyr{sup 25}-NH{sub 2})insulin. The truncated analogue with the lowest affinity for IDE ((B1-24-His{sup 25}-NH{sub 2})insulin) has one of the highest affinities for the insulin receptor. Therefore, they have identified a region of the insulin molecule responsible for its high-affinity interaction with IDE. Although the same region has been implicated in the binding of insulin to its receptor, the data suggest that the structural determinants required for binding to receptor and IDE differ.

Identification of residues in the insulin molecule important for binding to insulin-degrading enzyme

International Nuclear Information System (INIS)

Affholter, J.A.; Roth, R.A.; Cascieri, M.A.; Bayne, M.L.; Brange, J.; Casaretto, M.

1990-01-01

Insulin-degrading enzyme (IDE) hydrolyzes insulin at a limited number of sites. Although the positions of these cleavages are known, the residues of insulin important in its binding to IDE have not been defined. To this end, the authors have studied the binding of a variety of insulin analogues to the protease in a solid-phase binding assay using immunoimmobilized IDE. Since IDE binds insulin with 600-fold greater affinity than it does insulin-like growth factor, the first set of analogues studied were hybrid molecules of insulin and IGF I. Removal of the eight amino acid D-chain region of IGF I (which has been predicted to interfere with binding to the 23-25 region) results in a 25-fold increase in affinity for IDE, confirming the importance of residues 23-25 in the high-affinity recognition of IDE. A similar role for the corresponding (B24-26) residues of insulin is supported by the use of site-directed mutant and semisynthetic insulin analogues. Insulin mutants [B25-Asp]insulin and [B25-His]insulin display 16- and 20-fold decreases in IDE affinity versus wild-type insulin. Similar decreases in affinity are observed with the C-terminal truncation mutants [B1-24-His 25 -NH 2 ]insulin and [B1-24-Leu 25 -NH 2 ]insulin, but not [B1-24-Trp 25 -NH 2 ]insulin and [B1-24-Tyr 25 -NH 2 ]insulin. The truncated analogue with the lowest affinity for IDE ([B1-24-His 25 -NH 2 ]insulin) has one of the highest affinities for the insulin receptor. Therefore, they have identified a region of the insulin molecule responsible for its high-affinity interaction with IDE. Although the same region has been implicated in the binding of insulin to its receptor, the data suggest that the structural determinants required for binding to receptor and IDE differ

Continuation versus discontinuation of insulin secretagogues when initiating insulin in type 2 diabetes

NARCIS (Netherlands)

Swinnen, S. G.; Dain, M.-P.; Mauricio, D.; DeVries, J. H.; Hoekstra, J. B.; Holleman, F.

2010-01-01

We compared the combined use of basal insulin, metformin and insulin secretagogues with a combination of basal insulin and metformin in patients with type 2 diabetes starting basal insulin analogue therapy. This analysis was part of a 24-week trial, in which 964 insulin-naive patients with type 2

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

Science.gov (United States)

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.

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.

Rates of insulin secretion in INS-1 cells are enhanced by coupling to anaplerosis and Kreb's cycle flux independent of ATP synthesis.

Science.gov (United States)

Cline, Gary W; Pongratz, Rebecca L; Zhao, Xiaojian; Papas, Klearchos K

2011-11-11

Mechanistic models of glucose stimulated insulin secretion (GSIS) established in minimal media in vitro, may not accurately describe the complexity of coupling metabolism with insulin secretion that occurs in vivo. As a first approximation, we have evaluated metabolic pathways in a typical growth media, DMEM as a surrogate in vivo medium, for comparison to metabolic fluxes observed under the typical experimental conditions using the simple salt-buffer of KRB. Changes in metabolism in response to glucose and amino acids and coupling to insulin secretion were measured in INS-1 832/13 cells. Media effects on mitochondrial function and the coupling efficiency of oxidative phosphorylation were determined by fluorometrically measured oxygen consumption rates (OCRs) combined with (31)P NMR measured rates of ATP synthesis. Substrate preferences and pathways into the TCA cycle, and the synthesis of mitochondrial 2nd messengers by anaplerosis were determined by (13)C NMR isotopomer analysis of the fate of [U-(13)C] glucose metabolism. Despite similar incremental increases in insulin secretion, the changes of OCR in response to increasing glucose from 2.5 to 15mM were blunted in DMEM relative to KRB. Basal and stimulated rates of insulin secretion rates were consistently higher in DMEM, while ATP synthesis rates were identical in both DMEM and KRB, suggesting greater mitochondrial uncoupling in DMEM. The relative rates of anaplerosis, and hence synthesis and export of 2nd messengers from the mitochondria were found to be similar in DMEM to those in KRB. And, the correlation of total PC flux with insulin secretion rates in DMEM was found to be congruous with the correlation in KRB. Together, these results suggest that signaling mechanisms associated with both TCA cycle flux and with anaplerotic flux, but not ATP production, may be responsible for the enhanced rates of insulin secretion in more complex, and physiologically-relevant media. Copyright © 2011 Elsevier Inc. All

Enhanced hepatic insulin signaling in the livers of high altitude native rats under basal conditions and in the livers of low altitude native rats under insulin stimulation: a mechanistic study.

Science.gov (United States)

Al Dera, Hussain; Eleawa, Samy M; Al-Hashem, Fahaid H; Mahzari, Moeber M; Hoja, Ibrahim; Al Khateeb, Mahmoud

2017-07-01

This study was designed to investigate the role of the liver in lowering fasting blood glucose levels (FBG) in rats native to high (HA) and low altitude (LA) areas. As compared with LA natives, besides the improved insulin and glucose tolerance, HA native rats had lower FBG, at least mediated by inhibition of hepatic gluconeogenesis and activation of glycogen synthesis. An effect that is mediated by the enhancement of hepatic insulin signaling mediated by the decreased phosphorylation of TSC induced inhibition of mTOR function. Such effect was independent of activation of AMPK nor stabilization of HIF1α, but most probably due to oxidative stress induced REDD1 expression. However, under insulin stimulation, and in spite of the less activated mTOR function in HA native rats, LA native rats had higher glycogen content and reduced levels of gluconeogenic enzymes with a more enhanced insulin signaling, mainly due to higher levels of p-IRS1 (tyr612).

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

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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.

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

Science.gov (United States)

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

Insulin-loaded poly(epsilon-caprolactone) nanoparticles: efficient, sustained and safe insulin delivery system.

Science.gov (United States)

de Araújo, Thiago M; Teixeira, Zaine; Barbosa-Sampaio, Helena C; Rezende, Luiz F; Boschero, Antonio C; Durán, Nelson; Höehr, Nelci F

2013-06-01

The aim of this work was to develop an efficient, biodegradable, biocompatible and safe controlled release system using insulin-loaded poly(epsilon-caprolactone) (PCL) nanoparticles. The insulin-loaded PCL nanoparticles were prepared by double emulsion method (water-in-oil-in-water) using Pluronic F68 as emulsifier. Using the double emulsion method a high insulin encapsulation efficiency (90.6 +/-1.6%) with a zeta potential of -29 +/-2.7 mV and average particle size of 796 +/-10.5 nm was obtained. Insulin-loaded PCL nanoparticles showed no toxicity to MIN6 cells. Insulin nanoparticles administered subcutaneously and intraperitoneally in rats reduced glycaemia of basal levels after 15 minutes, and presented a sustainable hypoglycemic effect on insulin-dependent type 1 diabetic rats, showing to be more efficient than unencapsulated insulin. Furthermore, these nanoparticles were not hepatotoxic, as evaluated by the effect over liver cell-death and oxidative stress scavenger system in rats. These results suggest that insulin-loaded PCL nanoparticles prepared by water-in-oil-in-water emulsion method are biocompatible, efficient and safe insulin-delivering system with controlled insulin release, which indicates that it may be a powerful tool for insulin-dependent patients care.

Light-intensity physical activity is associated with insulin resistance in elderly Japanese women independent of moderate-to vigorous-intensity physical activity.

Science.gov (United States)

Gando, Yuko; Murakami, Haruka; Kawakami, Ryoko; Tanaka, Noriko; Sanada, Kiyoshi; Tabata, Izumi; Higuchi, Mitsuru; Miyachi, Motohiko

2014-02-01

It is unclear whether light physical activity is beneficially associated with insulin resistance, similar to moderate and/or vigorous physical activity. This cross-sectional study was performed to determine the relationship between the amount of light physical activity, as determined with a triaxial accelerometer, and insulin resistance. A total of 807 healthy men and women participated in this study. Physical activity was measured using a triaxial accelerometer worn for 28 days and summarized as light intensity (1.1-2.9 METs) or moderate to vigorous intensity (≥ 3.0 METs). Insulin resistance was evaluated by HOMA_R (FPG [mg/dL] × IRI [μU/mL]/405). The daily time spent in light physical activity was inversely associated with HOMA_R (r = -0.173, P physical activity and HOMA_R remained statistically significant (β = -0.119, P physical activity remained significantly associated with HOMA_R following further adjustment for moderate to vigorous intensity activity (β = -0.125, P physical activity was modeled as quartiles, especially in elderly women. These cross-sectional data suggest that light-intensity physical activity is beneficially associated with insulin resistance in elderly Japanese women.

Is Insulin Action in the Brain Relevant in Regulating Blood Glucose in Humans?

Science.gov (United States)

Dash, Satya; Xiao, Changting; Morgantini, Cecilia; Koulajian, Khajag; Lewis, Gary F

2015-07-01

In addition to its direct action on the liver to lower hepatic glucose production, insulin action in the central nervous system (CNS) also lowers hepatic glucose production in rodents after 4 hours. Although CNS insulin action (CNSIA) modulates hepatic glycogen synthesis in dogs, it has no net effect on hepatic glucose output over a 4-hour period. The role of CNSIA in regulating plasma glucose has recently been examined in humans and is the focus of this review. Intransal insulin (INI) administration increases CNS insulin concentration. Hence, INI can address whether CNSIA regulates plasma glucose concentration in humans. We and three other groups have sought to answer this question, with differing conclusions. Here we will review the critical aspects of each study, including its design, which may explain these discordant conclusions. The early glucose-lowering effect of INI is likely due to spillover of insulin into the systemic circulation. In the presence of simultaneous portal and CNS hyperinsulinemia, portal insulin action is dominant. INI administration does lower plasma glucose independent of peripheral insulin concentration (between ∼3 and 6 h after administration), suggesting that CNSIA may play a role in glucose homeostasis in the late postprandial period when its action is likely greatest and portal insulin concentration is at baseline. The potential physiological role and purpose of this pathway are discussed in this review. Because the effects of INI are attenuated in patients with type 2 diabetes and obesity, this is unlikely to be of therapeutic utility.

Central insulin administration improves odor-cued reactivation of spatial memory in young men.

Science.gov (United States)

Brünner, Yvonne F; Kofoet, Anja; Benedict, Christian; Freiherr, Jessica

2015-01-01

Insulin receptors are ubiquitously found in the human brain, comprising the olfactory bulb, essential for odor processing, and the hippocampus, important for spatial memory processing. The present study aimed at examining if intranasal insulin, which is known to transiently increase brain insulin levels in humans, would improve odor-cued reactivation of spatial memory in young men. We applied a double-blind, placebo-controlled, counterbalanced within-subject design. The study was conducted at the research unit of a university hospital. Interventions/Participants/Main Outcome Measures: Following intranasal administration of either insulin (40 I.U.) or placebo, male subjects (n = 18) were exposed to eight odors. During each odor exposure, a green-colored field was presented on a 17-in. computer screen. During immediate recall (comprising 3 runs), the participants were re-exposed to each odor cue, and were asked to select the corresponding field (with visual feedback after each response). The delayed recall was scheduled ∼10 min later (without feedback). To test if insulin's putative effect on odor-place memory would be domain-specific, participants also performed a separate place and odor recognition task. Intranasal insulin improved the delayed but not immediate odor-cued recall of spatial memory. This effect was independent of odor type and in the absence of systemic side effects (eg, fasting plasma glucose levels remained unaltered). Place and odor recognition were unaffected by the insulin treatment. These findings suggest that acute intranasal insulin improves odor-cued reactivation of spatial memory in young men.

Insulin pumps and insulin quality--requirements and problems.

Science.gov (United States)

Brange, J; Havelund, S

1983-01-01