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Sample records for outlying insulin sensitivity

  1. Insulin resistance and insulin sensitizers.

    PubMed

    Stumvoll, M; Häring, H

    2001-01-01

    Insulin resistance is a key factor in the pathogenesis of type 2 diabetes mellitus and a co-factor in the development of dyslipidaemia, hypertension and atherosclerosis. The causes of insulin resistance include factors such as obesity and physical inactivity, and there may also be genetic factors. The mechanism of obesity-related insulin resistance involves the release of factors from adipocytes which exert a negative effect on glucose metabolism: free fatty acids, tumour necrosis factor-alpha and the recently discovered hormone, resistin. The two resulting abnormalities observed consistently in glucose-intolerant states are impaired suppression of endogenous glucose production, and impaired stimulation of glucose uptake. Among the genetic factors, a polymorphism (Pro12Ala) in the peroxisome proliferator-activated receptor (PPAR) gamma is associated with a reduced risk of type 2 diabetes mellitus and increased insulin sensitivity, primarily that of lipolysis. On the other hand, the association with insulin resistance of a common polymorphism (Gly972Arg) in the insulin receptor substrate 1, long believed to be a plausible candidate gene, is weak at best. This polymorphism may instead be associated with reduced insulin secretion, which, in view of the recent recognition of the insulin signalling system in beta-cells, results in the development of a novel pathogenic concept. Finally, fine-mapping and positional cloning of the susceptibility locus on chromosome 2 resulted in the identification of a polymorphism (UCSNP-43 G/A) in the calpain-10 gene. In non-diabetic Pima Indians, this polymorphism was associated with insulin resistance of glucose disposal. The pharmacological treatment of insulin resistance has recently acquired a novel class of agents: the thiazolidinediones. They act through regulation of PPARgamma-dependent genes and probably interfere favourably with factors released from adipocytes which mediate obesity-associated insulin resistance. PMID:11684868

  2. Cinnamon, glucose and insulin sensitivity

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Compounds found in cinnamon not only improve the function of insulin but also function as antioxidants and may be anti-inflammatory. This is very important since insulin function, antioxidant status, and inflammatory response are closely linked; with decreased insulin sensitivity there is also decr...

  3. Anaphylaxis to subcutaneous neutral protamine Hagedorn insulin with simultaneous sensitization to protamine and insulin.

    PubMed

    Blanco, C; Castillo, R; Quiralte, J; Delgado, J; García, I; de Pablos, P; Carrillo, T

    1996-06-01

    We report an insulin-treated diabetic patient who suffered, in a 2-month period, three severe anaphylactic reactions immediately after self-administered subcutaneous injections of neutral protamine Hagedorn (NPH) human recombinant-DNA insulin. These reactions consisted of local and systemic symptoms, including dyspnea and hypotension. A simultaneous sensitization to human insulin and to protamine was demonstrated, both by skin tests and by the determination of serum specific IgE. Suspecting protamine allergy, we performed a test dose to human lente insulin with perfect tolerance. After a 1-year follow-up with lente-insulin treatment, no reactions have occurred, despite treatment interruptions. Therefore, protamine IgE-mediated allergy probably caused our patient's reactions. In conclusion, protamine sensitization should be ruled out in any patient with a history of reactions to subcutaneous protamine-containing insulins, even if insulin sensitization is present. PMID:8837667

  4. Quantification of adipose tissue insulin sensitivity.

    PubMed

    Søndergaard, Esben; Jensen, Michael D

    2016-06-01

    In metabolically healthy humans, adipose tissue is exquisitely sensitive to insulin. Similar to muscle and liver, adipose tissue lipolysis is insulin resistant in adults with central obesity and type 2 diabetes. Perhaps uniquely, however, insulin resistance in adipose tissue may directly contribute to development of insulin resistance in muscle and liver because of the increased delivery of free fatty acids to those tissues. It has been hypothesized that insulin adipose tissue resistance may precede other metabolic defects in obesity and type 2 diabetes. Therefore, precise and reproducible quantification of adipose tissue insulin sensitivity, in vivo, in humans, is an important measure. Unfortunately, no consensus exists on how to determine adipose tissue insulin sensitivity. We review the methods available to quantitate adipose tissue insulin sensitivity and will discuss their strengths and weaknesses. PMID:27073214

  5. Increased skeletal muscle capillarization enhances insulin sensitivity.

    PubMed

    Akerstrom, Thorbjorn; Laub, Lasse; Vedel, Kenneth; Brand, Christian Lehn; Pedersen, Bente Klarlund; Lindqvist, Anna Kaufmann; Wojtaszewski, Jørgen F P; Hellsten, Ylva

    2014-12-15

    Increased skeletal muscle capillarization is associated with improved glucose tolerance and insulin sensitivity. However, a possible causal relationship has not previously been identified. Therefore, we investigated whether increased skeletal muscle capillarization increases insulin sensitivity. Skeletal muscle-specific angiogenesis was induced by adding the α1-adrenergic receptor antagonist prazosin to the drinking water of Sprague-Dawley rats (n = 33), whereas 34 rats served as controls. Insulin sensitivity was measured ≥40 h after termination of the 3-wk prazosin treatment, which ensured that prazosin was cleared from the blood stream. Whole body insulin sensitivity was measured in conscious, unrestrained rats by hyperinsulinemic euglycemic clamp. Tissue-specific insulin sensitivity was assessed by administration of 2-deoxy-[(3)H]glucose during the plateau phase of the clamp. Whole body insulin sensitivity increased by ∼24%, and insulin-stimulated skeletal muscle 2-deoxy-[(3)H]glucose disposal increased by ∼30% concomitant with an ∼20% increase in skeletal muscle capillarization. Adipose tissue insulin sensitivity was not affected by the treatment. Insulin-stimulated muscle glucose uptake was enhanced independent of improvements in skeletal muscle insulin signaling to glucose uptake and glycogen synthesis, suggesting that the improvement in insulin-stimulated muscle glucose uptake could be due to improved diffusion conditions for glucose in the muscle. The prazosin treatment did not affect the rats on any other parameters measured. We conclude that an increase in skeletal muscle capillarization is associated with increased insulin sensitivity. These data point toward the importance of increasing skeletal muscle capillarization for prevention or treatment of type 2 diabetes. PMID:25352432

  6. SIRT2 regulates insulin sensitivity in insulin resistant neuronal cells.

    PubMed

    Arora, Amita; Dey, Chinmoy Sankar

    2016-06-10

    Insulin resistance in brain is well-associated with pathophysiology of deficits in whole-body energy metabolism, neurodegenerative diseases etc. Among the seven sirtuins, SIRT2 is the major deacetylase expressed in brain. Inhibition of SIRT2 confers neuroprotection in case of Parkinson's disease (PD) and Huntington's disease (HD). However, the role of this sirtuin in neuronal insulin resistance is not known. In this study, we report the role of SIRT2 in regulating insulin-sensitivity in neuronal cells in vitro. Using approaches like pharmacological inhibition of SIRT2, siRNA mediated SIRT2 knockdown and over-expression of wild-type and catalytically-mutated SIRT2, we observed that downregulation of SIRT2 ameliorated the reduced activity of AKT and increased insulin-stimulated glucose uptake in insulin resistant neuro-2a cells. The data was supported by over expression of catalytically-inactive SIRT2 in insulin-resistant human SH-SY5Y neuronal cells. Data highlights a crucial role of SIRT2 in regulation of neuronal insulin sensitivity under insulin resistant condition. PMID:27163642

  7. Heat stress increases insulin sensitivity in pigs

    PubMed Central

    Sanz Fernandez, M Victoria; Stoakes, Sara K; Abuajamieh, Mohannad; Seibert, Jacob T; Johnson, Jay S; Horst, Erin A; Rhoads, Robert P; Baumgard, Lance H

    2015-01-01

    Proper insulin homeostasis appears critical for adapting to and surviving a heat load. Further, heat stress (HS) induces phenotypic changes in livestock that suggest an increase in insulin action. The current study objective was to evaluate the effects of HS on whole-body insulin sensitivity. Female pigs (57 ± 4 kg body weight) were subjected to two experimental periods. During period 1, all pigs remained in thermoneutral conditions (TN; 21°C) and were fed ad libitum. During period 2, pigs were exposed to: (i) constant HS conditions (32°C) and fed ad libitum (n = 6), or (ii) TN conditions and pair-fed (PFTN; n = 6) to eliminate the confounding effects of dissimilar feed intake. A hyperinsulinemic euglycemic clamp (HEC) was conducted on d3 of both periods; and skeletal muscle and adipose tissue biopsies were collected prior to and after an insulin tolerance test (ITT) on d5 of period 2. During the HEC, insulin infusion increased circulating insulin and decreased plasma C-peptide and nonesterified fatty acids, similarly between treatments. From period 1 to 2, the rate of glucose infusion in response to the HEC remained similar in HS pigs while it decreased (36%) in PFTN controls. Prior to the ITT, HS increased (41%) skeletal muscle insulin receptor substrate-1 protein abundance, but did not affect protein kinase B or their phosphorylated forms. In adipose tissue, HS did not alter any of the basal or stimulated measured insulin signaling markers. In summary, HS increases whole-body insulin-stimulated glucose uptake. PMID:26243213

  8. Polyphenols, Insulin Sensitivity, and the Brain

    Technology Transfer Automated Retrieval System (TEKTRAN)

    We have isolated water-soluble polyphenols found in cinnamon that are multifunctional and improve insulin sensitivity, glucose uptake, and have antioxidant and anti-inflammatory properties in experimental animals and humans. These compounds may also be potentially neuroprotective as oxidative stres...

  9. Chromium and Polyphenols from Cinnamon and Insulin Sensitivity

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Factors that improve insulin sensitivity usually lead to improvements in risk factors associated with the metabolic syndrome, diabetes, and cardiovascular diseases. Naturally occurring bioactive compounds that have been shown to improve insulin sensitivity include chromium and polyphenols found in ...

  10. Adipocyte iron regulates adiponectin and insulin sensitivity

    PubMed Central

    Gabrielsen, J. Scott; Gao, Yan; Simcox, Judith A.; Huang, Jingyu; Thorup, David; Jones, Deborah; Cooksey, Robert C.; Gabrielsen, David; Adams, Ted D.; Hunt, Steven C.; Hopkins, Paul N.; Cefalu, William T.; McClain, Donald A.

    2012-01-01

    Iron overload is associated with increased diabetes risk. We therefore investigated the effect of iron on adiponectin, an insulin-sensitizing adipokine that is decreased in diabetic patients. In humans, normal-range serum ferritin levels were inversely associated with adiponectin, independent of inflammation. Ferritin was increased and adiponectin was decreased in type 2 diabetic and in obese diabetic subjects compared with those in equally obese individuals without metabolic syndrome. Mice fed a high-iron diet and cultured adipocytes treated with iron exhibited decreased adiponectin mRNA and protein. We found that iron negatively regulated adiponectin transcription via FOXO1-mediated repression. Further, loss of the adipocyte iron export channel, ferroportin, in mice resulted in adipocyte iron loading, decreased adiponectin, and insulin resistance. Conversely, organismal iron overload and increased adipocyte ferroportin expression because of hemochromatosis are associated with decreased adipocyte iron, increased adiponectin, improved glucose tolerance, and increased insulin sensitivity. Phlebotomy of humans with impaired glucose tolerance and ferritin values in the highest quartile of normal increased adiponectin and improved glucose tolerance. These findings demonstrate a causal role for iron as a risk factor for metabolic syndrome and a role for adipocytes in modulating metabolism through adiponectin in response to iron stores. PMID:22996660

  11. Pioglitazone Increases Whole Body Insulin Sensitivity in Obese, Insulin-Resistant Rhesus Monkeys

    PubMed Central

    Tozzo, Effie; Bhat, Gowri; Cheon, Kyeongmi; Camacho, Raul C.

    2015-01-01

    Hyperinsulinemic-euglycemic clamps are considered the "gold standard" for assessing whole body insulin sensitivity. When used in combination with tracer dilution techniques and physiological insulin concentrations, insulin sensitization can be dissected and attributed to hepatic and peripheral (primarily muscle) effects. Non-human primates (NHPs), such as rhesus monkeys, are the closest pre-clinical species to humans, and thus serve as an ideal model for testing of compound efficacy to support translation to human efficacy. We determined insulin infusion rates that resulted in high physiological insulin concentrations that elicited maximal pharmacodynamic responses during hyperinsulinemic-euglycemic clamps. These rates were then used with [U-13C]-D-glucose, to assess and document the degrees of hepatic and peripheral insulin resistance between healthy and insulin-resistant, dysmetabolic NHPs. Next, dysmetabolic NHPs were treated for 28 days with pioglitazone (3 mg/kg) and again had their insulin sensitivity assessed, illustrating a significant improvement in hepatic and peripheral insulin sensitivity. This coincided with a significant increase in insulin clearance, and normalization of circulating adiponectin. In conclusion, we have determined a physiological clamp paradigm (similar to humans) for assessing glucose turnover in NHPs. We have also demonstrated that insulin-resistant, dysmetabolic NHPs respond to the established insulin sensitizer, pioglitazone, thus confirming their use as an ideal pre-clinical translational model to assess insulin sensitizing compounds. PMID:25954816

  12. Vitamin D, Insulin Secretion, Sensitivity, and Lipids

    PubMed Central

    Grimnes, Guri; Figenschau, Yngve; Almås, Bjørg; Jorde, Rolf

    2011-01-01

    OBJECTIVE Vitamin D deficiency is associated with an unfavorable metabolic profile in observational studies. The intention was to compare insulin sensitivity (the primary end point) and secretion and lipids in subjects with low and high serum 25(OH)D (25-hydroxyvitamin D) levels and to assess the effect of vitamin D supplementation on the same outcomes among the participants with low serum 25(OH)D levels. RESEARCH DESIGN AND METHODS Participants were recruited from a population-based study (the Tromsø Study) based on their serum 25(OH)D measurements. A 3-h hyperglycemic clamp was performed, and the participants with low serum 25(OH)D levels were thereafter randomized to receive capsules of 20,000 IU vitamin D3 or identical-looking placebo twice weekly for 6 months. A final hyperglycemic clamp was then performed. RESULTS The 52 participants with high serum 25(OH)D levels (85.6 ± 13.5 nmol/L [mean ± SD]) had significantly higher insulin sensitivity index (ISI) and lower HbA1c and triglycerides (TGs) than the 108 participants with low serum 25(OH)D (40.3 ± 12.8 nmol/L), but the differences in ISI and TGs were not significant after adjustments. After supplementation, serum 25(OH)D was 142.7 ± 25.7 and 42.9 ± 17.3 nmol/L in 49 of 51 completing participants randomized to vitamin D and 45 of 53 randomized to placebo, respectively. At the end of the study, there were no statistically significant differences in the outcome variables between the two groups. CONCLUSIONS Vitamin D supplementation to apparently healthy subjects with insufficient serum 25(OH)D levels does not improve insulin sensitivity or secretion or serum lipid profile. PMID:21911741

  13. Effects of diet-induced weight gain and turnout to pasture on insulin sensitivity in moderately insulin resistant horses.

    PubMed

    Lindåse, Sanna S; Nostell, Katarina E; Müller, Cecilia E; Jensen-Waern, Marianne; Bröjer, Johan T

    2016-03-01

    OBJECTIVE To quantify insulin sensitivity and monitor glucose, insulin, and lipid concentrations in a group of moderately insulin-resistant horses during induction of obesity by use of a forage diet supplemented with fat and during subsequent turnout to pasture. ANIMALS 9 adult Standardbred mares (11 to 20 years old). PROCEDURES Weight gain of horses was induced during 22 weeks by use of a forage diet supplemented with fat fed in gradually increasing amounts, followed by feeding of that fat-supplemented diet at 2.5 times the daily maintenance requirements. Horses were then turned out to pasture. Insulin sensitivity was measured with the euglycemic hyperinsulinemic clamp method before and after weight gain and after 4 weeks at pasture. Body weight, body condition score, and cresty neck score as well as fasting and postprandial concentrations of plasma insulin, plasma glucose, serum triglyceride, and serum nonesterified fatty acids were measured during the study. RESULTS Body weight typically increased by 10%, and body condition score (scale, 1 to 9) increased by > 1.5 from the start to the end of the weight-gain period. There was no difference in insulin sensitivity or metabolic clearance rate of insulin during the weight-gain period. Four weeks at pasture generally improved insulin sensitivity and metabolic clearance rate of insulin by 54% and 32%, respectively, but there was no change in body weight or body condition score. CONCLUSIONS AND CLINICAL RELEVANCE Findings indicated that dietary composition played a more important role than did short-term weight gain on alterations in insulin sensitivity of horses. PMID:26919602

  14. Cerebral blood flow links insulin resistance and baroreflex sensitivity.

    PubMed

    Ryan, John P; Sheu, Lei K; Verstynen, Timothy D; Onyewuenyi, Ikechukwu C; Gianaros, Peter J

    2013-01-01

    Insulin resistance confers risk for diabetes mellitus and associates with a reduced capacity of the arterial baroreflex to regulate blood pressure. Importantly, several brain regions that comprise the central autonomic network, which controls the baroreflex, are also sensitive to the neuromodulatory effects of insulin. However, it is unknown whether peripheral insulin resistance relates to activity within central autonomic network regions, which may in turn relate to reduced baroreflex regulation. Accordingly, we tested whether resting cerebral blood flow within central autonomic regions statistically mediated the relationship between insulin resistance and an indirect indicator of baroreflex regulation; namely, baroreflex sensitivity. Subjects were 92 community-dwelling adults free of confounding medical illnesses (48 men, 30-50 years old) who completed protocols to assess fasting insulin and glucose levels, resting baroreflex sensitivity, and resting cerebral blood flow. Baroreflex sensitivity was quantified by measuring the magnitude of spontaneous and sequential associations between beat-by-beat systolic blood pressure and heart rate changes. Individuals with greater insulin resistance, as measured by the homeostatic model assessment, exhibited reduced baroreflex sensitivity (b = -0.16, p < .05). Moreover, the relationship between insulin resistance and baroreflex sensitivity was statistically mediated by cerebral blood flow in central autonomic regions, including the insula and cingulate cortex (mediation coefficients < -0.06, p-values < .01). Activity within the central autonomic network may link insulin resistance to reduced baroreflex sensitivity. Our observations may help to characterize the neural pathways by which insulin resistance, and possibly diabetes mellitus, relates to adverse cardiovascular outcomes. PMID:24358272

  15. PRLR Regulates Hepatic Insulin Sensitivity in Mice via STAT5

    PubMed Central

    Yu, Junjie; Xiao, Fei; Zhang, Qian; Liu, Bin; Guo, Yajie; Lv, Ziquan; Xia, Tingting; Chen, Shanghai; Li, Kai; Du, Ying; Guo, Feifan

    2013-01-01

    Insulin resistance is one of the major contributing factors in the development of metabolic diseases. The mechanisms responsible for insulin resistance, however, remain poorly understood. Although numerous functions of the prolactin receptor (PRLR) have been identified, a direct effect on insulin sensitivity has not been previously described. The aim of our current study is to investigate this possibility and elucidate underlying mechanisms. Here we show that insulin sensitivity is improved or impaired in mice injected with adenovirus that overexpress or knock down PRLR expression, respectively. Similar observations were obtained in in vitro studies. In addition, we discovered that the signal transducer and activator of transcription-5 pathway are required for regulating insulin sensitivity by PRLR. Moreover, we observed that PRLR expression is decreased or increased under insulin-resistant (db/db mice) or insulin-sensitive (leucine deprivation) conditions, respectively, and found that altering PRLR expression significantly reverses insulin sensitivity under both conditions. Finally, we found that PRLR expression levels are increased under leucine deprivation via a general control nonderepressible 2/mammalian target of rapamycin/ribosomal protein S6 kinase-1–dependent pathway. These results demonstrate a novel function for hepatic PRLR in the regulation of insulin sensitivity and provide important insights concerning the nutritional regulation of PRLR expression. PMID:23775766

  16. AMPK and Exercise: Glucose Uptake and Insulin Sensitivity

    PubMed Central

    2013-01-01

    AMPK is an evolutionary conserved sensor of cellular energy status that is activated during exercise. Pharmacological activation of AMPK promotes glucose uptake, fatty acid oxidation, mitochondrial biogenesis, and insulin sensitivity; processes that are reduced in obesity and contribute to the development of insulin resistance. AMPK deficient mouse models have been used to provide direct genetic evidence either supporting or refuting a role for AMPK in regulating these processes. Exercise promotes glucose uptake by an insulin dependent mechanism involving AMPK. Exercise is important for improving insulin sensitivity; however, it is not known if AMPK is required for these improvements. Understanding how these metabolic processes are regulated is important for the development of new strategies that target obesity-induced insulin resistance. This review will discuss the involvement of AMPK in regulating skeletal muscle metabolism (glucose uptake, glycogen synthesis, and insulin sensitivity). PMID:23441028

  17. Myocardial Fat Accumulation Is Independent of Measures of Insulin Sensitivity

    PubMed Central

    Noureldin, Radwa; Ouwerkerk, Ronald; Liu, Elizabeth Y.; Madan, Ritu; Abel, Brent S.; Mullins, Katherine; Walter, Mary F.; Skarulis, Monica C.; Gharib, Ahmed M.

    2015-01-01

    Background: Myocardial steatosis, an independent predictor of diastolic dysfunction, is frequently present in type 2 diabetes mellitus. High free fatty acid flux, hyperglycemia, and hyperinsulinemia may play a role in myocardial steatosis. There are no prior studies examining the relationship between insulin sensitivity (antilipolytic and glucose disposal actions of insulin) and cardiac steatosis. Objective: Using a cross-sectional study design of individuals with and without metabolic syndrome (MetSyn), we examined the relationships between cardiac steatosis and the sensitivity of the antilipolytic and glucose disposal actions of insulin. Methods: Pericardial fat (PF) volume, intramyocardial and hepatic fat (MF and HF) content, visceral fat (VF) and sc fat content were assessed by magnetic resonance imaging in 77 subjects (49 without MetSyn and 28 with MetSyn). In a subset of the larger cohort (n = 52), peripheral insulin sensitivity index (SI) and adipocyte insulin sensitivity (Adipo-SI) were determined from an insulin-modified frequently sampled iv glucose tolerance test. The Quantitative Insulin Sensitivity Check Index was used as a surrogate for hepatic insulin sensitivity. Results: Individuals with the MetSyn had significantly higher body mass index, total body fat, and MF, PF, HF, and VF content. HF and VF, but not MF, were negatively correlated with the Quantitative Insulin Sensitivity Check Index, Adipo-SI, and SI. Stepwise regression revealed that waist circumference and serum triglyceride levels independently predicted MF and PF, respectively. Adipo-SI and serum triglyceride levels independently predict HF. Conclusion: Myocardial steatosis is unrelated to hepatic, adipocyte, or peripheral insulin sensitivity. Although it is frequently observed in insulin-resistant subjects, further studies are necessary to identify and delineate pathogenic mechanisms that differentially affect cardiac and hepatic steatosis. PMID:26020762

  18. Skeletal Muscle Phospholipid Metabolism Regulates Insulin Sensitivity and Contractile Function.

    PubMed

    Funai, Katsuhiko; Lodhi, Irfan J; Spears, Larry D; Yin, Li; Song, Haowei; Klein, Samuel; Semenkovich, Clay F

    2016-02-01

    Skeletal muscle insulin resistance is an early defect in the development of type 2 diabetes. Lipid overload induces insulin resistance in muscle and alters the composition of the sarcoplasmic reticulum (SR). To test the hypothesis that skeletal muscle phospholipid metabolism regulates systemic glucose metabolism, we perturbed choline/ethanolamine phosphotransferase 1 (CEPT1), the terminal enzyme in the Kennedy pathway of phospholipid synthesis. In C2C12 cells, CEPT1 knockdown altered SR phospholipid composition and calcium flux. In mice, diet-induced obesity, which decreases insulin sensitivity, increased muscle CEPT1 expression. In high-fat diet-fed mice with skeletal muscle-specific knockout of CEPT1, systemic and muscle-based approaches demonstrated increased muscle insulin sensitivity. In CEPT1-deficient muscles, an altered SR phospholipid milieu decreased sarco/endoplasmic reticulum Ca(2+) ATPase-dependent calcium uptake, activating calcium-signaling pathways known to improve insulin sensitivity. Altered muscle SR calcium handling also rendered these mice exercise intolerant. In obese humans, surgery-induced weight loss increased insulin sensitivity and decreased skeletal muscle CEPT1 protein. In obese humans spanning a spectrum of metabolic health, muscle CEPT1 mRNA was inversely correlated with insulin sensitivity. These results suggest that high-fat feeding and obesity induce CEPT1, which remodels the SR to preserve contractile function at the expense of insulin sensitivity. PMID:26512026

  19. Effect of Insulin Sensitizer Therapy on Amino Acids and their Metabolites

    PubMed Central

    Irving, B.A.; Carter, R.E.; Soop, M.; Weymiller, A.; Syed, H.; Karakelides, H.; Bhagra, S.; Short, K.R.; Tatpati, L.; Barazzoni, R.; Nair, K.S.

    2015-01-01

    Aims Prior studies have reported that elevated concentrations of several plasma amino acids (AA) in plasma, particularly branched chain (BCAA) and aromatic AA predict the onset of type 2 diabetes. We sought to test the hypothesis that circulating BCAA, aromatic AA and related AA metabolites decline in response to the use of insulin sensitizing agents in overweight/obese adults with impaired fasting glucose or untreated diabetes. Methods We performed a secondary analysis of a randomized, double-blind, placebo, controlled study conducted in twenty five overweight/obese (BMI~30 kg/m2) adults with impaired fasting glucose or untreated diabetes. Participants were randomized to three months of pioglitazone (45 mg per day) plus metformin (1000 mg twice per day, N = 12 participants) or placebo (N = 13). We measured insulin sensitivity by the euglycemic-hyperinsulinemic clamp and fasting concentrations of AA and AA metabolites using ultra-pressure liquid chromatography tandem mass spectrometry before and after the three-month intervention. Results Insulin sensitizer therapy that significantly enhanced insulin sensitivity reduced 9 out of 33 AA and AA metabolites measured compared to placebo treatment. Moreover, insulin sensitizer therapy significantly reduced three functionally clustered AA and metabolite pairs: i) phenylalanine/tyrosine, ii) citrulline/arginine, and iii) lysine/α-aminoadipic acid. Conclusions Reductions in plasma concentrations of several AA and AA metabolites in response to three months of insulin sensitizer therapy support the concept that reduced insulin sensitivity alters AA and AA metabolites. PMID:25733201

  20. Insulin sensitivity indices: a proposal of cut-off points for simple identification of insulin-resistant subjects.

    PubMed

    Radikova, Z; Koska, J; Huckova, M; Ksinantova, L; Imrich, R; Vigas, M; Trnovec, T; Langer, P; Sebokova, E; Klimes, I

    2006-05-01

    Demanding measurement of insulin sensitivity using clamp methods does not simplify the identification of insulin resistant subjects in the general population. Other approaches such as fasting- or oral glucose tolerance test-derived insulin sensitivity indices were proposed and validated with the euglycemic clamp. Nevertheless, a lack of reference values for these indices prevents their wider use in epidemiological studies and clinical practice. The aim of our study was therefore to define the cut-off points of insulin resistance indices as well as the ranges of the most frequently obtained values for selected indices. A standard 75 g oral glucose tolerance test was carried out in 1156 subjects from a Caucasian rural population with no previous evidence of diabetes or other dysglycemias. Insulin resistance/sensitivity indices (HOMA-IR, HOMA-IR2, ISI Cederholm, and ISI Matsuda) were calculated. The 75th percentile value as the cut-off point to define IR corresponded with a HOMA-IR of 2.29, a HOMA-IR2 of 1.21, a 25th percentile for ISI Cederholm, and ISI Matsuda of 57 and 5.0, respectively. For the first time, the cut-off points for selected indices and their most frequently obtained values were established for groups of subjects as defined by glucose homeostasis and BMI. Thus, insulin-resistant subjects can be identified using this simple approach. PMID:16804799

  1. Attenuated insulin response and normal insulin sensitivity in lean patients with ankylosing spondylitis.

    PubMed

    Penesova, A; Rovensky, J; Zlnay, M; Dedik, L; Radikova, Z; Koska, J; Vigas, M; Imrich, R

    2005-01-01

    Chronic low-grade inflammation is associated with insulin resistance. The aim of this study was to determine insulin response to intravenous glucose load and insulin sensitivity in patients with ankylosing spondylitis (AS). Fourteen nonobese male patients with AS and 14 matched healthy controls underwent frequent-sampling intravenous glucose tolerance test (FSIVGTT). Insulin secretion and insulin sensitivity were calculated using the computer-minimal and homeostasis-model assessment 2 (HOMA2) models. Fasting glucose, insulin, cholesterol, high-density lipoprotein and low-density lipoprotein cholesterol, triglyceride levels, HOMA2, glucose effectiveness, insulin sensitivity and insulin response to FSIVGTT did not differ between patients and controls. Tumor necrosis factor-alpha and interleukin (IL)-6 concentrations tended to be higher in AS patients than in controls. Second-phase beta-cell responsiveness was 37% lower (p = 0.05) in AS patients than in controls. A negative correlation was found between the percentage of beta-cell secretion and IL-6 in all subjects (r = -0.54, p = 0.006). We found normal insulin sensitivity but attenuated glucose utilization in the second phase of FSIVGTT in AS patients. Our results indicate that elevated IL-6 levels may play a pathophysiological role in attenuating beta-cell responsiveness, which may explain the association between elevated IL-6 levels and increased risk for type 2 diabetes. PMID:16366418

  2. Mechanisms of human insulin resistance and thiazolidinedione-mediated insulin sensitization

    PubMed Central

    Sears, D. D.; Hsiao, G.; Hsiao, A.; Yu, J. G.; Courtney, C. H.; Ofrecio, J. M.; Chapman, J.; Subramaniam, S.

    2009-01-01

    Cellular and tissue defects associated with insulin resistance are coincident with transcriptional abnormalities and are improved after insulin sensitization with thiazolidinedione (TZD) PPARγ ligands. We characterized 72 human subjects by relating their clinical phenotypes with functional pathway alterations. We transcriptionally profiled 364 biopsies harvested before and after hyperinsulinemic-euglycemic clamp studies, at baseline and after 3-month TZD treatment. We have identified molecular and functional characteristics of insulin resistant subjects and distinctions between TZD treatment responder and nonresponder subjects. Insulin resistant subjects exhibited alterations in skeletal muscle (e.g., glycolytic flux and intramuscular adipocytes) and adipose tissue (e.g., mitochondrial metabolism and inflammation) that improved relative to TZD-induced insulin sensitization. Pre-TZD treatment expression of MLXIP in muscle and HLA-DRB1 in adipose tissue from insulin resistant subjects was linearly predictive of post-TZD insulin sensitization. We have uniquely characterized coordinated cellular and tissue functional pathways that are characteristic of insulin resistance, TZD-induced insulin sensitization, and potential TZD responsiveness. PMID:19841271

  3. Simultaneous measurement of insulin sensitivity, insulin secretion and the disposition index in conscious unhandled mice

    PubMed Central

    Alonso, L. C.; Watanabe, Y.; Stefanovski, D.; Lee, E. J.; Singamsetty, S.; Romano, L. C.; Zou, B.; Garcia-Ocana, A.; Bergman, R. N.; O’Donnell, C. P.

    2012-01-01

    Of the parameters that determine glucose disposal and progression to diabetes in humans: first-phase insulin secretion, glucose effectiveness, insulin sensitivity, and the disposition index, only insulin sensitivity can be reliably measured in conscious mice. To determine the importance of the other parameters in murine glucose homeostasis in lean and obese states, we developed the frequently sampled intravenous glucose tolerance test (FSIVGTT) for use in unhandled mice. We validated the conscious FSIVGTT against the euglycemic clamp for measuring insulin sensitivity in lean and obese mice. Insulin resistant mice had increased first-phase insulin secretion, decreased glucose effectiveness and a reduced disposition index, qualitatively similar to humans. Intriguingly, while insulin secretion explained most of the variation in glucose disposal in lean mice, glucose effectiveness and the disposition index more strongly predicted glucose disposal in obese mice. Disposition index curves identified individual diet-induced obese mice as having compensated or decompensated insulin secretion. Conscious FSIVGTT opens the door to apply mouse genetics to the determinants of in vivo insulin secretion, glucose effectiveness and disposition index, and further validates the mouse as a model of metabolic disease. PMID:22331130

  4. Chromium and Polyphenols From Cinnamon Improve Insulin Sensitivity

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Naturally occurring compounds that have been shown to improve insulin sensitivity include chromium and polyphenols found in cinnamon. These compounds also have similar effects on insulin signaling and glucose control. The signs of chromium deficiency are similar to those for the metabolic syndrome ...

  5. Effects of aldosterone on insulin sensitivity and secretion

    PubMed Central

    Luther, James M.

    2014-01-01

    Dr. Conn originally reported an increased risk of diabetes in patients with hyperaldosteronism in the 1950’s, although the mechanism remains unclear. Aldosterone-induced hypokalemia was initially described to impair glucose tolerance by impairing insulin secretion. Correction of hypokalemia by potassium supplementation only partially restored insulin secretion and glucose tolerance, however. Aldosterone also impairs glucose-stimulated insulin secretion in isolated pancreatic islets via reactive oxygen species in a mineralocorticoid receptor-independent manner. Aldosterone-induced mineralocorticoid receptor activation also impairs insulin sensitivity in adipocytes and skeletal muscle. Aldosterone may produce insulin resistance secondarily by altering potassium, increasing inflammatory cytokines, and reducing beneficial adipokines such as adiponectin. Renin-angiotensin system antagonists reduce circulating aldosterone concentrations and also the risk of type 2 diabetes in clinical trials. These data suggest that primary and secondary hyperaldosteronism may contribute to worsening glucose tolerance by impairing insulin sensitivity or insulin secretion in humans. Future studies should define the effects of MR antagonists and aldosterone on insulin secretion and sensitivity in humans. PMID:25194457

  6. Modulating DDAH/NOS Pathway to Discover Vasoprotective Insulin Sensitizers

    PubMed Central

    Lai, Li; Ghebremariam, Yohannes T.

    2016-01-01

    Insulin resistance syndrome (IRS) is a configuration of cardiovascular risk factors involved in the development of metabolic disorders including type 2 diabetes mellitus. In addition to diet, age, socioeconomic, and environmental factors, genetic factors that impair insulin signaling are centrally involved in the development and exacerbation of IRS. Genetic and pharmacological studies have demonstrated that the nitric oxide (NO) synthase (NOS) genes are critically involved in the regulation of insulin-mediated glucose disposal. The generation of NO by the NOS enzymes is known to contribute to vascular homeostasis including insulin-mediated skeletal muscle vasodilation and insulin sensitivity. By contrast, excessive inhibition of NOS enzymes by exogenous or endogenous factors is associated with insulin resistance (IR). Asymmetric dimethylarginine (ADMA) is an endogenous molecule that competitively inhibits all the NOS enzymes and contributes to metabolic perturbations including IR. The concentration of ADMA in plasma and tissue is enzymatically regulated by dimethylarginine dimethylaminohydrolase (DDAH), a widely expressed enzyme in the cardiovascular system. In preclinical studies, overexpression of DDAH has been shown to reduce ADMA levels, improve vascular compliance, and increase insulin sensitivity. This review discusses the feasibility of the NOS/DDAH pathway as a novel target to develop vasoprotective insulin sensitizers. PMID:26770984

  7. Autonomic blockade improves insulin sensitivity in obese subjects.

    PubMed

    Gamboa, Alfredo; Okamoto, Luis E; Arnold, Amy C; Figueroa, Rocio A; Diedrich, André; Raj, Satish R; Paranjape, Sachin Y; Farley, Ginnie; Abumrad, Naji; Biaggioni, Italo

    2014-10-01

    Obesity is an important risk factor for the development of insulin resistance. Initial compensatory mechanisms include an increase in insulin levels, which are thought to induce sympathetic activation in an attempt to restore energy balance. We have previously shown, however, that sympathetic activity has no beneficial effect on resting energy expenditure in obesity. On the contrary, we hypothesize that sympathetic activation contributes to insulin resistance. To test this hypothesis, we determined insulin sensitivity using a standard hyperinsulinemic euglycemic clamp protocol in obese subjects randomly assigned in a crossover design 1 month apart to receive saline (intact day) or trimetaphan (4 mg/min IV, autonomic blocked day). Whole-body glucose uptake (MBW in mg/kg per minute) was used as index of maximal muscle glucose use. During autonomic blockade, we clamped blood pressure with a concomitant titrated intravenous infusion of the nitric oxide synthase inhibitor N-monomethyl-L-arginine. Of the 21 obese subjects (43±2 years; 35±2 kg/m(2) body mass index) studied, 14 were insulin resistant; they were more obese, had higher plasma glucose and insulin, and had higher muscle sympathetic nerve activity (23.3±1.5 versus 17.2±2.1 burst/min; P=0.03) when compared with insulin-sensitive subjects. Glucose use improved during autonomic blockade in insulin-resistant subjects (MBW 3.8±0.3 blocked versus 3.1±0.3 mg/kg per minute intact; P=0.025), with no effect in the insulin-sensitive group. These findings support the concept that sympathetic activation contributes to insulin resistance in obesity and may result in a feedback loop whereby the compensatory increase in insulin levels contributes to greater sympathetic activation. PMID:25001269

  8. Insulin sensitivity and complications in type 1 diabetes: New insights

    PubMed Central

    Bjornstad, Petter; Snell-Bergeon, Janet K; Nadeau, Kristen J; Maahs, David M

    2015-01-01

    Despite improvements in glucose, lipids and blood pressure control, vascular complications remain the most important cause of morbidity and mortality in patients with type 1 diabetes. For that reason, there is a need to identify additional risk factors to utilize in clinical practice or translate to novel therapies to prevent vascular complications. Reduced insulin sensitivity is an increasingly recognized component of type 1 diabetes that has been linked with the development and progression of both micro- and macrovascular complications. Adolescents and adults with type 1 diabetes have reduced insulin sensitivity, even when compared to their non-diabetic counterparts of similar adiposity, serum triglycerides, high-density lipoprotein cholesterol, level of habitual physical activity, and in adolescents, pubertal stage. Reduced insulin sensitivity is thought to contribute both to the initiation and progression of macro- and microvascular complications in type 1 diabetes. There are currently clinical trials underway examining the benefits of improving insulin sensitivity with regards to vascular complications in type 1 diabetes. Reduced insulin sensitivity is an increasingly recognized component of type 1 diabetes, is implicated in the pathogenesis of vascular complications and is potentially an important therapeutic target to prevent vascular complications. In this review, we will focus on the pathophysiologic contribution of insulin sensitivity to vascular complications and summarize related ongoing clinical trials. PMID:25685274

  9. Insulin sensitivity and complications in type 1 diabetes: New insights.

    PubMed

    Bjornstad, Petter; Snell-Bergeon, Janet K; Nadeau, Kristen J; Maahs, David M

    2015-02-15

    Despite improvements in glucose, lipids and blood pressure control, vascular complications remain the most important cause of morbidity and mortality in patients with type 1 diabetes. For that reason, there is a need to identify additional risk factors to utilize in clinical practice or translate to novel therapies to prevent vascular complications. Reduced insulin sensitivity is an increasingly recognized component of type 1 diabetes that has been linked with the development and progression of both micro- and macrovascular complications. Adolescents and adults with type 1 diabetes have reduced insulin sensitivity, even when compared to their non-diabetic counterparts of similar adiposity, serum triglycerides, high-density lipoprotein cholesterol, level of habitual physical activity, and in adolescents, pubertal stage. Reduced insulin sensitivity is thought to contribute both to the initiation and progression of macro- and microvascular complications in type 1 diabetes. There are currently clinical trials underway examining the benefits of improving insulin sensitivity with regards to vascular complications in type 1 diabetes. Reduced insulin sensitivity is an increasingly recognized component of type 1 diabetes, is implicated in the pathogenesis of vascular complications and is potentially an important therapeutic target to prevent vascular complications. In this review, we will focus on the pathophysiologic contribution of insulin sensitivity to vascular complications and summarize related ongoing clinical trials. PMID:25685274

  10. Lipid-anthropometric index optimization for insulin sensitivity estimation

    NASA Astrophysics Data System (ADS)

    Velásquez, J.; Wong, S.; Encalada, L.; Herrera, H.; Severeyn, E.

    2015-12-01

    Insulin sensitivity (IS) is the ability of cells to react due to insulińs presence; when this ability is diminished, low insulin sensitivity or insulin resistance (IR) is considered. IR had been related to other metabolic disorders as metabolic syndrome (MS), obesity, dyslipidemia and diabetes. IS can be determined using direct or indirect methods. The indirect methods are less accurate and invasive than direct and they use glucose and insulin values from oral glucose tolerance test (OGTT). The accuracy is established by comparison using spearman rank correlation coefficient between direct and indirect method. This paper aims to propose a lipid-anthropometric index which offers acceptable correlation to insulin sensitivity index for different populations (DB1=MS subjects, DB2=sedentary without MS subjects and DB3=marathoners subjects) without to use OGTT glucose and insulin values. The proposed method is parametrically optimized through a random cross-validation, using the spearman rank correlation as comparator with CAUMO method. CAUMO is an indirect method designed from a simplification of the minimal model intravenous glucose tolerance test direct method (MINMOD-IGTT) and with acceptable correlation (0.89). The results show that the proposed optimized method got a better correlation with CAUMO in all populations compared to non-optimized. On the other hand, it was observed that the optimized method has better correlation with CAUMO in DB2 and DB3 groups than HOMA-IR method, which is the most widely used for diagnosing insulin resistance. The optimized propose method could detect incipient insulin resistance, when classify as insulin resistant subjects that present impaired postprandial insulin and glucose values.

  11. Insulin and Insulin-Sensitizing Drugs in Neurodegeneration: Mitochondria as Therapeutic Targets

    PubMed Central

    Cardoso, Susana; Santos, Renato; Correia, Sonia; Carvalho, Cristina; Zhu, Xiongwei; Lee, Hyoung-Gon; Casadesus, Gemma; Smith, Mark A.; Perry, George; Moreira, Paula I.

    2009-01-01

    Insulin, besides its glucose lowering effects, is involved in the modulation of lifespan, aging and memory and learning processes. As the population ages, neurodegenerative disorders become epidemic and a connection between insulin signaling dysregulation, cognitive decline and dementia has been established. Mitochondria are intracellular organelles that despite playing a critical role in cellular metabolism are also one of the major sources of reactive oxygen species. Mitochondrial dysfunction, oxidative stress and neuroinflammation, hallmarks of neurodegeneration, can result from impaired insulin signaling. Insulin-sensitizing drugs such as the thiazolidinediones are a new class of synthetic compounds that potentiate insulin action in the target tissues and act as specific agonists of the peroxisome proliferator-activated receptor gamma (PPAR-γ). Recently, several PPAR agonists have been proposed as novel and possible therapeutic agents for neurodegenerative disorders. Indeed, the literature shows that these agents are able to protect against mitochondrial dysfunction, oxidative damage, inflammation and apoptosis. This review discusses the role of mitochondria and insulin signaling in normal brain function and in neurodegeneration. Furthermore, the potential protective role of insulin and insulin sensitizers in Alzheimer´s, Parkinson´s and Huntington´s diseases and amyotrophic lateral sclerosis will be also discussed.

  12. Wear-Out Sensitivity Analysis Project Abstract

    NASA Technical Reports Server (NTRS)

    Harris, Adam

    2015-01-01

    During the course of the Summer 2015 internship session, I worked in the Reliability and Maintainability group of the ISS Safety and Mission Assurance department. My project was a statistical analysis of how sensitive ORU's (Orbital Replacement Units) are to a reliability parameter called the wear-out characteristic. The intended goal of this was to determine a worst case scenario of how many spares would be needed if multiple systems started exhibiting wear-out characteristics simultaneously. The goal was also to determine which parts would be most likely to do so. In order to do this, my duties were to take historical data of operational times and failure times of these ORU's and use them to build predictive models of failure using probability distribution functions, mainly the Weibull distribution. Then, I ran Monte Carlo Simulations to see how an entire population of these components would perform. From here, my final duty was to vary the wear-out characteristic from the intrinsic value, to extremely high wear-out values and determine how much the probability of sufficiency of the population would shift. This was done for around 30 different ORU populations on board the ISS.

  13. Normocaloric Diet Restores Weight Gain and Insulin Sensitivity in Obese Mice

    PubMed Central

    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 hypocaloric dietetic restriction. In this study, we evaluated in obese mice the effects of shifting from high-calorie foods to normal diet on insulin sensitivity. Male C57BL/6JOlaHsd mice (n = 20) were fed with high fat diet (HFD) for a 24-week period. Afterward, 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 (NCD) 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 HFD to NCD. PMID:27303363

  14. Morning Circadian Misalignment during Short Sleep Duration Impacts Insulin Sensitivity.

    PubMed

    Eckel, Robert H; Depner, Christopher M; Perreault, Leigh; Markwald, Rachel R; Smith, Mark R; McHill, Andrew W; Higgins, Janine; Melanson, Edward L; Wright, Kenneth P

    2015-11-16

    Short sleep duration and circadian misalignment are hypothesized to causally contribute to health problems including obesity, diabetes, metabolic syndrome, heart disease, mood disorders, cognitive impairment, and accidents. Here, we investigated the influence of morning circadian misalignment induced by an imposed short nighttime sleep schedule on impaired insulin sensitivity, a precursor to diabetes. Imposed short sleep duration resulted in morning wakefulness occurring during the biological night (i.e., circadian misalignment)-a time when endogenous melatonin levels were still high indicating the internal circadian clock was still promoting sleep and related functions. We show the longer melatonin levels remained high after wake time, insulin sensitivity worsened. Overall, we find a simulated 5-day work week of 5-hr-per-night sleep opportunities and ad libitum food intake resulted in ∼20% reduced oral and intravenous insulin sensitivity in otherwise healthy men and women. Reduced insulin sensitivity was compensated by an increased insulin response to glucose, which may reflect an initial physiological adaptation to maintain normal blood sugar levels during sleep loss. Furthermore, we find that transitioning from the imposed short sleep schedule to 9-hr sleep opportunities for 3 days restored oral insulin sensitivity to baseline, but 5 days with 9-hr sleep opportunities was insufficient to restore intravenous insulin sensitivity to baseline. These findings indicate morning wakefulness and eating during the biological night is a novel mechanism by which short sleep duration contributes to metabolic dysregulation and suggests food intake during the biological night may contribute to other health problems associated with short sleep duration. PMID:26549253

  15. Circulating Docosahexaenoic Acid Levels Are Associated with Fetal Insulin Sensitivity

    PubMed Central

    Zhao, Jin-Ping; Levy, Emile; Fraser, William D.; Julien, Pierre; Delvin, Edgard; Montoudis, Alain; Spahis, Schohraya; Garofalo, Carole; Nuyt, Anne Monique; Luo, Zhong-Cheng

    2014-01-01

    Background Arachidonic acid (AA; C20∶4 n-6) and docosahexaenoic acid (DHA; C22∶6 n-3) are important long-chain polyunsaturated fatty acids (LC-PUFA) in maintaining pancreatic beta-cell structure and function. Newborns of gestational diabetic mothers are more susceptible to the development of type 2 diabetes in adulthood. It is not known whether low circulating AA or DHA is involved in perinatally “programming” this susceptibility. This study aimed to assess whether circulating concentrations of AA, DHA and other fatty acids are associated with fetal insulin sensitivity or beta-cell function, and whether low circulating concentrations of AA or DHA are involved in compromised fetal insulin sensitivity in gestational diabetic pregnancies. Methods and Principal Findings In a prospective singleton pregnancy cohort, maternal (32-35 weeks gestation) and cord plasma fatty acids were assessed in relation to surrogate indicators of fetal insulin sensitivity (cord plasma glucose-to-insulin ratio, proinsulin concentration) and beta-cell function (proinsulin-to-insulin ratio) in 108 mother-newborn pairs. Cord plasma DHA levels (in percentage of total fatty acids) were lower comparing newborns of gestational diabetic (n = 24) vs. non-diabetic pregnancies (2.9% vs. 3.5%, P = 0.01). Adjusting for gestational age at blood sampling, lower cord plasma DHA levels were associated with lower fetal insulin sensitivity (lower glucose-to-insulin ratio, r = 0.20, P = 0.036; higher proinsulin concentration, r = −0.37, P <0.0001). The associations remained after adjustment for maternal and newborn characteristics. Cord plasma saturated fatty acids C18∶0 and C20∶0 were negatively correlated with fetal insulin sensitivity, but their levels were not different between gestational diabetic and non-diabetic pregnancies. Cord plasma AA levels were not correlated with fetal insulin sensitivity. Conclusion Low circulating DHA levels are associated with compromised

  16. Grizzly bears exhibit augmented insulin sensitivity while obese prior to a reversible insulin resistance during hibernation.

    PubMed

    Nelson, O Lynne; Jansen, Heiko T; Galbreath, Elizabeth; Morgenstern, Kurt; Gehring, Jamie Lauren; Rigano, Kimberly Scott; Lee, Jae; Gong, Jianhua; Shaywitz, Adam J; Vella, Chantal A; Robbins, Charles T; Corbit, Kevin C

    2014-08-01

    The confluence of obesity and diabetes as a worldwide epidemic necessitates the discovery of new therapies. Success in this endeavor requires translatable preclinical studies, which traditionally employ rodent models. As an alternative approach, we explored hibernation where obesity is a natural adaptation to survive months of fasting. Here we report that grizzly bears exhibit seasonal tripartite insulin responsiveness such that obese animals augment insulin sensitivity but only weeks later enter hibernation-specific insulin resistance (IR) and subsequently reinitiate responsiveness upon awakening. Preparation for hibernation is characterized by adiposity coupled to increased insulin sensitivity via modified PTEN/AKT signaling specifically in adipose tissue, suggesting a state of "healthy" obesity analogous to humans with PTEN haploinsufficiency. Collectively, we show that bears reversibly cope with homeostatic perturbations considered detrimental to humans and describe a mechanism whereby IR functions not as a late-stage metabolic adaptation to obesity, but rather a gatekeeper of the fed-fasting transition. PMID:25100064

  17. Adipose Tissue Hypoxia, Inflammation, and Fibrosis in Obese Insulin-Sensitive and Obese Insulin-Resistant Subjects.

    PubMed

    Lawler, Helen M; Underkofler, Chantal M; Kern, Philip A; Erickson, Christopher; Bredbeck, Brooke; Rasouli, Neda

    2016-04-01

    We confirmed fat hypoxia in obese as compared to lean subjects. However, fat oxygenation was similar in obese insulin sensitive and insulin resistant subjects suggesting fat hypoxia may be simply a consequence of fat expansion. PMID:26871994

  18. Reducing Plasma Membrane Sphingomyelin Increases Insulin Sensitivity

    PubMed Central

    Li, Zhiqiang; Zhang, Hongqi; Liu, Jing; Liang, Chien-Ping; Li, Yan; Li, Yue; Teitelman, Gladys; Beyer, Thomas; Bui, Hai H.; Peake, David A.; Zhang, Youyan; Sanders, Phillip E.; Kuo, Ming-Shang; Park, Tae-Sik; Cao, Guoqing; Jiang, Xian-Cheng

    2011-01-01

    It has been shown that inhibition of de novo sphingolipid synthesis increases insulin sensitivity. For further exploration of the mechanism involved, we utilized two models: heterozygous serine palmitoyltransferase (SPT) subunit 2 (Sptlc2) gene knockout mice and sphingomyelin synthase 2 (Sms2) gene knockout mice. SPT is the key enzyme in sphingolipid biosynthesis, and Sptlc2 is one of its subunits. Homozygous Sptlc2-deficient mice are embryonic lethal. However, heterozygous Sptlc2-deficient mice that were viable and without major developmental defects demonstrated decreased ceramide and sphingomyelin levels in the cell plasma membranes, as well as heightened sensitivity to insulin. Moreover, these mutant mice were protected from high-fat diet-induced obesity and insulin resistance. SMS is the last enzyme for sphingomyelin biosynthesis, and SMS2 is one of its isoforms. Sms2 deficiency increased cell membrane ceramide but decreased SM levels. Sms2 deficiency also increased insulin sensitivity and ameliorated high-fat diet-induced obesity. We have concluded that Sptlc2 heterozygous deficiency- or Sms2 deficiency-mediated reduction of SM in the plasma membranes leads to an improvement in tissue and whole-body insulin sensitivity. PMID:21844222

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

    PubMed Central

    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

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

    PubMed Central

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

    2013-01-01

    Objective To institute intensive insulin therapy protocol in an acute pediatric burn unit and study the mechanisms underlying its benefits. Design Prospective, randomized study. Setting An acute pediatric burn unit in a tertiary teaching hospital. Patients Children, 4–18 yrs old, with total body surface area burned ≥40% and who arrived within 1 wk after injury were enrolled in the study. Interventions 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 ≤215 mg/dL. Measurements and Main Results Twenty 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 post-burn (pretreatment) and at 21 days postburn (posttreatment). Resting energy expenditure significantly increased posttreatment (1476 ± 124 to 1925 ± 291 kcal/m2·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·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·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·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 μm O2/CS/mg protein/min for state 3, p = .004; and 0.7 ± 0.1 to 1.3 ± 0.1 μm O2/CS/mg protein

  1. Peripheral glucose metabolism and insulin sensitivity in Alzheimer's disease.

    PubMed

    Kilander, L; Boberg, M; Lithell, H

    1993-04-01

    Twenty-four patients with Alzheimer's disease and matched controls were examined with reference to metabolic parameters such as peripheral insulin and glucose metabolism, serum lipid concentrations and blood pressure levels. Blood glucose levels and insulin response were measured during an intravenous glucose tolerance test and peripheral insulin sensitivity was estimated with the hyperinsulinemic euglycemic clamp technique. There were no differences recorded between the two groups in glucose metabolism, triglyceride, cholesterol or HDL-cholesterol levels. The patients with Alzheimer's disease had significantly lower blood pressure levels, which partly could be explained by ongoing treatment with neuroleptics and antidepressives. Previous findings of higher insulin levels in Alzheimer's disease could not be verified. PMID:8503259

  2. MARCH1 regulates insulin sensitivity by controlling cell surface insulin receptor levels.

    PubMed

    Nagarajan, Arvindhan; Petersen, Max C; Nasiri, Ali R; Butrico, Gina; Fung, Annie; Ruan, Hai-Bin; Kursawe, Romy; Caprio, Sonia; Thibodeau, Jacques; Bourgeois-Daigneault, Marie-Claude; Sun, Lisha; Gao, Guangping; Bhanot, Sanjay; Jurczak, Michael J; Green, Michael R; Shulman, Gerald I; Wajapeyee, Narendra

    2016-01-01

    Insulin resistance is a key driver of type 2 diabetes (T2D) and is characterized by defective insulin receptor (INSR) signalling. Although surface INSR downregulation is a well-established contributor to insulin resistance, the underlying molecular mechanisms remain obscure. Here we show that the E3 ubiquitin ligase MARCH1 impairs cellular insulin action by degrading cell surface INSR. Using a large-scale RNA interference screen, we identify MARCH1 as a negative regulator of INSR signalling. March1 loss-of-function enhances, and March1 overexpression impairs, hepatic insulin sensitivity in mice. MARCH1 ubiquitinates INSR to decrease cell surface INSR levels, but unlike other INSR ubiquitin ligases, MARCH1 acts in the basal state rather than after insulin stimulation. Thus, MARCH1 may help set the basal gain of insulin signalling. MARCH1 expression is increased in white adipose tissue of obese humans, suggesting that MARCH1 contributes to the pathophysiology of T2D and could be a new therapeutic target. PMID:27577745

  3. The Adipose Transcriptional Response to Insulin Is Determined by Obesity, Not Insulin Sensitivity.

    PubMed

    Rydén, Mikael; Hrydziuszko, Olga; Mileti, Enrichetta; Raman, Amitha; Bornholdt, Jette; Boyd, Mette; Toft, Eva; Qvist, Veronica; Näslund, Erik; Thorell, Anders; Andersson, Daniel P; Dahlman, Ingrid; Gao, Hui; Sandelin, Albin; Daub, Carsten O; Arner, Peter

    2016-08-30

    Metabolically healthy obese subjects display preserved insulin sensitivity and a beneficial white adipose tissue gene expression pattern. However, this observation stems from fasting studies when insulin levels are low. We investigated adipose gene expression by 5'Cap-mRNA sequencing in 17 healthy non-obese (NO), 21 insulin-sensitive severely obese (ISO), and 30 insulin-resistant severely obese (IRO) subjects, before and 2 hr into a hyperinsulinemic euglycemic clamp. ISO and IRO subjects displayed a clear but globally similar transcriptional response to insulin, which differed from the small effects observed in NO subjects. In the obese, 231 genes were altered; 71 were enriched in ISO subjects (e.g., phosphorylation processes), and 52 were enriched in IRO subjects (e.g., cellular stimuli). Common cardio-metabolic risk factors and gender do not influence these findings. This study demonstrates that differences in the acute transcriptional response to insulin are primarily driven by obesity per se, challenging the notion of healthy obese adipose tissue, at least in severe obesity. PMID:27545890

  4. Mitochondrial inhibitor as a new class of insulin sensitizer.

    PubMed

    Zhang, Yong; Ye, Jianping

    2012-08-01

    Insulin resistance is a major risk factor for type 2 diabetes. AMP-activated protein kinase (AMPK) is a drug target in the improvement of insulin sensitivity. Several insulin-sensitizing medicines are able to activate AMPK through inhibition of mitochondrial functions. These drugs, such as metformin and STZ, inhibit ATP synthesis in mitochondria to raise AMP/ATP ratio in the process of AMPK activation. However, chemicals that activate AMPK directly or by activating its upstream kinases have not been approved for treatment of type 2 diabetes in humans. In an early study, we reported that berberine inhibited oxygen consumption in mitochondria, and increased AMP/ATP ratio in cells. The observation suggests an indirect mechanism for AMPK activation by berberine. Berberine stimulates glycolysis for ATP production that offsets the cell toxicity after mitochondria inhibition. The study suggests that mitochondrial inhibition is an approach for AMPK activation. In this review article, literature is critically reviewed to interpret the role of mitochondria function in the mechanism of insulin resistance, which supports that mitochondria inhibitors represent a new class of AMPK activator. The inhibitors are promising candidates for insulin sensitizers. This review provides a guideline in search for small molecule AMPK activators in the drug discovery for type 2 diabetes. PMID:23710432

  5. Gynostemma pentaphyllum Tea Improves Insulin Sensitivity in Type 2 Diabetic Patients

    PubMed Central

    Huyen, V. T. T.; Phan, D. V.; Thang, P.; Hoa, N. K.; Östenson, C. G.

    2013-01-01

    Aims. To evaluate the effect of the traditional Vietnamese herb Gynostemma pentaphyllum tea on insulin sensitivity in drug-naïve type 2 diabetic patients. Methods. Patients received GP or placebo tea 6 g daily for four weeks and vice versa with a 2-week wash-out period. At the end of each period, a somatostatin-insulin-glucose infusion test (SIGIT) was performed to evaluate the insulin sensitivity. Fasting plasma glucose (FPG), HbA1C, and oral glucose tolerance tests and insulin levels were measured before, during, and after the treatment. Results. FPG and steady-state plasma glucose (SIGIT mean) were lower after GP treatment compared to placebo treatment (P < 0.001). The levels of FPG in the control group were slightly reduced to 0.2 ± 1.5 versus 1.9 ± 1.0 mmol/L in GP group (P < 0.001), and the effect on FPG was reversed after exchanging treatments. The glycometabolic improvements were achieved without any major change of circulating insulin levels. There were no changes in lipids, body measurements, blood pressure, and no reported hypoglycemias or acute adverse effects regarding kidney and liver parameters. Conclusion. The results of this study suggested that the GP tea exerted antidiabetic effect by improving insulin sensitivity. PMID:23431428

  6. Zataria multiflora increases insulin sensitivity and PPARγ gene expression in high fructose fed insulin resistant rats

    PubMed Central

    Mohammadi, Abbas; Gholamhoseinian, Ahmad; Fallah, Hossein

    2014-01-01

    Objective(s): In insulin resistance, the insulin action in liver, muscles and adipocytes decreases and result in hyperglycemia, dyslipidemia and hyperinsulinemia. In this study we evaluate the effect of Zataria multiflora extract on insulin sensitivity in high fructose fed insulin resistant rats, since this extract was shown antihyperglycemic effect in streptozotocin induced diabetes in rats. Materials and Methods: Experimental rats were fed with high fructose diet for 6 weeks and then were treated with Z. multiflora extract or a pioglitazone solution for 2 weeks. Blood and tissue samples were collected for analysis at the end of two weeks. Blood glucose, serum level of triglyceride and cholesterol were measured by auto analyzer. Insulin and adiponectin levels were assayed by enzyme-linked immunosorbent assay (ELISA) method. Plasma free fatty acids profile was studied by gas chromatography. Peroxisome proliferator activated receptor (PPAR.γ) and Glucose transporter type 4 (GLUT.4) gene expressions were assessed by real time polymerase chain reaction (PCR) and western blotting. Results: Animals were treated by Z. multiflora extract showed insulin (43±11pmol/l), adiponectin (5.3±0.5 μg/ml), glucose (144±9.8 mg/dl), and triglyceride (120±10 mg/dl) levels significantly improved as compare with the control group [insulin (137±34 pmol/l), adiponectin (3.9±0.15 μg/ml), glucose (187±15mg/dl), and triglycerides (217±18 mg/dl)]. PPARγ protein level, also significantly increased in Zataria multiflora treated group. Conclusion: This study demonstrates the beneficial effects of Zataria multiflora extract on insulin resistance in rats fed with a high-fructose diet through at least three mechanisms including direct insulin like effect, increasing in adiponectin and of PPARγ protein expression. PMID:24904719

  7. Insulin sensitivity and metabolic clearance rate of insulin in familial multiple lipomatosis.

    PubMed

    Garcia Lopez, J M; Murias Taboada, E; Torre Carballada, J A; Vidal Vazquez, P; Iglesias Guerrero, M; Cabezas-Cerrato, J

    1988-01-01

    Intolerance to glucose in certain kinds of lipomatosis is well documented. This article describes a euglucaemic hyperinsulinaemic clamp study of alterations in glucose and/or insulin metabolism in four members of a single family with familial multiple lipomatosis. Fifteen normal subjects were studied as controls. The four patients exhibited no alteration in tolerance to orally administered glucose. When a Biostator Glucose-Controlled Insulin Infusion System (GCIIS) was used to clamp glycaemia at 4.44 mmol/L with successive insulin infusion rates of (a) 0.5 (b) 1.0 or (c) 5.0 mU/kg/min, there was no difference between patients and controls as regards the value of M, the rate of glucose infusion, but the concentrations of immunoreactive insulin recorded during the last 40 minutes of each phase of the clamp were greater in patients than in controls (45 +/- 2 vs 27 +/- 2 uU/mL (p less than 0.01), 83 +/- 2 vs 60 +/- 5 uU/mL (p less than 0.05) and 537 +/- 48 vs 377 +/- 25 uU/mL (p less than 0.05) for insulin infusion rates (a), (b) and (c) respectively), and the ratio M/IRI was consequently smaller for patients than controls (1.92 +/- 0.41 vs 3.06 +/- 0.19 (p less than 0.05) for an insulin infusion rate of 5 mU/kg/min). The metabolic clearance rate of insulin was likewise slower in patients than controls (p less than 0.01). It is concluded that the four patients studied (all members of the same family) have sub-normal sensitivity to insulin secondary to a sub-normal metabolic clearance rate for insulin. PMID:3044865

  8. Effects of prolonged fasting and sustained lipolysis on insulin secretion and insulin sensitivity in normal subjects.

    PubMed

    Salgin, B; Marcovecchio, M L; Humphreys, S M; Hill, N; Chassin, L J; Lunn, D J; Hovorka, R; Dunger, D B

    2009-03-01

    Normal beta-cells adjust their function to compensate for any decrease in insulin sensitivity. Our aim was to explore whether a prolonged fast would allow a study of the effects of changes in circulating free fatty acid (FFA) levels on insulin secretion and insulin sensitivity and whether any potential effects could be reversed by the antilipolytic agent acipimox. Fourteen (8 female, 6 male) healthy young adults (aged 22.8-26.9 yr) without a family history of diabetes and a body mass index of 22.6 +/- 3.2 kg/m(2) were studied on three occasions in random order. Growth hormone and FFA levels were regularly measured overnight (2200-0759), and subjects underwent an intravenous glucose tolerance test in the morning (0800-1100) on each visit. Treatment A was an overnight fast, treatment B was a 24-h fast with regular administrations of a placebo, and treatment C was a 24-h fast with regular ingestions of 250 mg of acipimox. The 24-h fast increased overnight FFA levels (as measured by the area under the curve) 2.8-fold [51.3 (45.6-56.9) vs. 18.4 (14.4-22.5) *10(4) micromol/l*min, P < 0.0001], and it led to decreases in insulin sensitivity [5.7 (3.6-8.9) vs. 2.6 (1.3-4.7) *10(-4) min(-1) per mU/l, P < 0.0001] and the acute insulin response [16.3 (10.9-21.6) vs. 12.7 (8.7-16.6) *10(2) pmol/l*min, P = 0.02], and therefore a reduction in the disposition index [93.1 (64.8-121.4) vs. 35.5 (21.6-49.4) *10(2) pmol/mU, P < 0.0001]. Administration of acipimox during the 24-h fast lowered FFA levels by an average of 20% (range: -62 to +49%; P = 0.03), resulting in a mean increase in the disposition index of 31% (P = 0.03). In conclusion, the 24-h fast was accompanied by substantial increases in fasting FFA levels and induced reductions in the acute glucose-simulated insulin response and insulin sensitivity. The use of acipimox during the prolonged fast increased the disposition index, suggesting a partial reversal of the effects of fasting on the acute insulin response and insulin

  9. Insulin secretion and sensitivity in space flight: diabetogenic effects.

    PubMed

    Tobin, Brian W; Uchakin, Peter N; Leeper-Woodford, Sandra K

    2002-10-01

    Nearly three decades of space flight research have suggested that there are subclinical diabetogenic changes that occur in microgravity. Alterations in insulin secretion, insulin sensitivity, glucose tolerance, and metabolism of protein and amino acids support the hypothesis that insulin plays an essential role in the maintenance of muscle mass in extended-duration space flight. Experiments in flight and after flight and ground-based bedrest studies have associated microgravity and its experimental paradigms with manifestations similar to those of diabetes, physical inactivity, and aging. We propose that these manifestations are characterized best by an etiology that falls into the clinical category of "other" causes of diabetes, including, but not restricted to, genetic beta-cell defects, insulin action defects, diseases of the endocrine pancreas, endocrinopathies, drug or chemically induced diabetes, infections, immune-mediated metabolic alteration, and a host of genetic related diseases. We present data showing alterations in tumor necrosis factor-alpha production, insulin secretion, and amino acid metabolism in pancreatic islets of Langerhans cultured in a ground-based cell culture bioreactor that mimics some of the effects of microgravity. Taken together, space flight research, ground-based studies, and bioreactor studies of pancreatic islets of Langerhans support the hypothesis that the pancreas is unable to overcome peripheral insulin resistance and amino acid dysregulation during space flight. We propose that measures of insulin secretion and insulin action will be necessary to design effective countermeasures against muscle loss, and we advance the "disposition index" as an essential model to be used in the clinical management of space flight-induced muscle loss. PMID:12361776

  10. Insulin secretion and sensitivity in space flight: diabetogenic effects

    NASA Technical Reports Server (NTRS)

    Tobin, Brian W.; Uchakin, Peter N.; Leeper-Woodford, Sandra K.

    2002-01-01

    Nearly three decades of space flight research have suggested that there are subclinical diabetogenic changes that occur in microgravity. Alterations in insulin secretion, insulin sensitivity, glucose tolerance, and metabolism of protein and amino acids support the hypothesis that insulin plays an essential role in the maintenance of muscle mass in extended-duration space flight. Experiments in flight and after flight and ground-based bedrest studies have associated microgravity and its experimental paradigms with manifestations similar to those of diabetes, physical inactivity, and aging. We propose that these manifestations are characterized best by an etiology that falls into the clinical category of "other" causes of diabetes, including, but not restricted to, genetic beta-cell defects, insulin action defects, diseases of the endocrine pancreas, endocrinopathies, drug or chemically induced diabetes, infections, immune-mediated metabolic alteration, and a host of genetic related diseases. We present data showing alterations in tumor necrosis factor-alpha production, insulin secretion, and amino acid metabolism in pancreatic islets of Langerhans cultured in a ground-based cell culture bioreactor that mimics some of the effects of microgravity. Taken together, space flight research, ground-based studies, and bioreactor studies of pancreatic islets of Langerhans support the hypothesis that the pancreas is unable to overcome peripheral insulin resistance and amino acid dysregulation during space flight. We propose that measures of insulin secretion and insulin action will be necessary to design effective countermeasures against muscle loss, and we advance the "disposition index" as an essential model to be used in the clinical management of space flight-induced muscle loss.

  11. Greater omentectomy improves insulin sensitivity in nonobese dogs.

    PubMed

    Lottati, Maya; Kolka, Cathryn M; Stefanovski, Darko; Kirkman, Erlinda L; Bergman, Richard N

    2009-04-01

    Visceral adiposity is strongly associated with insulin resistance; however, little evidence directly demonstrates that visceral fat per se impairs insulin action. Here, we examine the effects of the surgical removal of the greater omentum and its occupying visceral fat, an omentectomy (OM), on insulin sensitivity (S(I)) and beta-cell function in nonobese dogs. Thirteen male mongrel dogs were used in this research study; animals were randomly assigned to surgical treatment with either OM (n = 7), or sham-surgery (SHAM) (n = 6). OM failed to generate measurable changes in body weight (+2%; P = 0.1), or subcutaneous adiposity (+3%; P = 0.83) as assessed by magnetic resonance imaging (MRI). The removal of the greater omentum did not significantly reduce total visceral adipose volume (-7.3 +/- 6.4%; P = 0.29); although primary analysis showed a trend for OM to increase S(I) when compared to sham operated animals (P = 0.078), further statistical analysis revealed that this minor reduction in visceral fat alleviated insulin resistance by augmenting S(I) of the periphery (+67.7 +/- 35.2%; P = 0.03), as determined by the euglycemic-hyperinsulinemic clamp. Insulin secretory response during the hyperglycemic step clamp was not directly influenced by omental fat removal (presurgery 6.82 +/- 1.4 vs. postsurgery: 6.7 +/- 1.2 pmol/l/mg/dl, P = 0.9). These findings provide new evidence for the deleterious role of visceral fat in insulin resistance, and suggest that a greater OM procedure may effectively improve insulin sensitivity. PMID:19214178

  12. Abatacept Improves Whole-Body Insulin Sensitivity in Rheumatoid Arthritis

    PubMed Central

    Ursini, Francesco; Russo, Emilio; Letizia Hribal, Marta; Mauro, Daniele; Savarino, Francesca; Bruno, Caterina; Tripolino, Cesare; Rubino, Mariangela; Naty, Saverio; Grembiale, Rosa Daniela

    2015-01-01

    Abstract Rheumatoid arthritis (RA) is characterized by increased insulin resistance, a well-known risk factor for diabetes and cardiovascular diseases. The aim of the present study was to evaluate the effect of abatacept on insulin sensitivity in RA patients with moderate to severe disease despite treatment with methotrexate. Fifteen RA patients were recruited for the present study. Patients were evaluated at time 0 and after 6 months of the treatment with i.v. abatacept at the dosage recommended for weight range. Evaluation included oral glucose tolerance test (OGTT) at both time points. Insulin sensitivity was estimated with insulin sensitivity index (ISI) by Matsuda, a measure of whole-body insulin sensitivity. ISI significantly increased after the treatment with abatacept from 3.7 ± 2.6 to 5.0 ± 3.2 (P = 0.003) with a mean difference of 1.23. Analysis of glucose and insulin values during OGTT revealed a reduction of both glucose (303.9 ± 73.4 mg/dL min versus 269.2 ± 69.5 mg/dL min, P = 0.009) and insulin (208.4 ± 119.7 mg/dL min versus 158.0 ± 95.3 mg/dL min, P = 0.01) area under the curves (AUCs). Accordingly also glycated hemoglobin significantly improved (5.5 ± 0.4% versus 5.3 ± 0.3%, P = 0.04). No significant differences were found for measures of β-cell function insulinogenic index (1.11 ± 1.19 versus 1.32 ± 0.82, P = 0.77) and oral disposition index (2.0 ± 5.4 versus 6.0 ± 6.0, P = 0.25). Treatment with abatacept seems to be able to improve whole-body insulin sensitivity in RA patients without affecting β-cell function. PMID:26020396

  13. Differences in Cardiometabolic Risk between Insulin-Sensitive and Insulin-Resistant Overweight and Obese Children

    PubMed Central

    McGinn, Aileen P.; Isasi, Carmen R.; Groisman-Perelstein, Adriana; Diamantis, Pamela M.; Ginsberg, Mindy; Wylie-Rosett, Judith

    2015-01-01

    Abstract Background: It is known that 15–30% overweight/obese adults do not suffer cardiometabolic consequences. There is limited literature examining factors that can be used to assess cardiometabolic health in overweight/obese children. If such factors can be identified, they would aid in differentiating those most in need for aggressive management. Methods: Baseline data from 7- to 12-year-old, overweight, and obese children enrolled in a weight management program at an urban hospital were analyzed. Homeostatic model assessment for insulin resistance (HOMA-IR) <2.6 was used to define insulin-sensitive and HOMA-IR ≥2.6 was used to defined insulin-resistant participants. Demographics, physical activity measures, and cardiometabolic risk factors were compared between the two phenotypes. Odds ratios (ORs) examining the association between intermediate endpoints (metabolic syndrome [MetS], nonalcoholic fatty liver disease [NAFLD], systemic inflammation, and microalbuminuria) and the two metabolic phenotypes were evaluated. Results: Of the 362 overweight/obese participants, 157 (43.5%) were insulin sensitive and 204 (56.5%) were insulin resistant. Compared to the insulin-sensitive group, the insulin-resistant group was older (8.6±1.6 vs. 9.9±1.7; p<0.001) and had a higher BMI z-score (1.89±0.42 vs. 2.04±0.42; p=0.001). After multivariable adjustment, compared to the insulin-sensitive group, the insulin-resistant group had higher odds of having MetS (OR, 5.47; 95% confidence interval [CI]: 1.72, 17.35; p=0.004) and NAFLD (OR, 8.66; 95% CI, 2.48, 30.31; p=0.001), but not systemic inflammation (OR, 1.06; 95% CI: 0.56, 2.03; p=0.86) or microalbuminuria (OR, 1.71; 95% CI, 0.49, 6.04; p=0.403). Conclusions: Using a HOMA-IR value of ≥2.6, clinical providers can identify prepubertal and early pubertal children most at risk. Focusing limited resources on aggressive weight interventions may lead to improvement in cardiometabolic health. PMID:25774664

  14. High levels of chorionic gonadotrophin attenuate insulin sensitivity and promote inflammation in adipocytes.

    PubMed

    Ma, Qinyun; Fan, Jianxia; Wang, Jiqiu; Yang, Shuai; Cong, Qing; Wang, Rui; Lv, Qianqian; Liu, Ruixin; Ning, Guang

    2015-04-01

    Gestational diabetes mellitus (GDM) presents with moderate inflammation, insulin resistance and impaired glucose uptake, which may result from increased maternal fat mass and increased circulation of placental hormones and adipokines. In this study, we set out to test whether the surge in chorionic gonadotrophin (CG) secretion is a cause of inflammation and impaired insulin sensitivity in GDM. We first found that LH/chorionic gonadotrophin receptors (CG/LHR) were expressed at low levels in insulin-sensitive murine 3T3-L1 adipocytes and murine C2C12 myocytes. CG treatment not only directly reduced insulin-responsive gene expression, including that of glucose transporter 4 (GLUT4), but also impaired insulin-stimulated glucose uptake in 3T3-L1 cells. Moreover, CG treatment increased the expression of the proinflammatory cytokine monocyte chemotactic protein 1 (MCP1) and upregulated nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) activity in 3T3-L1 cells. Clinically, pregnant women who had higher CG levels and elevated MCP1 developed GDM. Above all, apart from prepregnancy BMI and MCP1 level, CG level was associated with abnormal glucose tolerance. In summary, our findings confirmed that higher CG levels in pregnancy possibly played a role in GDM development partly by impairing the functions of insulin, such those involved in as glucose uptake, while promoting inflammation in adipocyte. PMID:25691497

  15. Novel repressor regulates insulin sensitivity through interaction with Foxo1

    PubMed Central

    Nakae, Jun; Cao, Yongheng; Hakuno, Fumihiko; Takemori, Hiroshi; Kawano, Yoshinaga; Sekioka, Risa; Abe, Takaya; Kiyonari, Hiroshi; Tanaka, Toshiya; Sakai, Juro; Takahashi, Shin-Ichiro; Itoh, Hiroshi

    2012-01-01

    Forkhead box-containing protein o (Foxo) 1 is a key transcription factor in insulin and glucose metabolism. We identified a Foxo1-CoRepressor (FCoR) protein in mouse adipose tissue that inhibits Foxo1's activity by enhancing acetylation via impairment of the interaction between Foxo1 and the deacetylase Sirt1 and via direct acetylation. FCoR is phosphorylated at Threonine 93 by catalytic subunit of protein kinase A and is translocated into nucleus, making it possible to bind to Foxo1 in both cytosol and nucleus. Knockdown of FCoR in 3T3-F442A cells enhanced expression of Foxo target and inhibited adipocyte differentiation. Overexpression of FCoR in white adipose tissue decreased expression of Foxo-target genes and adipocyte size and increased insulin sensitivity in Leprdb/db mice and in mice fed a high-fat diet. In contrast, Fcor knockout mice were lean, glucose intolerant, and had decreased insulin sensitivity that was accompanied by increased expression levels of Foxo-target genes and enlarged adipocytes. Taken together, these data suggest that FCoR is a novel repressor that regulates insulin sensitivity and energy metabolism in adipose tissue by acting to fine-tune Foxo1 activity. PMID:22510882

  16. Soy pinitol acts partly as an insulin sensitizer or insulin mediator in 3T3-L1 preadipocytes

    PubMed Central

    Do, Gyeong-Min; Choi, Myung-Sook; Kim, Hye-Jin; Woo, Myung-Nam; Lee, Mi-Kyung

    2007-01-01

    The blood glucose-lowering property of pinitol is mediated via the insulin signaling pathway. This study was carried out to evaluate the effects of soy pinitol on adipogenesis in a 3T3-L1 cell line; 3T3-L1 preadipocytes were treated with pinitol (0–1 mM) together with insulin for 9 days. The regulation of lipid metabolism was assessed by oil-red-O staining of intracellular lipids and real-time PCR of adipogenesis-related factors. The inhibition of cell proliferation was estimated by MTT assay. Pinitol treatment did not inhibit lipid accumulation, nor did it affect expression of adipogenesis-related factors, including ADD1, aP2 and FAS, in a dose-dependent manner. Expression of adiponectin, GLUT4, IRS, C/EBPα and PPARγ mRNAs, however, increased in cells treated with 0.5 mM and/or 1 mM pinitol. Pinitol treatment did not affect the inhibition of cell growth and proliferation in a dose-dependent manner. Accordingly, we suggest that pinitol is nontoxic to this cell line, and that it enhances adipogenesis by acting as an insulin sensitizer or insulin mediator via the upregulation of adiponectin, GLUT4, IRS, C/EBPα and PPARγ in 3T3-L1 preadipocytes. PMID:18850231

  17. Environmental factors and dam characteristics associated with insulin sensitivity and insulin secretion in newborn Holstein calves.

    PubMed

    Kamal, M M; Van Eetvelde, M; Bogaert, H; Hostens, M; Vandaele, L; Shamsuddin, M; Opsomer, G

    2015-09-01

    The objective of the present retrospective cohort study was to evaluate potential associations between environmental factors and dam characteristics, including level of milk production during gestation, and insulin traits in newborn Holstein calves. Birth weight and gestational age of the calves at delivery were determined. On the next day, heart girth, wither height and diagonal length of both the calves and their dams were measured. Parity, body condition score and age at calving were recorded for all dams. For the cows, days open before last gestation, lactation length (LL), length of dry period (DP) and calving interval were also calculated. The magnitude and shape of the lactation curve both quantified using the MilkBot model based on monthly milk weights, were used to calculate the amount of milk produced during gestation. Using the same procedure, cumulative milk production from conception to drying off (MGEST) was calculated. A blood sample was collected from all calves (n=481; 169 born to heifers and 312 born to cows) at least 5 h after a milk meal on day 3 of life to measure basal glucose and insulin levels. In addition, an intravenous glucose-stimulated insulin secretion test was performed in a subset of the calves (n=316). After descriptive analysis, generalized linear mixed models were used to identify factors that were significantly associated with the major insulin traits (Insb, basal insulin level; QUICKI, quantitative insulin sensitivity check index; AIR, acute insulin response; DI, disposition index) of the newborn calves. The overall average birth weight of the calves was 42.7 ± 5.92 kg. The insulin traits were significantly associated with gender and season of birth when data of all calves were analyzed. In addition, the insulin traits in calves born to cows were significantly associated with MGEST, DP and LL. The Insb was estimated to be higher in calves born to the cows having passed a higher MGEST (P=0.076) and longer DP (P=0.034). The

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

    PubMed

    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. PMID:26740602

  19. PROXIMITY TO DELIVERY ALTERS INSULIN SENSITIVITY AND GLUCOSE METABOLISM IN PREGNANT MICE

    PubMed Central

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

    2016-01-01

    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, day (D) 16, and near term, D19, (term 20.5D). Non-pregnant (NP) and pregnant mice were assessed for metabolite and hormone concentrations, body composition by dual energy X-ray absorptiometry, tissue insulin signalling protein abundance by Western blotting, glucose tolerance and utilisation, and insulin sensitivity using acute insulin administration and hyperinsulinaemic-euglycaemic clamps with 3H-glucose infusion. Whole body insulin resistance occurred in D16 pregnant dams in association with basal hyperinsulinaemia, insulin-resistant endogenous glucose production and downregulation of several proteins in hepatic and skeletal muscle insulin signalling 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 signalling proteins. At D16, insulin resistance at whole body, tissue and molecular levels will favour 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. PMID:26740602

  20. Green Tea Increases Insulin Sensitivity and Decreases Brain Oxidative Stress in Fructose Fed Rats

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Hyperglycemia and insulin resistance are leading causes of early brain alterations. Our objective was to investigate the in vivo effects of green tea extract on insulin sensitivity, insulin signaling, and brain oxidative stress using an experimental rodent model of diet-induced insulin resistance, t...

  1. Aromatase Inhibition Reduces Insulin Sensitivity in Healthy Men

    PubMed Central

    Homer, Natalie Z. M.; Faqehi, Abdullah M. M.; Upreti, Rita; Livingstone, Dawn E.; McInnes, Kerry J.; Andrew, Ruth; Walker, Brian R.

    2016-01-01

    Context: Deficiency of aromatase, the enzyme that catalyzes the conversion of androgens to estrogens, is associated with insulin resistance in humans and mice. Objective: We hypothesized that pharmacological aromatase inhibition results in peripheral insulin resistance in humans. Design: This was a double-blind, randomized, controlled, crossover study. Setting: The study was conducted at a clinical research facility. Participants: Seventeen healthy male volunteers (18–50 y) participated in the study. Intervention: The intervention included oral anastrozole (1 mg daily) and placebo, each for 6 weeks with a 2-week washout period. Main Outcome Measure: Glucose disposal and rates of lipolysis were measured during a stepwise hyperinsulinemic euglycemic clamp. Data are mean (SEM). Results: Anastrozole therapy resulted in significant estradiol suppression (59.9 ± 3.6 vs 102.0 ± 5.7 pmol/L, P = < .001) and a more modest elevation of total T (25.8 ± 1.2 vs 21.4 ± 0.7 nmol/L, P = .003). Glucose infusion rate, during the low-dose insulin infusion, was lower after anastrozole administration (12.16 ± 1.33 vs 14.15 ± 1.55 μmol/kg·min, P = .024). No differences in hepatic glucose production or rate of lipolysis were observed. Conclusion: Aromatase inhibition reduces insulin sensitivity, with respect to peripheral glucose disposal, in healthy men. Local generation and action of estradiol, at the level of skeletal muscle, is likely to be an important determinant of insulin sensitivity. PMID:26967690

  2. Heart Rate Variability, Insulin Resistance, and Insulin Sensitivity in Japanese Adults: The Toon Health Study

    PubMed Central

    Saito, Isao; Hitsumoto, Shinichi; Maruyama, Koutatsu; Nishida, Wataru; Eguchi, Eri; Kato, Tadahiro; Kawamura, Ryoichi; Takata, Yasunori; Onuma, Hiroshi; Osawa, Haruhiko; Tanigawa, Takeshi

    2015-01-01

    Background Although impaired cardiac autonomic function is associated with an increased risk of type 2 diabetes in Caucasians, evidence in Asian populations with a lower body mass index is limited. Methods Between 2009–2012, the Toon Health Study recruited 1899 individuals aged 30–79 years who were not taking medication for diabetes. A 75-g oral glucose tolerance test was used to diagnose type 2 diabetes, and fasting and 2-h-postload glucose and insulin concentrations were measured. We assessed the homeostasis model assessment index for insulin resistance (HOMA-IR) and Gutt’s insulin sensitivity index (ISI). Pulse was recorded for 5 min, and time-domain heart rate variability (HRV) indices were calculated: the standard deviation of normal-to-normal intervals (SDNN) and the root mean square of successive difference (RMSSD). Power spectral analysis provided frequency domain measures of HRV: high frequency (HF) power, low frequency (LF) power, and the LF:HF ratio. Results Multivariate-adjusted logistic regression models showed decreased SDNN, RMSSD, and HF, and increased LF:HF ratio were associated significantly with increased HOMA-IR and decreased ISI. When stratified by overweight status, the association of RMSSD, HF, and LF:HF ratio with decreased ISI was also apparent in non-overweight individuals. The interaction between LF:HF ratio and decreased ISI in overweight individuals was significant, with the odds ratio for decreased ISI in the highest quartile of LF:HF ratio in non-overweight individuals being 2.09 (95% confidence interval, 1.41–3.10). Conclusions Reduced HRV was associated with insulin resistance and lower insulin sensitivity. Decreased ISI was linked with parasympathetic dysfunction, primarily in non-overweight individuals. PMID:26277879

  3. The Importance of Palmitoleic Acid to Adipocyte Insulin Resistance and Whole-Body Insulin Sensitivity in Type 1 Diabetes

    PubMed Central

    Howard, David; Schauer, Irene E.; Maahs, David M.; Snell-Bergeon, Janet K.; Clement, Timothy W.; Eckel, Robert H.; Perreault, Leigh; Rewers, Marian

    2013-01-01

    Context: Type 1 diabetes is an insulin-resistant state, but it is less clear which tissues are affected. Our previous report implicated skeletal muscle and liver insulin resistance in people with type 1 diabetes, but this occurred independently of generalized, visceral, or ectopic fat. Objective: The aim of the study was to measure adipose tissue insulin sensitivity and plasma triglyceride composition in individuals with type 1 diabetes after overnight insulin infusion to lower fasting glucose. Design, Patients, and Methods: Fifty subjects (25 individuals with type 1 diabetes and 25 controls without) were studied. After 3 d of dietary control and overnight insulin infusion, we performed a three-stage hyperinsulinemic/euglycemic clamp infusing insulin at 4, 8, and 40 mU/m2 · min. Infusions of [1,1,2,3,3-2H2]glycerol and [1-13C]palmitate were used to quantify lipid metabolism. Results: Basal glycerol and palmitate rates of appearance were similar between groups, decreased more in control subjects during the first two stages of the clamp, and similarly suppressed during the highest insulin dose. The concentration of insulin required for 50% inhibition of lipolysis was twice as high in individuals with type 1 diabetes. Plasma triglyceride saturation was similar between groups, but palmitoleic acid in plasma triglyceride was inversely related to adipocyte insulin sensitivity. Unesterified palmitoleic acid in plasma was positively related to insulin sensitivity in controls, but not in individuals with type 1 diabetes. Conclusions: Adipose tissue insulin resistance is a significant feature of type 1 diabetes. Palmitoleic acid is not related to insulin sensitivity in type 1 diabetes, as it was in controls, suggesting a novel mechanism for insulin resistance in this population. PMID:23150678

  4. pH sensitive thiolated cationic hydrogel for oral insulin delivery.

    PubMed

    Sonia, T A; Sharma, Chandra P

    2014-04-01

    The objective of this work is to study the efficacy of pH sensitive thiolated Polydimethylaminoethylmethacrylate for oral delivery of insulin. Synthesis of pH sensitive thiolated Polydimethylaminoethylmethacrylate (PDCPA) was carried out by crosslinking Polymethacrylic acid with thiolated Polydimethylaminoethylmethacrylate (PDCys) via carbodiimide chemistry. Prior to in vivo experiment, various physicochemical and biological characterisation were carried out to evaluate the efficacy of PDCPA. Modification was confirmed by IR and NMR spectroscopy. The particle size was found to be 284 nm with a zeta potential of 37.3+/-1.58 mV. Texture analyser measurements showed that PDCPA is more mucoadhesive than the parent polymer. Transepithelial electrical measurements showed a reduction of greater than 50% on incubation with PDCPA particles. Permeation studies showed that PDCPA is more permeable than the parent polymer. On in vivo evaluation on male diabetic rats, insulin loaded PDCPA exhibited a blood glucose reduction of 19%. PMID:24734516

  5. Fructose, but not glucose, impairs insulin signaling in the three major insulin-sensitive tissues

    PubMed Central

    Baena, Miguel; Sangüesa, Gemma; Dávalos, Alberto; Latasa, María-Jesús; Sala-Vila, Aleix; Sánchez, Rosa María; Roglans, Núria; Laguna, Juan Carlos; Alegret, Marta

    2016-01-01

    Human studies support the relationship between high intake of fructose-sweetened beverages and type 2 diabetes, but there is a debate on whether this effect is fructose-specific or it is merely associated to an excessive caloric intake. Here we investigate the effects of 2 months’ supplementation to female rats of equicaloric 10% w/v fructose or glucose solutions on insulin sensitivity in target tissues. Fructose supplementation caused hepatic deposition of triglycerides and changed the fatty acid profile of this fraction, with an increase in monounsaturated and a decrease in polyunsaturated species, but did not cause inflammation and oxidative stress. Fructose but not glucose-supplemented rats displayed an abnormal glucose tolerance test, and did not show increased phosphorylation of V-akt murine thymoma viral oncogene homolog-2 (Akt) in white adipose tissue and liver after insulin administration. In skeletal muscle, phosphorylation of Akt and of Akt substrate of 160 kDA (AS160) was not impaired but the expression of the glucose transporter type 4 (GLUT4) in the plasma membrane was reduced only in fructose-fed rats. In conclusion, fructose but not glucose supplementation causes fatty liver without inflammation and oxidative stress and impairs insulin signaling in the three major insulin-responsive tissues independently from the increase in energy intake. PMID:27194405

  6. Fructose, but not glucose, impairs insulin signaling in the three major insulin-sensitive tissues.

    PubMed

    Baena, Miguel; Sangüesa, Gemma; Dávalos, Alberto; Latasa, María-Jesús; Sala-Vila, Aleix; Sánchez, Rosa María; Roglans, Núria; Laguna, Juan Carlos; Alegret, Marta

    2016-01-01

    Human studies support the relationship between high intake of fructose-sweetened beverages and type 2 diabetes, but there is a debate on whether this effect is fructose-specific or it is merely associated to an excessive caloric intake. Here we investigate the effects of 2 months' supplementation to female rats of equicaloric 10% w/v fructose or glucose solutions on insulin sensitivity in target tissues. Fructose supplementation caused hepatic deposition of triglycerides and changed the fatty acid profile of this fraction, with an increase in monounsaturated and a decrease in polyunsaturated species, but did not cause inflammation and oxidative stress. Fructose but not glucose-supplemented rats displayed an abnormal glucose tolerance test, and did not show increased phosphorylation of V-akt murine thymoma viral oncogene homolog-2 (Akt) in white adipose tissue and liver after insulin administration. In skeletal muscle, phosphorylation of Akt and of Akt substrate of 160 kDA (AS160) was not impaired but the expression of the glucose transporter type 4 (GLUT4) in the plasma membrane was reduced only in fructose-fed rats. In conclusion, fructose but not glucose supplementation causes fatty liver without inflammation and oxidative stress and impairs insulin signaling in the three major insulin-responsive tissues independently from the increase in energy intake. PMID:27194405

  7. Measuring beta-cell function relative to insulin sensitivity in youth: Does the hyperglycemic clamp suffice?

    Technology Transfer Automated Retrieval System (TEKTRAN)

    To compare beta-cell function relative to insulin sensitivity, disposition index (DI), calculated from two clamps (2cDI, insulin sensitivity from the hyperinsulinemic-euglycemic clamp and first-phase insulin from the hyperglycemic clamp) with the DI calculated from the hyperglycemic clamp alone (hcD...

  8. Overweight and impaired insulin sensitivity present in growing cats.

    PubMed

    Häring, T; Haase, B; Zini, E; Hartnack, S; Uebelhart, D; Gaudenz, D; Wichert, B A

    2013-10-01

    Obesity is a growing problem in pets as well as in humans. Overweight and obesity are linked to insulin sensitivity and subsequently in older cats, to an increased risk of developing diabetes mellitus. In the experimental cat population of the Institute of Animal Nutrition of the Vetsuisse Faculty, University of Zurich, an overweight phenotype in intact cats younger than 1 year became evident. The aims of the present study were to determine whether an association between insulin sensitivity and body condition score (BCS) or feline body mass index (FBMI) is already present during young adulthood in these cats and to test the hypothesis that the phenotype lean/overweight is significantly associated with monthly body weight during the growing period. Therefore, 41 kittens from the mentioned cat breeding colony were studied. They were weighed weekly and checked monthly (third to eighth month after birth) for BCS and FBMI. At the age of 8 months, they were classified into an overweight and lean phenotype based on BCS on a scale of 9 (median; maximum and minimum: overweight male (6.4; 6.8; 6.0); overweight female (6.1; 6.2; 6.0); lean male (5.4; 5.7; 5.0); lean female (5.2; 5.6; 5.0). A significant association between the phenotype and body weight was obvious during the growing period from the third to the 8 months (p = 0.0001). At month 8, body fat content was measured by dual energy X-ray absorptiometry and a glucose tolerance test to determine the insulin sensitivity index was performed. Insulin sensitivity was significantly associated with BCS (p = 0.0007) and body fat content (p < 0.0001) but not with sex (p = 0.61). Our data provide evidence that already in young intact cats; insulin insensitivity is significantly associated with BCS or a presumed phenotype lean/overweight. PMID:22812383

  9. Identification and validation of N-acetyltransferase 2 as an insulin sensitivity gene.

    PubMed

    Knowles, Joshua W; Xie, Weijia; Zhang, Zhongyang; Chennamsetty, Indumathi; Chennemsetty, Indumathi; Assimes, Themistocles L; Paananen, Jussi; Hansson, Ola; Pankow, James; Goodarzi, Mark O; Carcamo-Orive, Ivan; Morris, Andrew P; Chen, Yii-Der I; Mäkinen, Ville-Petteri; Ganna, Andrea; Mahajan, Anubha; Guo, Xiuqing; Abbasi, Fahim; Greenawalt, Danielle M; Lum, Pek; Molony, Cliona; Lind, Lars; Lindgren, Cecilia; Raffel, Leslie J; Tsao, Philip S; Schadt, Eric E; Rotter, Jerome I; Sinaiko, Alan; Reaven, Gerald; Yang, Xia; Hsiung, Chao A; Groop, Leif; Cordell, Heather J; Laakso, Markku; Hao, Ke; Ingelsson, Erik; Frayling, Timothy M; Weedon, Michael N; Walker, Mark; Quertermous, Thomas

    2015-04-01

    Decreased insulin sensitivity, also referred to as insulin resistance (IR), is a fundamental abnormality in patients with type 2 diabetes and a risk factor for cardiovascular disease. While IR predisposition is heritable, the genetic basis remains largely unknown. The GENEticS of Insulin Sensitivity consortium conducted a genome-wide association study (GWAS) for direct measures of insulin sensitivity, such as euglycemic clamp or insulin suppression test, in 2,764 European individuals, with replication in an additional 2,860 individuals. The presence of a nonsynonymous variant of N-acetyltransferase 2 (NAT2) [rs1208 (803A>G, K268R)] was strongly associated with decreased insulin sensitivity that was independent of BMI. The rs1208 "A" allele was nominally associated with IR-related traits, including increased fasting glucose, hemoglobin A1C, total and LDL cholesterol, triglycerides, and coronary artery disease. NAT2 acetylates arylamine and hydrazine drugs and carcinogens, but predicted acetylator NAT2 phenotypes were not associated with insulin sensitivity. In a murine adipocyte cell line, silencing of NAT2 ortholog Nat1 decreased insulin-mediated glucose uptake, increased basal and isoproterenol-stimulated lipolysis, and decreased adipocyte differentiation, while Nat1 overexpression produced opposite effects. Nat1-deficient mice had elevations in fasting blood glucose, insulin, and triglycerides and decreased insulin sensitivity, as measured by glucose and insulin tolerance tests, with intermediate effects in Nat1 heterozygote mice. Our results support a role for NAT2 in insulin sensitivity. PMID:25798622

  10. Chromium propionate in broilers: effect on insulin sensitivity.

    PubMed

    Brooks, M A; Grimes, J L; Lloyd, K E; Krafka, K; Lamptey, A; Spears, J W

    2016-05-01

    The objective of this study was to evaluate the effects of dietary chromium (Cr), as chromium propionate, on measures of insulin sensitivity. Liver and muscle glycogen, and plasma glucose and non-esterified fatty acid (NEFA) concentrations were used as indicators of insulin sensitivity. In total, 288 newly hatched male Ross broilers were divided into 4 dietary treatments consisting of 0 (control diet analyzed 0.43 to 0.45 mg Cr/kg), 0.2, 0.4, or 0.6 mg supplemental Cr/kg diet, resulting in 4 treatments with 9 replicate pens per treatment containing eight birds per pen. At d 21, 2 birds per cage were removed based on the greatest deviation from pen mean BW, resulting in each pen containing 6 birds for the final analyses. Final BW were taken on d 40, and on d 42 two birds from each pen were sampled for plasma NEFA, glucose, and muscle and liver glycogen determination at the initiation and termination of a 22 h fast. The remaining 2 fasted birds were sampled after a 30 min refeeding period. No differences were observed in feed intake, BW gain, or feed efficiency on d 21 or d 40. Liver glycogen tended (P=0.10) to be greater in Cr-supplemented chicks in the fed state, and muscle glycogen concentrations tended (P=0.07) to be greater in Cr-supplemented chicks compared with controls following fasting and refeeding. Plasma glucose concentrations were not affected by dietary Cr in the fed, fasted, or refed state. Plasma NEFA levels were not affected by treatment in fed or fasted birds. However, plasma NEFA concentrations were lower (P<0.01) in chicks supplemented with Cr than in controls following fasting and refeeding, suggesting that Cr increased insulin sensitivity. No differences were detected among birds supplemented with 0.2 or 0.4 mg Cr/kg, and among those receiving 0.4 or 0.6 mg Cr/kg. Results of this study indicate that Cr propionate supplementation of a control diet containing 0.43 to 0.45 mg Cr/kg enhanced insulin sensitivity. PMID:26933236

  11. A simple method for quantitation of insulin sensitivity and insulin release from an intravenous glucose tolerance test.

    PubMed

    Galvin, P; Ward, G; Walters, J; Pestell, R; Koschmann, M; Vaag, A; Martin, I; Best, J D; Alford, F

    1992-12-01

    Both insulin secretion and insulin sensitivity are important in the development of diabetes but current methods used for their measurements are complex and cannot be used for epidemiological surveys. This study describes a simplified approach for the estimation of first phase insulin release and insulin sensitivity from a standard 40-min intravenous glucose tolerance test (IVGTT), and compares these parameter estimations with the sophisticated minimal model analysis of a frequently sampled 3-h IVGTT and the euglycaemic clamp technique. For the simplified IVGTT, first phase insulin release was measured as the insulin area above basal post glucose load unit-1 incremental change (i.e. peak rise) in plasma glucose over 0-10 min, and insulin sensitivity as a rate of glucose disappearance (Kg) unit-1 insulin increase above basal from 0-40 min post-glucose load in 18 subjects who were studied twice, either basally or in a perturbed pathophysiological state (i.e. pre- and post-ultramarathon race, n = 5; pre- and post-20 h pulsatile hyperinsulinaemia, n = 8; pre- and post-thyrotoxic state, n = 5). A further 12 subjects were compared by IVGTT, and glucose clamp. In addition, seven dogs were studied three times by IVGTT during normal saline infusion and after short-term (1/2 hour) or long-term (72 hour) adrenaline infusions. First phase insulin release and insulin sensitivity estimated from the simplified IVGTT as calculated by the two methods correlated closely (rs = 0.89 and rs = 0.87, respectively), although less precisely in markedly insulin-resistant subjects and the slopes and y intercepts of the linear regression lines were similar in the basal and perturbed states.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1478037

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

    PubMed

    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. PMID:27016579

  13. Dietary composition and its associations with insulin sensitivity and insulin secretion in youth.

    PubMed

    Henderson, Mélanie; Benedetti, Andrea; Gray-Donald, Katherine

    2014-02-01

    The objectives of the present study were to examine the associations between macronutrient intake and insulin sensitivity (IS) and insulin secretion (ISct), taking into consideration moderate-to-vigorous physical activity (MVPA), fitness and sedentary behaviour. Caucasian youth (n 630) aged 8-10 years at recruitment, with at least one obese biological parent, were studied (QUebec Adipose and Lifestyle InvesTigation in Youth cohort). IS was measured using the homeostasis model assessment (HOMA) of insulin resistance and Matsuda IS index. ISct was measured using HOMA2%-β, the ratio of the AUC of insulin:glucose over the first 30 min (AUC I/G(t= 30 min)) of the oral glucose tolerance test and AUC I/G(t= 120 min) over 2 h. Fitness was measured using VO₂(peak), percentage of fat mass by dual-energy X-ray absorptiometry, and 7 d MVPA using accelerometry; screen time (ST) by average daily hours of self-reported television, video game or computer use. Dietary composition was measured using three non-consecutive dietary recalls. Non-parametric smoothing splines were used to model non-linear associations; all models were adjusted for age, sex, season, pubertal stage, MVPA, fitness, ST and adiposity. The percentage of total daily energy from dietary protein, fat, saturated fat and carbohydrate and the consumption of dietary vitamin D, sugar-sweetened beverages, fibre and portions of fruits and vegetables were taken into consideration. No dietary component was associated with any measure of IS after adjusting for MVPA, fitness, ST and adiposity. For every 1% increase in daily protein intake (%), AUC I/G(t= 30 min) decreased by 1·1% (P= 0·033). Otherwise, dietary composition was not associated with ISct. While long-term excess of energy intake has been shown to lead to overweight and obesity, dietary macronutrient composition is not independently correlated with IS or ISct in youth. PMID:24047611

  14. Hepatic circadian-clock system altered by insulin resistance, diabetes and insulin sensitizer in mice.

    PubMed

    Tseng, Huey-Ling; Yang, Shu-Chuan; Yang, Shih-Hsien; Shieh, Kun-Ruey

    2015-01-01

    Circadian rhythms are intrinsic rhythms that are coordinated with the rotation of the Earth and are also generated by a set of circadian-clock genes at the intracellular level. Growing evidence suggests a strong link between circadian rhythms and energy metabolism; however, the fundamental mechanisms remain unclear. In the present study, neonatal streptozotocin (STZ)-treated mice were used to model the molecular and physiological progress from insulin resistance to diabetes. Two-day-old male C57BL/6 mice received a single injection of STZ and were tested for non-obese, hyperglycemic and hyperinsulinemic conditions in the early stage, insulin resistance in the middle stage, and diabetes in the late stage. Gene expression levels of the hepatic circadian-clock system were examined by real-time quantitative PCR. Most of the components of the hepatic circadian-clock gene expression system, such as the mRNAs of Bmal1 (brain and muscle Arnt-like protein-1), Per2 (period 2) and Cry1 (cryptochrome 1), were elevated, and circadian patterns were retained in the early and middle stages of insulin-resistant conditions. The insulin sensitizer, rosiglitazone, returns the physiological and molecular changes associated with the diabetic phenotype to normal levels through peroxisome proliferator-activated receptor γ (PPARγ) rather than PPARα. Early and chronic treatment with rosiglitazone has been shown to be effective to counter the diabetic condition. Over time, this effect acts to attenuate the increased gene expression levels of the hepatic circadian-clock system and delay the severity of diabetic conditions. Together, these results support an essential role for the hepatic circadian-clock system in the coordinated regulation and/or response of metabolic pathways. PMID:25799429

  15. Hepatic Circadian-Clock System Altered by Insulin Resistance, Diabetes and Insulin Sensitizer in Mice

    PubMed Central

    Yang, Shih-Hsien; Shieh, Kun-Ruey

    2015-01-01

    Circadian rhythms are intrinsic rhythms that are coordinated with the rotation of the Earth and are also generated by a set of circadian-clock genes at the intracellular level. Growing evidence suggests a strong link between circadian rhythms and energy metabolism; however, the fundamental mechanisms remain unclear. In the present study, neonatal streptozotocin (STZ)-treated mice were used to model the molecular and physiological progress from insulin resistance to diabetes. Two-day-old male C57BL/6 mice received a single injection of STZ and were tested for non-obese, hyperglycemic and hyperinsulinemic conditions in the early stage, insulin resistance in the middle stage, and diabetes in the late stage. Gene expression levels of the hepatic circadian-clock system were examined by real-time quantitative PCR. Most of the components of the hepatic circadian-clock gene expression system, such as the mRNAs of Bmal1 (brain and muscle Arnt-like protein-1), Per2 (period 2) and Cry1 (cryptochrome 1), were elevated, and circadian patterns were retained in the early and middle stages of insulin-resistant conditions. The insulin sensitizer, rosiglitazone, returns the physiological and molecular changes associated with the diabetic phenotype to normal levels through peroxisome proliferator-activated receptor γ (PPARγ) rather than PPARα. Early and chronic treatment with rosiglitazone has been shown to be effective to counter the diabetic condition. Over time, this effect acts to attenuate the increased gene expression levels of the hepatic circadian-clock system and delay the severity of diabetic conditions. Together, these results support an essential role for the hepatic circadian-clock system in the coordinated regulation and/or response of metabolic pathways. PMID:25799429

  16. Insulin-like growth factor I stimulates lipid oxidation, reduces protein oxidation, and enhances insulin sensitivity in humans.

    PubMed Central

    Hussain, M A; Schmitz, O; Mengel, A; Keller, A; Christiansen, J S; Zapf, J; Froesch, E R

    1993-01-01

    To elucidate the effects of insulin-like growth factor I (IGF-I) on fuel oxidation and insulin sensitivity, eight healthy subjects were treated with saline and recombinant human (IGF-I (10 micrograms/kg.h) during 5 d in a crossover, randomized fashion, while receiving an isocaloric diet (30 kcal/kg.d) throughout the study period. On the third and fourth treatment days, respectively, an L-arginine stimulation test and an intravenous glucose tolerance test were performed. A euglycemic, hyperinsulinemic clamp combined with indirect calorimetry and a glucose tracer infusion were performed on the fifth treatment day. IGF-I treatment led to reduced fasting and stimulated (glucose and/or L-arginine) insulin and growth hormone secretion. Basal and stimulated glucagon secretion remained unchanged. Intravenous glucose tolerance was unaltered despite reduced insulin secretion. Resting energy expenditure and lipid oxidation were both elevated, while protein oxidation was reduced, and glucose turnover rates were unaltered on the fifth treatment day with IGF-I as compared to the control period. Enhanced lipolysis was reflected by elevated circulating free fatty acids. Moreover, insulin-stimulated oxidative and nonoxidative glucose disposal (i.e., insulin sensitivity) were enhanced during IGF-I treatment. Thus, IGF-I treatment leads to marked changes in lipid and protein oxidation, whereas, at the dose used, carbohydrate metabolism remains unaltered in the face of reduced insulin levels and enhanced insulin sensitivity. Images PMID:8227340

  17. Cinnamon improves insulin sensitivity and alters body composition in an animal model of the metabolic syndrome

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Polyphenols from cinnamon (CN) have been described recently as insulin sensitizers and antioxidants, but their effects on the glucose/insulin system in vivo have not been totally investigated. The aim of this study was to determine the effects of CN on insulin resistance and body composition, using ...

  18. Ex vivo generation of glucose sensitive insulin secreting mesenchymal stem cells derived from human adipose tissue

    PubMed Central

    Dave, Shruti D.; Vanikar, Aruna V.; Trivedi, Hargovind L

    2012-01-01

    Background: Diabetics are incapable of producing insulin/have autoimmune mechanisms making it ineffective to control glucose secretion. We present a prospective study of glucose-sensitive insulin-secreting mesenchymal stem cells (IS-MSC) generated from human adipose tissue (h-AD) sans xenogenic material. Materials and Methods: Ten grams h-AD from donor anterior abdominal wall was collected in proliferation medium composed of α-Minimum Essential Media (α-MEM), albumin, fibroblast-growth factor and antibiotics, minced, incubated in collagenase-I at 37°C with shaker and centrifuged. Supernatant and pellets were separately cultured in proliferation medium on cell+ plates at 37°C with 5% CO2 for 10 days. Cells were harvested by trypsinization, checked for viability, sterility, counts, flow-cytometry (CD45-/90+/73+), and differentiated into insulin-expressing cells using medium composed of DMEM, gene expressing up-regulators and antibiotics for 3 days. They were studied for transcriptional factors Pax-6, Isl-1, pdx-1 (immunofluorescence). C-peptide and insulin were measured by chemiluminescence. In vitro glucose sensitivity assay was carried out by measuring levels of insulin and C-peptide secretion in absence of glucose followed by 2 hours incubation after glucose addition. Results: Mean IS-AD-MSC quantum was 3.21 ml, cell count, 1.5 ×103 cells/μl), CD45-/90+/73+ cells were 44.37% /25.52%. All of them showed presence of pax-6, pdx-1, and Isl-1. Mean C-Peptide and insulin levels were 0.36 ng/ml and 234 μU/ml, respectively, pre-glucose and 0.87 ng/ml and 618.3 μU/ml post-glucose additions. The mean rise in secretion levels was 2.42 and 2.65 fold, respectively. Conclusion: Insulin-secreting h-AD-MSC can be generated safely and effectively showing in vitro glucose responsive alteration in insulin and C-peptide secretion levels. PMID:22701849

  19. Effect of body weight gain on insulin sensitivity after retirement from exercise training

    NASA Technical Reports Server (NTRS)

    Dolkas, Constantine B.; Rodnick, Kenneth J.; Mondon, Carl E.

    1990-01-01

    The effect of the body-weight gain after retirement from an exercise-training program on the retained increase in insulin sensitivity elicited by the training was investigated in exercise-trained (ET) rats. Insulin sensitivity was assessed by oral glucose tolerance and insulin suppression tests immediately after training and during retirement. Results show that, compared with sedentary controls, exercise training enhanced insulin-induced glucose uptake, but the enhanced sensitivity was gradually lost with the end of running activity until after seven days of retirement, when it became equal to that of controls. This loss of enhanced sensitivity to insulin was associated with an accelerated gain in body weight beginning one day after the start of retirement. However, those animals that gained weight only at rates similar to those of control rats, retained their enhanced sensitivity to insulin.

  20. Maternal Hyperleptinemia Improves Offspring Insulin Sensitivity in Mice.

    PubMed

    Talton, Omonseigho O; Pennington, Kathleen A; Pollock, Kelly E; Bates, Keenan; Ma, Lixin; Ellersieck, Mark R; Schulz, Laura C

    2016-07-01

    Maternal obesity and gestational diabetes are prevalent worldwide. Offspring of mothers with these conditions weigh more and are predisposed to metabolic syndrome. A hallmark of both conditions is maternal hyperleptinemia, but the role of elevated leptin levels during pregnancy on developmental programming is largely unknown. We previously found that offspring of hyperleptinemic mothers weighed less and had increased activity. The goal of this study was to determine whether maternal leptin affects offspring insulin sensitivity by investigating offspring glucose metabolism and lipid accumulation. Offspring from two maternal hyperleptinemic models were compared. The first model of hyperleptinemia is the Lepr(db/+) mouse, which has a mutation in one copy of the gene that encodes the leptin receptor, resulting in a truncated long form of the receptor, and hyperleptinemia. Wild-type females served as the control for the Lepr(db/+) females. For the second hyperleptinemic model, wild-type females were implanted with miniosmotic pumps, which released leptin (350 ng/h) or saline (as the control) just prior to mating and throughout gestation. In the offspring of these dams, we measured glucose tolerance; serum leptin, insulin, and triglyceride levels; liver triglycerides; pancreatic α- and β-cell numbers; body composition; incidence of nonalcoholic fatty liver disease; and the expression of key metabolic genes in the liver and adipose tissue. We found that the offspring of hyperleptinemic dams exhibited improved glucose tolerance, reduced insulin and leptin concentrations, reduced liver triglycerides, and a lower incidence of nonalcoholic fatty liver disease. Overall, maternal hyperleptinemia was beneficial for offspring glucose and lipid metabolism. PMID:27145007

  1. Low fish oil intake improves insulin sensitivity, lipid profile and muscle metabolism on insulin resistant MSG-obese rats

    PubMed Central

    2011-01-01

    Background Obesity is commonly associated with diabetes, cardiovascular diseases and cancer. The purpose of this study was to determinate the effect of a lower dose of fish oil supplementation on insulin sensitivity, lipid profile, and muscle metabolism in obese rats. Methods Monosodium glutamate (MSG) (4 mg/g body weight) was injected in neonatal Wistar male rats. Three-month-old rats were divided in normal-weight control group (C), coconut fat-treated normal weight group (CO), fish oil-treated normal weight group (FO), obese control group (Ob), coconut fat-treated obese group (ObCO) and fish oil-treated obese group (ObFO). Obese insulin-resistant rats were supplemented with fish oil or coconut fat (1 g/kg/day) for 4 weeks. Insulin sensitivity, fasting blood biochemicals parameters, and skeletal muscle glucose metabolism were analyzed. Results Obese animals (Ob) presented higher Index Lee and 2.5 fold epididymal and retroperitoneal adipose tissue than C. Insulin sensitivity test (Kitt) showed that fish oil supplementation was able to maintain insulin sensitivity of obese rats (ObFO) similar to C. There were no changes in glucose and HDL-cholesterol levels amongst groups. Yet, ObFO revealed lower levels of total cholesterol (TC; 30%) and triacylglycerol (TG; 33%) compared to Ob. Finally, since exposed to insulin, ObFO skeletal muscle revealed an increase of 10% in lactate production, 38% in glycogen synthesis and 39% in oxidation of glucose compared to Ob. Conclusions Low dose of fish oil supplementation (1 g/kg/day) was able to reduce TC and TG levels, in addition to improved systemic and muscle insulin sensitivity. These results lend credence to the benefits of n-3 fatty acids upon the deleterious effects of insulin resistance mechanisms. PMID:21526994

  2. Adiponectin, driver or passenger on the road to insulin sensitivity?

    PubMed Central

    Ye, Risheng; Scherer, Philipp E.

    2013-01-01

    Almost 20 years have passed since the first laboratory evidence emerged that an abundant message encoding a protein with homology to the C1q superfamily is highly specifically expressed in adipocytes. At this stage, we refer to this protein as adiponectin. Despite more than 10,000 reports in the literature since its initial description, we seem to have written only the first chapter in the textbook on adiponectin physiology. With every new aspect we learn about adiponectin, a host of new questions arise with respect to the underlying molecular mechanisms. Here, we aim to summarize recent findings in the field and bring the rodent studies that suggest a causal relationship between adiponectin levels in plasma and systemic insulin sensitivity in perspective with the currently available data on the clinical side. PMID:24049728

  3. Effects of stevioside on glucose transport activity in insulin-sensitive and insulin-resistant rat skeletal muscle.

    PubMed

    Lailerd, Narissara; Saengsirisuwan, Vitoon; Sloniger, Julie A; Toskulkao, Chaivat; Henriksen, Erik J

    2004-01-01

    Stevioside (SVS), a natural sweetener extracted from Stevia rebaudiana, has been used as an antihyperglycemic agent. However, little is known regarding its potential action on skeletal muscle, the major site of glucose disposal. Therefore, the purpose of the present study was to determine the effect of SVS treatment on skeletal muscle glucose transport activity in both insulin-sensitive lean (Fa/-) and insulin-resistant obese (fa/fa) Zucker rats. SVS was administered (500 mg/kg body weight by gavage) 2 hours before an oral glucose tolerance test (OGTT). Whereas the glucose incremental area under the curve (IAUC(glucose)) was not affected by SVS in lean Zucker rats, the insulin incremental area under the curve (IAUC(insulin)) and the glucose-insulin index (product of glucose and insulin IAUCs and inversely related to whole-body insulin sensitivity) were decreased (P<.05) by 42% and 45%, respectively. Interestingly, in the obese Zucker rat, SVS also reduced the IAUC(insulin) by 44%, and significantly decreased the IAUC(glucose) (30%) and the glucose-insulin index (57%). Muscle glucose transport was assessed following in vitro SVS treatment. In lean Zucker rats, basal glucose transport in type I soleus and type IIb epitrochlearis muscles was not altered by 0.01 to 0.1 mmol/L SVS. In contrast, 0.1 mmol/L SVS enhanced insulin-stimulated (2 mU/mL) glucose transport in both epitrochlearis (15%) and soleus (48%). At 0.5 mmol/L or higher, the SVS effect was reversed. Similarly, basal glucose transport in soleus and epitrochlearis muscles in obese Zucker rats was not changed by lower doses of SVS (0.01 to 0.1 mmol/L). However, these lower doses of SVS significantly increased insulin-stimulated glucose transport in both obese epitrochlearis and soleus (15% to 20%). In conclusion, acute oral SVS increased whole-body insulin sensitivity, and low concentrations of SVS (0.01 to 0.1 mmol/L) modestly improved in vitro insulin action on skeletal muscle glucose transport in both lean

  4. Dissociation of in vitro sensitivities of glucose transport and antilipolysis to insulin in NIDDM

    SciTech Connect

    Yki-Jaervinen, H.; Kubo, K.; Zawadzki, J.; Lillioja, S.; Young, A.; Abbott, W.; Foley, J.E.

    1987-09-01

    It is unclear from previous studies whether qualitative or only quantitative differences exist in insulin action in adipocytes obtained from obese subjects with non-insulin-dependent diabetes mellitus (NIDDM) when compared with equally obese nondiabetic subjects. In addition, the role of changes in insulin binding as a cause of insulin resistance in NIDDM is still controversial. The authors compared the sensitivities of (/sup 14/C)-glucose transport and antilipolysis to insulin and measured (/sup 125/I)-insulin binding in abdominal adipocytes obtained from 45 obese nondiabetic, obese diabetic, and 15 nonobese female southwestern American Indians. Compared with the nonobese group, the sensitivities of glucose transport antilipolysis were reduced in both the obese nondiabetic and obese diabetic groups. Compared with the obese nondiabetic subjects, the ED/sub 50/ for stimulation of glucose transport was higher in the obese patients with NIDDM. In contrast, the ED/sub 50/S for antilipolysis were similar in obese diabetic patients and obese nondiabetic subjects. No differences was found in insulin binding in patients with NIDDM when compared with the equally obese nondiabetic subjects. These data indicate 1) the mechanism of insulin resistance differs in NIDDM and obesity, and 2) the selective loss of insulin sensitivity in NIDDM precludes changes in insulin binding as a cause of insulin resistance in this disorder.

  5. Central GLP-2 enhances hepatic insulin sensitivity via activating PI3K signaling in POMC neurons

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Glucagon-like peptides (GLP-1/GLP-2) are coproduced and highlighted as key modulators to improve glucose homeostasis and insulin sensitivity after bariatric surgery. However, it is unknown if CNS GLP-2 plays any physiological role in the control of glucose homeostasis and insulin sensitivity. We sho...

  6. LOCAL IGF-I ENHANCES THE SENSITIVITY OF MUSCLE PROTEIN SYNTHESIS TO INSULIN

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Skeletal muscle protein synthesis in the immature muscle is highly sensitive to insulin and nutrients. We hypothesized that this sensitivity of protein synthesis to insulin is attributable to local IGFs that are expressed at a significant level by immature skeletal muscle. To test the hypothesis, t...

  7. The neuropilin-like protein ESDN regulates insulin signaling and sensitivity.

    PubMed

    Li, Xuan; Jung, Jae-Joon; Nie, Lei; Razavian, Mahmoud; Zhang, Jiasheng; Samuel, Varman; Sadeghi, Mehran M

    2016-05-01

    Insulin effects on cell metabolism, growth, and survival are mediated by its binding to, and activation of, insulin receptor. With increasing prevalence of insulin resistance and diabetes there is considerable interest in identifying novel regulators of insulin signal transduction. The transmembrane protein endothelial and smooth muscle cell-derived neuropilin-like protein (ESDN) is a novel regulator of vascular remodeling and angiogenesis. Here, we investigate a potential role of ESDN in insulin signaling, demonstrating that Esdn gene deletion promotes insulin-induced vascular smooth muscle cell proliferation and migration. This is associated with enhanced protein kinase B and mitogen-activated protein kinase activation as well as insulin receptor phosphorylation. Likewise, insulin signaling in the liver, muscle, and adipose tissue is enhanced in Esdn(-/-) mice, and these animals exhibit improved insulin sensitivity and glucose homeostasis in vivo. The effect of ESDN on insulin signaling is traced back to its interaction with insulin receptor, which alters the receptor interaction with regulatory adaptor protein-E3 ubiquitin ligase pairs, adaptor protein with pleckstrin homology and Src homology 2 domain-c-Cbl and growth factor receptor bound protein 10-neuronal precursor cell-expressed developmentally downregulated 4. In conclusion, our findings establish ESDN as an inhibitor of insulin receptor signal transduction through a novel regulatory mechanism. Loss of ESDN potentiates insulin's metabolic and mitotic effects and provides insights into a novel therapeutic avenue. PMID:26921437

  8. Neuronal Sirt1 Deficiency Increases Insulin Sensitivity in Both Brain and Peripheral Tissues*

    PubMed Central

    Lu, Min; Sarruf, David A.; Li, Pingping; Osborn, Olivia; Sanchez-Alavez, Manuel; Talukdar, Saswata; Chen, Ai; Bandyopadhyay, Gautam; Xu, Jianfeng; Morinaga, Hidetaka; Dines, Kevin; Watkins, Steven; Kaiyala, Karl; Schwartz, Michael W.; Olefsky, Jerrold M.

    2013-01-01

    Sirt1 is a NAD+-dependent class III deacetylase that functions as a cellular energy sensor. In addition to its well-characterized effects in peripheral tissues, emerging evidence suggests that neuronal Sirt1 activity plays a role in the central regulation of energy balance and glucose metabolism. To assess this idea, we generated Sirt1 neuron-specific knockout (SINKO) mice. On both standard chow and HFD, SINKO mice were more insulin sensitive than Sirt1f/f mice. Thus, SINKO mice had lower fasting insulin levels, improved glucose tolerance and insulin tolerance, and enhanced systemic insulin sensitivity during hyperinsulinemic euglycemic clamp studies. Hypothalamic insulin sensitivity of SINKO mice was also increased over controls, as assessed by hypothalamic activation of PI3K, phosphorylation of Akt and FoxO1 following systemic insulin injection. Intracerebroventricular injection of insulin led to a greater systemic effect to improve glucose tolerance and insulin sensitivity in SINKO mice compared with controls. In line with the in vivo results, insulin-induced AKT and FoxO1 phosphorylation were potentiated by inhibition of Sirt1 in a cultured hypothalamic cell line. Mechanistically, this effect was traced to a reduced effect of Sirt1 to directly deacetylate and repress IRS-1 function. The enhanced central insulin signaling in SINKO mice was accompanied by increased insulin receptor signal transduction in liver, muscle, and adipose tissue. In summary, we conclude that neuronal Sirt1 negatively regulates hypothalamic insulin signaling, leading to systemic insulin resistance. Interventions that reduce neuronal Sirt1 activity have the potential to improve systemic insulin action and limit weight gain on an obesigenic diet. PMID:23457303

  9. Effect of Sodium Fluoride on Bone Biomechanical and Histomorphometric Parameters and on Insulin Signaling and Insulin Sensitivity in Ovariectomized Rats.

    PubMed

    de Cássia Alves Nunes, Rita; Chiba, Fernando Yamamoto; Pereira, Amanda Gomes; Pereira, Renato Felipe; de Lima Coutinho Mattera, Maria Sara; Ervolino, Edilson; Louzada, Mário Jefferson Quirino; Buzalaf, Marília Afonso Rabelo; Silva, Cristina Antoniali; Sumida, Doris Hissako

    2016-09-01

    Osteoporosis is a systemic disease characterized by bone degradation and decreased bone mass that promotes increased bone fragility and eventual fracture risk. Studies have investigated the use of sodium fluoride (NaF) for the treatment of osteoporosis. However, fluoride can alter glucose homeostasis. The aim of this study was to evaluate the effects of NaF intake (50 mg/L) from water on the following parameters of ovariectomized (OVX) rats: (1) tyrosine phosphorylation status of insulin receptor substrate (pp185 (IRS-1/IRS-2)) in white adipose tissue; (2) insulin sensitivity; (3) plasma concentrations of glucose, insulin, total cholesterol, triglyceride, TNF-α, IL-6, osteocalcin, calcium, and fluoride; (4) bone density and biomechanical properties in the tibia; and (5) tibia histomorphometric analysis. Fifty-two Wistar rats (2 months old) were ovariectomized and distributed into two groups: control group (OVX-C) and NaF group (OVX-F), which was subjected to treatment with NaF (50 mg/L) administered in drinking water for 42 days. The chronic treatment with NaF promoted (1) a decrease in pp185 (IRS-1/IRS-2) tyrosine phosphorylation status after insulin infusion in white adipose tissue and in insulin sensitivity; (2) an increase in the plasma concentration of insulin, fluoride, osteocalcin, calcium, triglyceride, VLDL-cholesterol, TNF-α, and IL-6; (3) a reduction in the trabecular width, bone area, stiffness, maximum strength, and tenacity; (4) no changes in body weight, food and water intake, plasma glucose, total cholesterol, HDL-cholesterol, LDL-cholesterol, bone mineral content, and bone mineral density. It was concluded that chronic treatment with NaF (50 mg/L) in OVX rats causes a decrease in insulin sensitivity, insulin signaling transduction, and biochemical, biomechanical, and histomorphometric bone parameters. PMID:26876375

  10. Current approaches for assessing insulin sensitivity and resistance in vivo: advantages, limitations, and appropriate usage.

    PubMed

    Muniyappa, Ranganath; Lee, Sihoon; Chen, Hui; Quon, Michael J

    2008-01-01

    Insulin resistance contributes to the pathophysiology of diabetes and is a hallmark of obesity, metabolic syndrome, and many cardiovascular diseases. Therefore, quantifying insulin sensitivity/resistance in humans and animal models is of great importance for epidemiological studies, clinical and basic science investigations, and eventual use in clinical practice. Direct and indirect methods of varying complexity are currently employed for these purposes. Some methods rely on steady-state analysis of glucose and insulin, whereas others rely on dynamic testing. Each of these methods has distinct advantages and limitations. Thus, optimal choice and employment of a specific method depends on the nature of the studies being performed. Established direct methods for measuring insulin sensitivity in vivo are relatively complex. The hyperinsulinemic euglycemic glucose clamp and the insulin suppression test directly assess insulin-mediated glucose utilization under steady-state conditions that are both labor and time intensive. A slightly less complex indirect method relies on minimal model analysis of a frequently sampled intravenous glucose tolerance test. Finally, simple surrogate indexes for insulin sensitivity/resistance are available (e.g., QUICKI, HOMA, 1/insulin, Matusda index) that are derived from blood insulin and glucose concentrations under fasting conditions (steady state) or after an oral glucose load (dynamic). In particular, the quantitative insulin sensitivity check index (QUICKI) has been validated extensively against the reference standard glucose clamp method. QUICKI is a simple, robust, accurate, reproducible method that appropriately predicts changes in insulin sensitivity after therapeutic interventions as well as the onset of diabetes. In this Frontiers article, we highlight merits, limitations, and appropriate use of current in vivo measures of insulin sensitivity/resistance. PMID:17957034

  11. CLOCK and BMAL1 Regulate Muscle Insulin Sensitivity via SIRT1 in Male Mice.

    PubMed

    Liu, Jun; Zhou, Ben; Yan, Menghong; Huang, Rui; Wang, Yuangao; He, Zhishui; Yang, Yonggang; Dai, Changgui; Wang, Yiqian; Zhang, Fang; Zhai, Qiwei

    2016-06-01

    Circadian misalignment induces insulin resistance in both human and animal models, and skeletal muscle is the largest organ response to insulin. However, how circadian clock regulates muscle insulin sensitivity and the underlying molecular mechanisms are still largely unknown. Here we show circadian locomotor output cycles kaput (CLOCK) and brain and muscle aryl hydrocarbon receptor nuclear translocator-like protein (BMAL)-1, two core circadian transcription factors, are down-regulated in insulin-resistant C2C12 myotubes and mouse skeletal muscle. Furthermore, insulin signaling is attenuated in the skeletal muscle of Clock(Δ19/Δ19) mice, and knockdown of CLOCK or BMAL1 by small interfering RNAs induces insulin resistance in C2C12 myotubes. Consistently, ectopic expression of CLOCK and BMAL1 improves insulin sensitivity in C2C12 myotubes. Moreover, CLOCK and BMAL1 regulate the expression of sirtuin 1 (SIRT1), an important regulator of insulin sensitivity, in C2C12 myotubes and mouse skeletal muscle, and two E-box elements in Sirt1 promoter are responsible for its CLOCK- and BMAL1-dependent transcription in muscle cells. Further studies show that CLOCK and BMAL1 regulate muscle insulin sensitivity through SIRT1. In addition, we find that BMAL1 and SIRT1 are decreased in the muscle of mice maintained in constant darkness, and resveratrol supplementation activates SIRT1 and improves insulin sensitivity. All these data demonstrate that CLOCK and BMAL1 regulate muscle insulin sensitivity via SIRT1, and activation of SIRT1 might be a potential valuable strategy to attenuate muscle insulin resistance related to circadian misalignment. PMID:27035655

  12. Human gut microbes impact host serum metabolome and insulin sensitivity.

    PubMed

    Pedersen, Helle Krogh; Gudmundsdottir, Valborg; Nielsen, Henrik Bjørn; Hyotylainen, Tuulia; Nielsen, Trine; Jensen, Benjamin A H; Forslund, Kristoffer; Hildebrand, Falk; Prifti, Edi; Falony, Gwen; Le Chatelier, Emmanuelle; Levenez, Florence; Doré, Joel; Mattila, Ismo; Plichta, Damian R; Pöhö, Päivi; Hellgren, Lars I; Arumugam, Manimozhiyan; Sunagawa, Shinichi; Vieira-Silva, Sara; Jørgensen, Torben; Holm, Jacob Bak; Trošt, Kajetan; Kristiansen, Karsten; Brix, Susanne; Raes, Jeroen; Wang, Jun; Hansen, Torben; Bork, Peer; Brunak, Søren; Oresic, Matej; Ehrlich, S Dusko; Pedersen, Oluf

    2016-07-21

    Insulin resistance is a forerunner state of ischaemic cardiovascular disease and type 2 diabetes. Here we show how the human gut microbiome impacts the serum metabolome and associates with insulin resistance in 277 non-diabetic Danish individuals. The serum metabolome of insulin-resistant individuals is characterized by increased levels of branched-chain amino acids (BCAAs), which correlate with a gut microbiome that has an enriched biosynthetic potential for BCAAs and is deprived of genes encoding bacterial inward transporters for these amino acids. Prevotella copri and Bacteroides vulgatus are identified as the main species driving the association between biosynthesis of BCAAs and insulin resistance, and in mice we demonstrate that P. copri can induce insulin resistance, aggravate glucose intolerance and augment circulating levels of BCAAs. Our findings suggest that microbial targets may have the potential to diminish insulin resistance and reduce the incidence of common metabolic and cardiovascular disorders. PMID:27409811

  13. Dietary supplementation with short-chain fructo-oligosaccharides improves insulin sensitivity in obese horses.

    PubMed

    Respondek, F; Myers, K; Smith, T L; Wagner, A; Geor, R J

    2011-01-01

    Obesity and insulin resistance are risk factors for laminitis in horses and ponies, and diet can play an important role in modulating these risk factors. Dietary supplementation with prebiotic fibers, such as short-chain fructo-oligosaccharides (scFOS), has resulted in improvement of insulin sensitivity in obese dogs and rodents. Thus, we hypothesized that scFOS may reduce insulin resistance in obese horses and designed a study to evaluate the effect of dietary supplementation with scFOS on insulin sensitivity. Eight mature Arabian geldings (BW = 523.0 ± 56.5 kg) with an average BCS of 8 were included in a crossover study. In each period, 4 horses were provided 45 g/d per horse of maltodextrin (control) and 4 horses received the same amount of scFOS for 6 wk, with a 3-wk washout between periods. Resting plasma concentrations of glucose, insulin, triglycerides, and leptin were measured. Minimal model analysis of a frequently sampled intravenous glucose tolerance test was used to evaluate insulin sensitivity, glucose effectiveness, acute insulin response to glucose, and disposition index. Without affecting BW and BCS, dietary supplementation with scFOS increased (P < 0.05) insulin sensitivity and reduced (P < 0.05) acute insulin response to glucose in comparison with maltodextrin but did not alter (P > 0.05) glucose effectiveness and disposition index. Resting serum insulin concentration also was reduced (P < 0.05) by scFOS supplementation but not by maltodextrin (P > 0.05). There was no effect (P > 0.05) of scFOS supplementation on plasma glucose or serum triglyceride and leptin concentrations. This study demonstrated that scFOS can moderately improve insulin sensitivity of obese horses, a finding that has potential relevance to the dietary management of obese, insulin-resistant horses at increased risk for laminitis. PMID:20870952

  14. Impact of Major Depressive Disorder on Prediabetes by Impairing Insulin Sensitivity

    PubMed Central

    Li, Li; Shelton, Richard Charles; Chassan, Rachel Ann; Hammond, John Charles; Gower, Barbara Ann; Garvey, Timothy W

    2016-01-01

    Reports regarding the associations between major depressive disorder (MDD) and diabetes remain heterogeneous. Our aim was to investigate whether glucose homeostasis and insulin sensitivity were impaired in the MDD patients and its mechanisms. A total of 30 patients with MDD and 30 matched controls were recruited. The oral glucose tolerance test and dual-energy X-ray absorptiometry scan were performed in each participant. Insulin signaling in postmortem brain tissues from other depressive patients and controls (obtained from Alabama brain bank) was examined. Insulin sensitivity was reduced substantially in the MDD patients, however, the fasting and 2-h glucose concentrations remained within the normal range through compensatory insulin secretion. Despite increased insulin secretion, 1-h glucose concentrations in the MDD patients were significantly elevated compared with the controls. MDD patients had greater visceral fat mass but lower adiponectin levels compared with the controls. Furthermore, phosphorylated-AKT levels in insulin signaling were decreased in postmortem brain tissues in patients with MDD. These results suggest that MDD patients are at a greater risk for diabetes due to decreased insulin sensitivity, reduced disposition index, and impaired glucose tolerance as manifested by elevated 1-h glucose concentrations following an oral glucose challenge. Mechanistic studies reveal that decreased insulin sensitivity is associated with increased visceral fat mass, lower adiponectin levels and impaired insulin action in postmortem brain tissues in the MDD patients. Our findings emphasize the importance of screening depressive patients to identify susceptible individuals for developing future diabetes with the hope of improving their health outcomes. PMID:27274905

  15. Bitter gourd (Momordica charantia) improves insulin sensitivity by increasing skeletal muscle insulin-stimulated IRS-1 tyrosine phosphorylation in high-fat-fed rats.

    PubMed

    Sridhar, M G; Vinayagamoorthi, R; Arul Suyambunathan, V; Bobby, Z; Selvaraj, N

    2008-04-01

    The aim of this present study was to investigate the effect of bitter gourd extract on insulin sensitivity and proximal insulin signalling pathways in high-fat-fed rats. High-fat feeding of male Wistar rats for 10 weeks decreased the glucose tolerance and insulin sensitivity compared to chow-fed control rats. Bitter gourd extract supplementation for 2 weeks (9th and 10th) of high-fat feeding improved the glucose tolerance and insulin sensitivity. In addition bitter gourd extract reduced the fasting insulin (43 (se 4.4) v. 23 (se 5.2) microU/ml, P < 0.05), TAG (134 (se 12) v. 96 (se 5.5) mg/dl, P < 0.05), cholesterol (97 (se 6.3) v. 72 (se 5.2) mg/dl, P < 0.05) and epidydimal fat (4.8 (se 0.29) v. 3.6 (se 0.24) g, P < 0.05), which were increased by high-fat diet (HFD). High-fat feeding and bitter gourd supplementation did not have any effect on skeletal muscle insulin receptor, insulin receptor subtrate-1 (IRS-1) and insulin- stimulated insulin receptor tyrosine phosphorylation compared to chow-fed control rats. However high-fat feeding for 10 weeks reduced the insulin-stimulated IRS-1 tyrosine phosphorylation compared to control rats. Bitter gourd supplementation together with HFD for 2 weeks improved the insulin-stimulated IRS-1 tyrosine phosphorylation compared to rats fed with HFD alone. Our results show that bitter gourd extract improves insulin sensitivity, glucose tolerance and insulin signalling in HFD-induced insulin resistance. Identification of potential mechanism(s) by which bitter gourd improves insulin sensitivity and insulin signalling in high-fat-fed rats may open new therapeutic targets for the treatment of obesity/dyslipidemia-induced insulin resistance. PMID:17942003

  16. Selective enhancement of insulin sensitivity in the mature adipocyte is sufficient for systemic metabolic improvements.

    PubMed

    Morley, Thomas S; Xia, Jonathan Y; Scherer, Philipp E

    2015-01-01

    Dysfunctional adipose tissue represents a hallmark of type 2 diabetes and systemic insulin resistance, characterized by fibrotic deposition of collagens and increased immune cell infiltration within the depots. Here we generate an inducible model of loss of function of the protein phosphatase and tensin homologue (PTEN), a phosphatase critically involved in turning off the insulin signal transduction cascade, to assess the role of enhanced insulin signalling specifically in mature adipocytes. These mice gain more weight on chow diet and short-term as well as long-term high-fat diet exposure. Despite the increase in weight, they retain enhanced insulin sensitivity, show improvements in oral glucose tolerance tests, display reduced adipose tissue inflammation and maintain elevated adiponectin levels. These improvements also lead to reduced hepatic steatosis and enhanced hepatic insulin sensitivity. Prolonging insulin action selectively in the mature adipocyte is therefore sufficient to maintain normal systemic metabolic homeostasis. PMID:26243466

  17. Bioactives from Artemisia dracunculus L. Enhance Insulin Sensitivity via Modulation of Skeletal Muscle Protein Phosphorylation

    PubMed Central

    Kheterpal, Indu; Scherp, Peter; Kelley, Lauren; Wang, Zhong; Johnson, William; Ribnicky, David; Cefalu, William T.

    2014-01-01

    A botanical extract from Artemisia dracunculus L., termed PMI 5011, has been shown previously to improve insulin sensitivity by increasing cellular insulin signaling in in vitro and in vivo studies. These studies suggest that PMI 5011 effects changes in phosphorylation levels of proteins involved in insulin signaling. To explore effects of this promising botanical extract on the human skeletal muscle phosphoproteome, changes in site-specific protein phosphorylation levels in primary skeletal muscle cultures from obese, insulin resistant individuals were evaluated with and without insulin stimulation. Insulin resistance is a condition in which a normal or elevated insulin level results in an abnormal biologic response, e.g., glucose uptake. Using isobaric tagging for relative and absolute quantification (iTRAQ™) followed by phosphopeptide enrichment and liquid chromatography – tandem mass spectrometry, 125 unique phosphopeptides and 159 unique phosphorylation sites from 80 unique proteins were identified and quantified. Insulin stimulation of primary cultured muscle cells from insulin resistant individuals resulted in minimal increase in phosphorylation, demonstrating impaired insulin action in this condition. Treatment with PMI 5011 resulted in significant up regulation of 35 phosphopeptides that were mapped to proteins participating in the regulation of transcription, translation, actin cytoskeleton signaling, caveolae translocation and GLUT4 transport. These data further showed that PMI 5011 increased phosphorylation levels of specific amino acids in proteins in the insulin resistant state that are normally phosphorylated by insulin (thus, increasing cellular insulin signaling) and PMI 5011 also increased the abundance of phosphorylation sites of proteins regulating anti-apoptotic effects. Thus, the phosphoproteomics analysis demonstrated conclusively that PMI 5011 effects changes in phosphorylation levels of proteins and identified novel pathways by which

  18. Comparison of several insulin sensitivity indices derived from basal plasma insulin and glucose levels with minimal model indices.

    PubMed

    García-Estévez, D A; Araújo-Vilar, D; Fiestras-Janeiro, G; Saavedra-González, A; Cabezas-Cerrato, J

    2003-01-01

    Some techniques for the evaluation of insulin resistance (IR), such as the clamp technique, are not viable for the study of large populations; and for this reason, alternative approaches based on fasting plasma glucose (FPG) and plasma insulin (FPI) have been proposed. The aim of this study was to compare the IR calculations obtained from FPI and FPG values with the insulin sensitivity (IS) index derived from the minimal model. Eighty-seven healthy subjects with a wide range of body mass index (18 - 44 kg x m -2) and 16 DM2 non-obese patients were included in the study. All of the patients underwent a frequently sampled intravenous glucose tolerance test (FSIGTT), and the minimal model of glucose was used for the estimation of insulin sensitivity (IS MINIMAL ). The HOMA-IR index, the Avignon index, and the quotient FPG/FPI were used to calculate basal steady-state IR. The basal IR value that best correlated with IS was Log (1/HOMA-IR) (r = 0.70, p < 0.001). All of the basal indices showed a high correlation with each other. In conclusions, insulin sensitivity indices as determined from the basal glycaemia and insulinemia values are not good estimators for metabolic reality from the perspective of the minimal model. Nevertheless, they might well have an IR screening value for epidemiological studies, as long as there is no pancreatic beta-cell dysfunction. PMID:12669265

  19. Insulin Causes Hyperthermia by Direct Inhibition of Warm-Sensitive Neurons

    PubMed Central

    Sanchez-Alavez, Manuel; Tabarean, Iustin V.; Osborn, Olivia; Mitsukawa, Kayo; Schaefer, Jean; Dubins, Jeffrey; Holmberg, Kristina H.; Klein, Izabella; Klaus, Joe; Gomez, Luis F.; Kolb, Hartmuth; Secrest, James; Jochems, Jeanine; Myashiro, Kevin; Buckley, Peter; Hadcock, John R.; Eberwine, James; Conti, Bruno; Bartfai, Tamas

    2010-01-01

    OBJECTIVE Temperature and nutrient homeostasis are two interdependent components of energy balance regulated by distinct sets of hypothalamic neurons. The objective is to examine the role of the metabolic signal insulin in the control of core body temperature (CBT). RESEARCH DESIGN AND METHODS The effect of preoptic area administration of insulin on CBT in mice was measured by radiotelemetry and respiratory exchange ratio. In vivo 2-[18F]fluoro-2-deoxyglucose uptake into brown adipose tissue (BAT) was measured in rats after insulin treatment by positron emission tomography combined with X-ray computed tomography imaging. Insulin receptor–positive neurons were identified by retrograde tracing from the raphe pallidus. Insulin was locally applied on hypothalamic slices to determine the direct effects of insulin on intrinsically warm-sensitive neurons by inducing hyperpolarization and reducing firing rates. RESULTS Injection of insulin into the preoptic area of the hypothalamus induced a specific and dose-dependent elevation of CBT mediated by stimulation of BAT thermogenesis as shown by imaging and respiratory ratio measurements. Retrograde tracing indicates that insulin receptor–expressing warm-sensitive neurons activate BAT through projection via the raphe pallidus. Insulin applied on hypothalamic slices acted directly on intrinsically warm-sensitive neurons by inducing hyperpolarization and reducing firing rates. The hyperthermic effects of insulin were blocked by pretreatment with antibodies to insulin or with a phosphatidylinositol 3–kinase inhibitor. CONCLUSIONS Our findings demonstrate that insulin can directly modulate hypothalamic neurons that regulate thermogenesis and CBT and indicate that insulin plays an important role in coupling metabolism and thermoregulation at the level of anterior hypothalamus. PMID:19846801

  20. Prolonged insulin treatment sensitizes apoptosis pathways in pancreatic β cells.

    PubMed

    Bucris, E; Beck, A; Boura-Halfon, S; Isaac, R; Vinik, Y; Rosenzweig, T; Sampson, S R; Zick, Y

    2016-09-01

    Insulin resistance results from impaired insulin signaling in target tissues that leads to increased levels of insulin required to control plasma glucose levels. The cycle of hyperglycemia and hyperinsulinemia eventually leads to pancreatic cell deterioration and death by a mechanism that is yet unclear. Insulin induces ROS formation in several cell types. Furthermore, death of pancreatic cells induced by oxidative stress could be potentiated by insulin. Here, we investigated the mechanism underlying this phenomenon. Experiments were done on pancreatic cell lines (Min-6, RINm, INS-1), isolated mouse and human islets, and on cell lines derived from nonpancreatic sources. Insulin (100nM) for 24h selectively increased the production of ROS in pancreatic cells and isolated pancreatic islets, but only slightly affected the expression of antioxidant enzymes. This was accompanied by a time- and dose-dependent decrease in cellular reducing power of pancreatic cells induced by insulin and altered expression of several ER stress response elements including a significant increase in Trb3 and a slight increase in iNos The effect on iNos did not increase NO levels. Insulin also potentiated the decrease in cellular reducing power induced by H2O2 but not cytokines. Insulin decreased the expression of MCL-1, an antiapoptotic protein of the BCL family, and induced a modest yet significant increase in caspase 3/7 activity. In accord with these findings, inhibition of caspase activity eliminated the ability of insulin to increase cell death. We conclude that prolonged elevated levels of insulin may prime apoptosis and cell death-inducing mechanisms as a result of oxidative stress in pancreatic cells. PMID:27411561

  1. Age-dependent association of serum prolactin with glycaemia and insulin sensitivity in humans.

    PubMed

    Wagner, R; Heni, M; Linder, K; Ketterer, C; Peter, A; Böhm, A; Hatziagelaki, E; Stefan, N; Staiger, H; Häring, H-U; Fritsche, A

    2014-02-01

    The dopamine agonist bromocriptine has been approved for the treatment of type 2 diabetes in the United States. Bromocriptine inhibits prolactin secretion, and patients with hyperprolactinaemia display impaired insulin sensitivity. We therefore hypothesized that low prolactin levels are associated with lower glycaemia and higher insulin sensitivity in healthy subjects. Prolactin levels were determined from fasting serum in participants without diabetes from the cross-sectional Tübingen family study for type 2 diabetes (m/f = 562/1,121, age = 40 ± 13 years, BMI = 30 ± 9 kg/m(2)). A 75 g oral glucose tolerance test was performed, and the area under the glucose curve (AUC(0-120)Glucose) and insulin sensitivity index were calculated. A subgroup (n = 494) underwent hyperinsulinaemic-euglycaemic clamp tests. Prolactin associated positively with insulin sensitivity (p = 0.001, adjusted for gender, age, and BMI). Age strongly interacted (p < 0.0001) with the effect of prolactin on insulin sensitivity, inverting the positive relationship to a negative one in younger participants. Glycated haemoglobin (HbA1c) and AUC(0-120)Glucose correlated negatively with prolactin, and an interaction with age was found as well. Higher prolactin levels are associated with improved insulin sensitivity and lower glucose in individuals without diabetes. This relationship turns to its opposite in younger persons. As prolactin is a proxy for the dopaminergic tone in the central nervous system, these associations may indicate an age-dependent influence of the brain on peripheral insulin sensitivity. PMID:23836327

  2. Effect of Artemisia dracunculus Administration on Glycemic Control, Insulin Sensitivity, and Insulin Secretion in Patients with Impaired Glucose Tolerance.

    PubMed

    Méndez-Del Villar, Miriam; Puebla-Pérez, Ana M; Sánchez-Peña, María J; González-Ortiz, Luis J; Martínez-Abundis, Esperanza; González-Ortiz, Manuel

    2016-05-01

    To evaluate the effect of Artemisia dracunculus on glycemic control, insulin sensitivity, and insulin secretion in patients with impaired glucose tolerance (IGT). A randomized, double blind, placebo-controlled clinical trial was performed in 24 patients with diagnosis of IGT. Before and after the intervention, glucose and insulin levels were measured every 30 min for 2 h after a 75-g dextrose load, along with glycated hemoglobin A1c (A1C) and lipid profile. Twelve patients received A. dracunculus (1000 mg) before breakfast and dinner for 90 days; the remaining 12 patients received placebo. Area under the curve (AUC) of glucose and insulin, total insulin secretion, first phase of insulin secretion, and insulin sensitivity were calculated. Wilcoxon signed-rank, Mann-Whitney U, and chi-square tests were used for statistical analyses. The institutional ethics committee approved the protocol. After A. dracunculus administration, there were significant decreases in systolic blood pressure (SBP; 120.0 ± 11.3 vs. 113.0 ± 11.2 mmHg, P < .05), A1C (5.8 ± 0.3 vs. 5.6% ± 0.4%, P < .05), AUC of insulin (56,136.0 ± 27,426.0 vs. 44,472.0 ± 23,370.0 pmol/L, P < .05), and total insulin secretion (0.45 ± 0.23 vs. 0.35 ± 0.18, P < .05), with a significant increase in high-density lipoprotein cholesterol (HDL-C) (1.3 ± 0.3 vs. 1.4 ± 0.3 mmol/L, P < .05). There were no significant differences after placebo administration. A. dracunculus administration for 90 days in patients with IGT significantly decreased SBP, A1C, AUC of insulin, and total insulin secretion with a significant increase in HDL-C levels. PMID:27097076

  3. (-)-Epicatechin improves insulin sensitivity in high fat diet-fed mice.

    PubMed

    Cremonini, Eleonora; Bettaieb, Ahmed; Haj, Fawaz G; Fraga, Cesar G; Oteiza, Patricia I

    2016-06-01

    Obesity constitutes a major public health concern, being frequently associated with type 2 diabetes (T2D). Evidence from studies in humans and experimental animals suggest that consumption of the flavan-3-ol (-)-epicatechin (EC) and of EC-rich foods may improve insulin sensitivity. To further understand the potential benefits of dietary EC consumption on insulin resistance, this study investigated the capacity of EC supplementation to prevent high fat diet (HFD)-induced insulin resistance in mice. To assess the underlying mechanisms, the effects of HFD and EC consumption on the activation of the insulin cascade and of its negative modulators were evaluated. HFD consumption for 15 w caused obesity and insulin resistance in C57BL/6J mice as evidenced by high fasted and fed plasma glucose and insulin levels, and impaired ITT and GTT tests. This was associated with alterations in the activation of components of the insulin-triggered signaling cascade (insulin receptor, IRS1, ERK1/2, Akt) in adipose and liver tissues. EC supplementation prevented/ameliorated all these parameters. EC acted improving insulin sensitivity in the HFD-fed mice in part through a downregulation of the inhibitory molecules JNK, IKK, PKC and protein tyrosine phosphatase 1B (PTP1B). Thus, the above results suggest that consumption of EC-rich foods could constitute a dietary strategy to mitigate obesity-associated insulin resistance. PMID:26968772

  4. [PPAR receptors and insulin sensitivity: new agonists in development].

    PubMed

    Pégorier, J-P

    2005-04-01

    Thiazolidinediones (or glitazones) are synthetic PPARgamma (Peroxisome Proliferator-Activated Receptors gamma) ligands with well recognized effects on glucose and lipid metabolism. The clinical use of these PPARgamma agonists in type 2 diabetic patients leads to an improved glycemic control and an inhanced insulin sensitivity, and at least in animal models, to a protective effect on pancreatic beta-cell function. However, they can produce adverse effects, generally mild or moderate, but some of them (mainly peripheral edema and weight gain) may conduct to treatment cessation. Several pharmacological classes are currently in pre-clinical or clinical development, with the objective to retain the beneficial metabolic properties of PPARgamma agonists, either alone or in association with the PPARalpha agonists (fibrates) benefit on lipid profile, but devoid of the side-effects on weight gain and fluid retention. These new pharmacological classes: partial PPARgamma agonists, PPARgamma antagonists, dual PPARalpha/PPARgamma agonists, pan PPARalpha/beta(delta)/gamma agonists, RXR receptor agonists (rexinoids), are presented in this review. Main results from in vitro cell experiments and animal model studies are discussed, as well as the few published short-term studies in type 2 diabetic patients. PMID:15959400

  5. Endocrinization of FGF1 produces a neomorphic and potent insulin sensitizer.

    PubMed

    Suh, Jae Myoung; Jonker, Johan W; Ahmadian, Maryam; Goetz, Regina; Lackey, Denise; Osborn, Olivia; Huang, Zhifeng; Liu, Weilin; Yoshihara, Eiji; van Dijk, Theo H; Havinga, Rick; Fan, Weiwei; Yin, Yun-Qiang; Yu, Ruth T; Liddle, Christopher; Atkins, Annette R; Olefsky, Jerrold M; Mohammadi, Moosa; Downes, Michael; Evans, Ronald M

    2014-09-18

    Fibroblast growth factor 1 (FGF1) is an autocrine/paracrine regulator whose binding to heparan sulphate proteoglycans effectively precludes its circulation. Although FGF1 is known as a mitogenic factor, FGF1 knockout mice develop insulin resistance when stressed by a high-fat diet, suggesting a potential role in nutrient homeostasis. Here we show that parenteral delivery of a single dose of recombinant FGF1 (rFGF1) results in potent, insulin-dependent lowering of glucose levels in diabetic mice that is dose-dependent but does not lead to hypoglycaemia. Chronic pharmacological treatment with rFGF1 increases insulin-dependent glucose uptake in skeletal muscle and suppresses the hepatic production of glucose to achieve whole-body insulin sensitization. The sustained glucose lowering and insulin sensitization attributed to rFGF1 are not accompanied by the side effects of weight gain, liver steatosis and bone loss associated with current insulin-sensitizing therapies. We also show that the glucose-lowering activity of FGF1 can be dissociated from its mitogenic activity and is mediated predominantly via FGF receptor 1 signalling. Thus we have uncovered an unexpected, neomorphic insulin-sensitizing action for exogenous non-mitogenic human FGF1 with therapeutic potential for the treatment of insulin resistance and type 2 diabetes. PMID:25043058

  6. Aerobic exercise increases peripheral and hepatic insulin sensitivity in sedentary adolescents

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Data are limited on the effects of controlled aerobic exercise programs (without weight loss) on insulin sensitivity and glucose metabolism in children and adolescents. To determine whether a controlled aerobic exercise program (without weight loss) improves peripheral and hepatic insulin sensitivi...

  7. Ethnic differences in insulin sensitivity and beta-cell function among Asian men

    PubMed Central

    Tan, V M H; Lee, Y S; Venkataraman, K; Khoo, E Y H; Tai, E S; Chong, Y S; Gluckman, P; Leow, M K S; Khoo, C M

    2015-01-01

    Background and objectives: Lean Asian Indians are less insulin sensitive compared with Chinese and Malays, but the pancreatic beta-cell function among these ethnic groups has yet to be studied in depth. We aimed to study beta-cell function in relation to insulin sensitivity among individuals of Chinese, Malay and Asian-Indian ethnicity living in Singapore. Subjects and methods: This is a sub-group analysis of 59 normoglycemic lean (body mass index (BMI) <23 kg m−2) adult males (14 Chinese, 21 Malays and 24 Asian Indians) from the Singapore Adults Metabolism Study. Insulin sensitivity was determined using fasting state indices (homeostatic model assessment—insulin resistance), the euglycemic-hyperinsulinemic clamp (ISI-clamp) and a liquid mixed-meal tolerance test (LMMTT) (Matsuda insulin sensitivity index (ISI-Mat)). Beta-cell function was assessed using fasting state indices (homeostatic model assessment—beta-cell function) and from the LMMTT (insulinogenic index and insulin secretion index). The oral disposition index (DI), a measure of beta-cell function relative to insulin sensitivity during the LMMTT, was calculated as a product of ISI-Mat and insulin secretion index. Results: Asian Indians had higher waist circumference and percent body fat than Chinese and Malays despite similar BMI. Overall, Asian Indians were the least insulin sensitive whereas the Chinese were most insulin sensitive. Asian Indians had higher beta-cell function compared with Chinese or Malays but these were not statistically different. Malays had the highest incremental area under the curve for glucose during LMMTT compared with Asian Indians and Chinese. However, there were no significant ethnic differences in the incremental insulin area under the curve. The oral DI was the lowest in Malays, followed by Asian Indians and Chinese. Conclusion: Among lean Asians, Chinese are the most insulin sensitive whereas Asian Indians are the least insulin sensitive. However, Malays

  8. Endocrine Determinants of Changes in Insulin Sensitivity and Insulin Secretion during a Weight Cycle in Healthy Men

    PubMed Central

    Karschin, Judith; Lagerpusch, Merit; Enderle, Janna; Eggeling, Ben; Müller, Manfred J.; Bosy-Westphal, Anja

    2015-01-01

    Objective Changes in insulin sensitivity (IS) and insulin secretion occur with perturbations in energy balance and glycemic load (GL) of the diet that may precede the development of insulin resistance and hyperinsulinemia. Determinants of changes in IS and insulin secretion with weight cycling in non-obese healthy subjects remain unclear. Methods In a 6wk controlled 2-stage randomized dietary intervention 32 healthy men (26±4y, BMI: 24±2kg/m2) followed 1wk of overfeeding (OF), 3wks of caloric restriction (CR) containing either 50% or 65% carbohydrate (CHO) and 2wks of refeeding (RF) with the same amount of CHO but either low or high glycaemic index at ±50% energy requirement. Measures of IS (basal: HOMA-index, postprandial: Matsuda-ISI), insulin secretion (early: Stumvoll-index, total: tAUC-insulin/tAUC-glucose) and potential endocrine determinants (ghrelin, leptin, adiponectin, thyroid hormone levels, 24h-urinary catecholamine excretion) were assessed. Results IS improved and insulin secretion decreased due to CR and normalized upon RF. Weight loss-induced improvements in basal and postprandial IS were associated with decreases in leptin and increases in ghrelin levels, respectively (r = 0.36 and r = 0.62, p<0.05). Weight regain-induced decrease in postprandial IS correlated with increases in adiponectin, fT3, TSH, GL of the diet and a decrease in ghrelin levels (r-values between -0.40 and 0.83, p<0.05) whereas increases in early and total insulin secretion were associated with a decrease in leptin/adiponectin-ratio (r = -0.52 and r = -0.46, p<0.05) and a decrease in fT4 (r = -0.38, p<0.05 for total insulin secretion only). After controlling for GL associations between RF-induced decrease in postprandial IS and increases in fT3 and TSH levels were no longer significant. Conclusion Weight cycling induced changes in IS and insulin secretion were associated with changes in all measured hormones, except for catecholamine excretion. While leptin, adiponectin and

  9. Can insulin signaling pathways be targeted to transport Aβ out of the brain?

    PubMed

    Vandal, Milene; Bourassa, Philippe; Calon, Frédéric

    2015-01-01

    Although the causal role of Amyloid-β (Aβ) in Alzheimer's disease (AD) is unclear, it is still reasonable to expect that lowering concentrations of Aβ in the brain may decrease the risk of developing the neurocognitive symptoms of the disease. Brain capillary endothelial cells forming the blood-brain barrier (BBB) express transporters regulating the efflux of Aβ out of the cerebral tissue. Age-related BBB dysfunctions, that have been identified in AD patients, might impair Aβ clearance from the brain. Thus, targeting BBB outward transport systems has been suggested as a way to stimulate the clearance of Aβ from the brain. Recent data indicate that the increase in soluble brain Aβ and behavioral impairments in 3×Tg-AD mice generated by months of intake of a high-fat diet can be acutely reversed by the administration of a single dose of insulin. A concomitant increase in plasma Aβ suggests that clearance from the brain through the BBB is a likely mechanism for this rapid effect of insulin. Here, we review how BBB insulin response pathways could be stimulated to decrease brain Aβ concentrations and improve cognitive performance, at least on the short term. PMID:26136681

  10. P21-activated kinase 2 (PAK2) regulates glucose uptake and insulin sensitivity in neuronal cells.

    PubMed

    Varshney, Pallavi; Dey, Chinmoy Sankar

    2016-07-01

    P21-activated kinases (PAKs) are recently reported as important players of insulin signaling and glucose homeostasis in tissues like muscle, pancreas and liver. However, their role in neuronal insulin signaling is still unknown. Present study reports the involvement of PAK2 in neuronal insulin signaling, glucose uptake and insulin resistance. Irrespective of insulin sensitivity, insulin stimulation decreased PAK2 activity. PAK2 downregulation displayed marked enhancement of GLUT4 translocation with increase in glucose uptake whereas PAK2 over-expression showed its reduction. Treatment with Akti-1/2 and wortmannin suggested that Akt and PI3K are mediators of insulin effect on PAK2 and glucose uptake. Rac1 inhibition demonstrated decreased PAK2 activity while inhibition of PP2A resulted in increased PAK2 activity, with corresponding changes in glucose uptake. Taken together, present study demonstrates an inhibitory role of insulin signaling (via PI3K-Akt) and PP2A on PAK2 activity and establishes PAK2 as a Rac1-dependent negative regulator of neuronal glucose uptake and insulin sensitivity. PMID:27040307

  11. Insulin sensitizers for the treatment of non-alcoholic fatty liver disease

    PubMed Central

    Ozturk, Zeynel Abidin; Kadayifci, Abdurrahman

    2014-01-01

    Non-alcoholic fatty liver disease (NAFLD) is the leading cause of liver disease in the Western world and is closely associated with metabolic syndrome, which includes hypertension, central obesity, dyslipidemia and insulin resistance. NAFLD includes a wide spectrum of liver alterations, ranging from simple hepatic steatosis to variable degrees of fibrosis, cirrhosis and even hepatocellular carcinoma. Although the etiology and progression of the disorder remain poorly understood, insulin resistance is considered to play a pivotal role in the pathogenesis. Insulin sensitizers such as biguanides, thiazolidinediones (TZDs), glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase 4 inhibitors have been studied as therapeutic approaches for NAFLD in recent years. Metformin improves insulin sensitivity and serum alanine transaminase and aspartate transaminase (ALT/AST) levels in the majority of subjects; however, it has no significant effect on liver histology. TZDs improve insulin sensitivity, serum ALT/AST levels and histology in some cases, but there are some concerns about the safety of long-term therapy. Selection of appropriate patients for avoiding side effects and the treatment of underlying disease are the main points. These drugs are the best choice for the treatment of NAFLD in patients with type 2 DM who are also candidates for treatment with an insulin sensitizer. The present review provides an overview of insulin sensitizers in the treatment of NAFLD. PMID:24799988

  12. Relationship between Insulin Sensitivity and Muscle Lipids may Differ with Muscle Group and Ethnicity

    PubMed Central

    Lawrence, Jeannine C.; Gower, Barbara A.; Garvey, W. Timothy; Muñoz, A. Julian; Darnell, Betty E.; Oster, Robert A.; Buchthal, Steven D.; Goran, Michael I.; Newcomer, Bradley R.

    2011-01-01

    Intramyocellular lipid (IMCL) has been inversely associated with insulin sensitivity in some, but not all, studies. This study utilized fast, high-resolution, magnetic resonance spectroscopic imaging (MRSI) to: investigate relationships between muscle lipids (IMCL and extramyocellular lipid (EMCL)) and insulin sensitivity in muscles of varying oxidative capacity, explore ethnic differences in these relationships, and determine whether a eucaloric, low-fat dietary intervention would reduce IMCL and increase insulin sensitivity. Subjects were 30 healthy, African-American (AA; n=14) and European-American (EA; n=16) males, BMI 26.49 (±5.57) kg/m2, age 21.80 (±7.84) yrs. Soleus and tibialis anterior muscle lipids were quantified using MRSI. Insulin sensitivity was assessed via intravenous glucose tolerance test. A 2-week, eucaloric, low-fat diet intervention was conducted in a sub-group (n=12) subjects with assessments at baseline and post-intervention. Neither IMCL nor EMCL levels differed between ethnicities. In the total group, and within EA (but not AA), both tibialis anterior IMCL and EMCL were inversely associated with insulin sensitivity (P<0.05 for both); soleus muscle lipids were not associated with insulin sensitivity. Soleus, but not tibialis anterior, IMCL declined in both ethnic groups (average 25.3%; p<0.01) following dietary intervention; insulin sensitivity was unchanged. Results suggest that an association of muscle lipids with insulin sensitivity may be influenced by the oxidative capacity of the muscle group studied and may vary with ethnicity. PMID:22039395

  13. The effect of acute exercise on undercarboxylated osteocalcin and insulin sensitivity in obese men.

    PubMed

    Levinger, Itamar; Jerums, George; Stepto, Nigel K; Parker, Lewan; Serpiello, Fabio R; McConell, Glenn K; Anderson, Mitchell; Hare, David L; Byrnes, Elizabeth; Ebeling, Peter R; Seeman, Ego

    2014-12-01

    Acute exercise improves insulin sensitivity for hours after the exercise is ceased. The skeleton contributes to glucose metabolism and insulin sensitivity via osteocalcin (OC) in its undercarboxylated (ucOC) form in mice. We tested the hypothesis that insulin sensitivity over the hours after exercise is associated with circulating levels of ucOC. Eleven middle-aged (58.1 ± 2.2 years mean ± SEM), obese (body mass index [BMI] = 33.1 ± 1.4 kg/m(2) ) nondiabetic men completed a euglycemic-hyperinsulinemic clamp at rest (rest-control) and at 60 minutes after exercise (4 × 4 minutes of cycling at 95% of HRpeak ). Insulin sensitivity was determined by glucose infusion rate relative to body mass (GIR, mL/kg/min) as well as GIR per unit of insulin (M-value). Blood samples and five muscle biopsies were obtained; two at the resting-control session, one before and one after clamping, and three in the exercise session, at rest, 60 minutes after exercise, and after the clamp. Exercise increased serum ucOC (6.4 ± 2.1%, p = 0.013) but not total OC (p > 0.05). Blood glucose was ∼6% lower and insulin sensitivity was ∼35% higher after exercise compared with control (both p < 0.05). Phosphorylated (P)-AKT (Ak thymoma) was higher after exercise and insulin compared with exercise alone (no insulin) and insulin alone (no exercise, all p < 0.05). In a multiple-linear regression including BMI, age, and aerobic fitness, ucOC was associated with whole-body insulin sensitivity at rest (β = 0.59, p = 0.023) and after exercise (β = 0.66, p = 0.005). Insulin sensitivity, after acute exercise, is associated with circulating levels of ucOC in obese men. Whether ucOC has a direct effect on skeletal muscle insulin sensitivity after exercise is yet to be determined. PMID:24861730

  14. AgRP Neurons Control Systemic Insulin Sensitivity via Myostatin Expression in Brown Adipose Tissue.

    PubMed

    Steculorum, Sophie M; Ruud, Johan; Karakasilioti, Ismene; Backes, Heiko; Engström Ruud, Linda; Timper, Katharina; Hess, Martin E; Tsaousidou, Eva; Mauer, Jan; Vogt, Merly C; Paeger, Lars; Bremser, Stephan; Klein, Andreas C; Morgan, Donald A; Frommolt, Peter; Brinkkötter, Paul T; Hammerschmidt, Philipp; Benzing, Thomas; Rahmouni, Kamal; Wunderlich, F Thomas; Kloppenburg, Peter; Brüning, Jens C

    2016-03-24

    Activation of Agouti-related peptide (AgRP) neurons potently promotes feeding, and chronically altering their activity also affects peripheral glucose homeostasis. We demonstrate that acute activation of AgRP neurons causes insulin resistance through impairment of insulin-stimulated glucose uptake into brown adipose tissue (BAT). AgRP neuron activation acutely reprograms gene expression in BAT toward a myogenic signature, including increased expression of myostatin. Interference with myostatin activity improves insulin sensitivity that was impaired by AgRP neurons activation. Optogenetic circuitry mapping reveals that feeding and insulin sensitivity are controlled by both distinct and overlapping projections. Stimulation of AgRP → LHA projections impairs insulin sensitivity and promotes feeding while activation of AgRP → anterior bed nucleus of the stria terminalis (aBNST)vl projections, distinct from AgRP → aBNSTdm projections controlling feeding, mediate the effect of AgRP neuron activation on BAT-myostatin expression and insulin sensitivity. Collectively, our results suggest that AgRP neurons in mice induce not only eating, but also insulin resistance by stimulating expression of muscle-related genes in BAT, revealing a mechanism by which these neurons rapidly coordinate hunger states with glucose homeostasis. PMID:27015310

  15. Effects of Lactobacillus acidophilus NCFM on insulin sensitivity and the systemic inflammatory response in human subjects.

    PubMed

    Andreasen, Anne Sofie; Larsen, Nadja; Pedersen-Skovsgaard, Theis; Berg, Ronan M G; Møller, Kirsten; Svendsen, Kira Dynnes; Jakobsen, Mogens; Pedersen, Bente Klarlund

    2010-12-01

    According to animal studies, intake of probiotic bacteria may improve glucose homeostasis. We hypothesised that probiotic bacteria improve insulin sensitivity by attenuating systemic inflammation. Therefore, the effects of oral supplementation with the probiotic bacterium Lactobacillus acidophilus NCFM on insulin sensitivity and the inflammatory response were investigated in subjects with normal or impaired insulin sensitivity. In a double-blinded, randomised fashion, forty-five males with type 2 diabetes, impaired or normal glucose tolerance were enrolled and allocated to a 4-week treatment course with either L. acidophilus NCFM or placebo. L. acidophilus was detected in stool samples by denaturating gradient gel electrophoresis and real-time PCR. Separated by the 4-week intervention period, two hyperinsulinaemic-euglycaemic clamps were performed to estimate insulin sensitivity. Furthermore, the systemic inflammatory response was evaluated by subjecting the participants to Escherichia coli lipopolysaccharide injection (0·3 ng/kg) before and after the treatment course. L. acidophilus NCFM was detected in 75 % of the faecal samples after treatment with the probiotic bacterium. Insulin sensitivity was preserved among volunteers in the L. acidophilus NCFM group, whereas it decreased in the placebo group. Both baseline inflammatory markers and the systemic inflammatory response were, however, unaffected by the intervention. In conclusion, intake of L. acidophilus NCFM for 4 weeks preserved insulin sensitivity compared with placebo, but did not affect the systemic inflammatory response. PMID:20815975

  16. pH sensitive N-succinyl chitosan grafted polyacrylamide hydrogel for oral insulin delivery.

    PubMed

    Mukhopadhyay, Piyasi; Sarkar, Kishor; Bhattacharya, Sourav; Bhattacharyya, Aditi; Mishra, Roshnara; Kundu, P P

    2014-11-01

    pH sensitive PAA/S-chitosan hydrogel was prepared using ammonium persulfate (APS) as an initiator and methylenebisacrylamide (MBA) as a crosslinker for oral insulin delivery. The synthesized copolymer was characterized by Fourier transform infrared spectroscopy (FT-IR) and X-ray diffraction (XRD) study; morphology was observed under scanning electron microscope (SEM). The PAA/S-chitosan with ∼ 38% of insulin loading efficiency (LE) and ∼ 76% of insulin encapsulation efficiency (EE), showed excellent pH sensitivity, retaining ∼ 26% of encapsulated insulin in acidic stomach pH 1.2 and releasing of ∼ 98% of insulin in the intestine (pH 7.4), providing a prolonged attachment with the intestinal tissue. The oral administration of insulin loaded PAA/S-chitosan hydrogel was successful in lowering the blood glucose level of diabetic mice. The bioavailability of insulin was ∼ 4.43%. Furthermore, no lethality or toxicity was documented after its peroral administration. Thus, PAA/S-chitosan hydrogel could serve as a promising oral insulin carrier in future. PMID:25129792

  17. Clinical trial demonstrates exercise following bariatric surgery improves insulin sensitivity

    PubMed Central

    Coen, Paul M.; Tanner, Charles J.; Helbling, Nicole L.; Dubis, Gabriel S.; Hames, Kazanna C.; Xie, Hui; Eid, George M.; Stefanovic-Racic, Maja; Toledo, Frederico G.S.; Jakicic, John M.; Houmard, Joseph A.; Goodpaster, Bret H.

    2014-01-01

    BACKGROUND. Roux-en-Y gastric bypass (RYGB) surgery causes profound weight loss and improves insulin sensitivity (SI) in obese patients. Regular exercise can also improve SI in obese individuals; however, it is unknown whether exercise and RYGB surgery–induced weight loss would additively improve SI and other cardiometabolic factors. METHODS. We conducted a single-blind, prospective, randomized trial with 128 men and women who recently underwent RYGB surgery (within 1–3 months). Participants were randomized to either a 6-month semi-supervised moderate exercise protocol (EX, n = 66) or a health education control (CON; n = 62) intervention. Main outcomes measured included SI and glucose effectiveness (SG), which were determined from an intravenous glucose tolerance test and minimal modeling. Secondary outcomes measured were cardiorespiratory fitness (VO2 peak) and body composition. Data were analyzed using an intention-to-treat (ITT) and per-protocol (PP) approach to assess the efficacy of the exercise intervention (>120 min of exercise/week). RESULTS. 119 (93%) participants completed the interventions, 95% for CON and 91% for EX. There was a significant decrease in body weight and fat mass for both groups (P < 0.001 for time effect). SI improved in both groups following the intervention (ITT: CON vs. EX; +1.64 vs. +2.24 min–1/μU/ml, P = 0.18 for Δ, P < 0.001 for time effect). A PP analysis revealed that exercise produced an additive SI improvement (PP: CON vs. EX; +1.57 vs. +2.69 min–1/μU/ml, P = 0.019) above that of surgery. Exercise also improved SG (ITT: CON vs. EX; +0.0023 vs. +0.0063 min–1, P = 0.009) compared with the CON group. Exercise improved cardiorespiratory fitness (VO2 peak) compared with the CON group. CONCLUSION. Moderate exercise following RYGB surgery provides additional improvements in SI, SG, and cardiorespiratory fitness compared with a sedentary lifestyle during similar weight loss. TRIAL REGISTRATION. clinicaltrials.gov identifier

  18. Insulin

    MedlinePlus

    ... pump is connected to your body by a flexible tube that has a tip that sticks under your skin. A cartridge of insulin is put in the pump. The insulin flows through the tube into your body. The pump controls how much insulin goes into your body. The ...

  19. Fish oil supplementation for two generations increases insulin sensitivity in rats.

    PubMed

    Hirabara, Sandro M; Folador, Alessandra; Fiamoncini, Jarlei; Lambertucci, Rafael H; Rodrigues, Carlos F; Rocha, Marlene S; Aikawa, Julia; Yamazaki, Ricardo K; Martins, Amanda R; Rodrigues, Alice C; Carpinelli, Angelo R; Pithon-Curi, Tania C; Fernandes, Luiz C; Gorjão, Renata; Curi, Rui

    2013-06-01

    We investigated the effect of fish oil supplementation for two consecutive generations on insulin sensitivity in rats. After the nursing period (21 days), female rats from the same prole were divided into two groups: (a) control group and (b) fish oil group. Female rats were supplemented with water (control) or fish oil at 1 g/kg body weight as a single bolus for 3 months. After this period, female rats were mated with male Wistar rats fed on a balanced chow diet (not supplemented). Female rats continued to receive supplementation throughout gestation and lactation periods. The same treatment was performed for the next two generations (G1 and G2). At 75 days of age, male offspring from G1 and G2 generations from both groups were used in the experiments. G1 rats did not present any difference with control rats. However, G2 rats presented reduction in glycemia and lipidemia and improvement in in vivo insulin sensitivity (model assessment of insulin resistance, insulin tolerance test) as well as in vitro insulin sensitivity in soleus muscle (glucose uptake and metabolism). This effect was associated with increased insulin-stimulated p38 MAP kinase phosphorylation and lower n-6/n-3 fatty acid ratio, but not with activation of proteins from insulin signaling (IR, IRS-1 and Akt). Global DNA methylation was decreased in liver but not in soleus muscle. These results suggest that long-term fish oil supplementation improves insulin sensitivity in association with increased insulin-stimulated p38 activation and decreased n-6:n-3 ratio in skeletal muscle and decreased global DNA methylation in liver. PMID:23246156

  20. Continuous nutrient administration decreases insulin sensitivity in neonatal pigs

    Technology Transfer Automated Retrieval System (TEKTRAN)

    We previously showed that chronic TPN compared to intermittent feeding of a formula results in hepatic insulin resistance and steatosis in neonatal pigs. We hypothesized that the route of feeding (IV vs enteral) rather than the nature of the diet (elemental vs polymeric) or the feeding regimen (cont...

  1. TonEBP suppresses adipogenesis and insulin sensitivity by blocking epigenetic transition of PPARγ2

    PubMed Central

    Ho Lee, Jun; Hee Lee, Hwan; Jin Ye, Byeong; Lee-Kwon, Whaseon; Youn Choi, Soo; Moo Kwon, Hyug

    2015-01-01

    TonEBP is a key transcription factor in cellular adaptation to hypertonic stress, and also in macrophage activation. Since TonEBP is involved in inflammatory diseases such as rheumatoid arthritis and atherosclerosis, we asked whether TonEBP played a role in adipogenesis and insulin resistance. Here we report that TonEBP suppresses adipogenesis and insulin signaling by inhibiting expression of the key transcription factor PPARγ2. TonEBP binds to the PPARγ2 promoter and blocks the epigenetic transition of the locus which is required for the activation of the promoter. When TonEBP expression is reduced, the epigenetic transition and PPARγ2 expression are markedly increased leading to enhanced adipogenesis and insulin response while inflammation is reduced. Thus, TonEBP is an independent determinant of adipose insulin sensitivity and inflammation. TonEBP is an attractive therapeutic target for insulin resistance in lieu of PPARγ agonists. PMID:26042523

  2. Fault sensitivity and wear-out analysis of VLSI systems

    NASA Astrophysics Data System (ADS)

    Choi, Gwan Seung

    1994-07-01

    This thesis describes simulation approaches to conduct fault sensitivity and wear-out failure analysis of VLSI systems. A fault-injection approach to study transient impact in VLSI systems is developed. Through simulated fault injection at the device level and, subsequent fault propagation at the gate functional and software levels, it is possible to identify critical bottlenecks in dependability. Techniques to speed up the fault simulation and to perform statistical analysis of fault-impact are developed. A wear-out simulation environment is also developed to closely mimic dynamic sequences of wear-out events in a device through time, to localize weak location/aspect of target chip and to allow generation of TTF (Time-to-failure) distribution of VLSI chip as a whole. First, an accurate simulation of a target chip and its application code is performed to acquire trace data (real workload) on switch activity. Then, using this switch activity information, wear-out of the each component in the entire chip is simulated using Monte Carlo techniques.

  3. Thazolidinediones and the Promise of Insulin Sensitization in Type 2 Diabetes

    PubMed Central

    Soccio, Raymond E.; Chen, Eric R.; Lazar, Mitchell A.

    2014-01-01

    Type 2 diabetes is caused by insulin resistance coupled with an inability to produce enough insulin to control blood glucose, and thiazolidinediones (TZDs) are the only current antidiabetic agents that function primarily by increasing insulin sensitivity. However, despite clear benefits in glycemic control, this class of drugs has recently fallen into disuse due to concerns over side effects and adverse events. Here we review the clinical data and attempt to balance the benefits and risks of TZD therapy. We also examine potential mechanisms of action for the beneficial and harmful effects of TZDs, mainly via agonism of the nuclear receptor PPARγ. Based on critical appraisal of both preclinical and clinical studies, we discuss the prospect of harnessing the insulin sensitizing effects of PPARγ for more effective, safe, and potentially personalized treatments of type 2 diabetes. PMID:25242225

  4. Putative hormone with anti-obesogenic and insulin-sensitizing effect.

    PubMed

    Sosa, Ivan; Grubesic, Aron

    2016-03-01

    It was confirmed that bone morphogenetic protein-9 (BMP-9), like insulin, improves glycemia in diabetic mice and regulates glucose metabolism in hepatocytes, which is why it is proposed as a candidate for the hepatic insulin-sensitizing substance (HISS). Regarding the fact that BMP-9 has a signaling pathway similar to other BMPs as well as insulin, it is expected that BMP-9 would also have certain effects on the liver. In our 2011 hypothesis, we aimed towards BMP-9 as a possible "hepatic insulin-sensitizing substance" (HISS) and in this article, we provide further evidence, derived from existing studies, suggesting that this putative hormone might in fact be none other than BMP-9. PMID:26714521

  5. Enhanced skeletal muscle insulin sensitivity in year-old rats adapted to hypergravity

    NASA Technical Reports Server (NTRS)

    Mondon, C. E.; Dolkas, C. B.; Oyama, J.

    1981-01-01

    Rats induced into a hypermetabolic state by exposure to chronic (7 mo) centrifugation at 4.15 g exhibited increased glucose uptake at lower plasma insulin levels than weight-matched control animals following oral glucose administration. In order to determine the insulin sensitivity of specific tissues, the effect of exogenous insulin on glucose uptake by isolated perfused livers and hindlim skeletal muscle from rats adapted to chronic centrifugation for one year was compared with perfused tissue from 2.5 mo-old noncentrifuged control animals of equal body weight. Metabolic glucose clearance by skeletal muscle from hypergravic rats did not prove significantly greater than control muscle when perfused in the absence of insulin (10.6 vs 8.1 microliters/min-g-muscle), but was twice as fast (23.0 vs 9.5) at perfusate insulin levels of 35 micro-U/ml. Conversely, glucose uptake by hypergravic livers was significantly decreased (P is less than 0.001) compared with control livers (10.3 vs 27.8) at perfusate insulin levels of 40 micro-U/ml. Results suggest that skeletal muscle rather than liver is primarily responsible for the enhanced sensitivity to insulin and the increased energy expenditure observed in rats subjected to hypergravity.

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

    PubMed

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

    2015-01-01

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

  7. Placental restriction reduces insulin sensitivity and expression of insulin signaling and glucose transporter genes in skeletal muscle, but not liver, in young sheep.

    PubMed

    De Blasio, Miles J; Gatford, Kathryn L; Harland, M Lyn; Robinson, Jeffrey S; Owens, Julie A

    2012-05-01

    Poor growth before birth is associated with impaired insulin sensitivity later in life, increasing the risk of type 2 diabetes. The tissue sites at which insulin resistance first develops after intrauterine growth restriction (IUGR), and its molecular basis, are unclear. We have therefore characterized the effects of placental restriction (PR), a major cause of IUGR, on whole-body insulin sensitivity and expression of molecular determinants of insulin signaling and glucose uptake in skeletal muscle and liver of young lambs. Whole-body insulin sensitivity was measured at 30 d by hyperinsulinaemic euglycaemic clamp and expression of insulin signaling genes (receptors, pathways, and targets) at 43 d in muscle and liver of control (n = 15) and PR (n = 13) lambs. PR reduced size at birth and increased postnatal growth, fasting plasma glucose (+15%, P = 0.004), and insulin (+115%, P = 0.009). PR reduced whole-body insulin sensitivity (-43%, P < 0.001) and skeletal muscle expression of INSR (-36%), IRS1 (-28%), AKT2 (-44%), GLUT4 (-88%), GSK3α (-35%), and GYS1 (-31%) overall (each P < 0.05) and decreased AMPKγ3 expression in females (P = 0.030). PR did not alter hepatic expression of insulin signaling and related genes but increased GLUT2 expression (P = 0.047) in males. Whole-body insulin sensitivity correlated positively with skeletal muscle expression of IRS1, AKT2, HK, AMPKγ2, and AMPKγ3 in PR lambs only (each P < 0.05) but not with hepatic gene expression in control or PR lambs. Onset of insulin resistance after PR and IUGR is accompanied by, and can be accounted for by, reduced expression of insulin signaling and metabolic genes in skeletal muscle but not liver. PMID:22434080

  8. Co-associations between insulin sensitivity and measures of liver function, subclinical inflammation, and hematology.

    PubMed

    Godsland, Ian F; Johnston, Desmond G

    2008-09-01

    Clustering of risk factors for coronary heart disease and diabetes is well established, particularly in relation to insulin resistance. To determine whether evaluation of risk factor clustering will contribute to risk assessment, it is first necessary to discriminate co-association between risk factors from correlation. We undertook this in a large homogenous group, using a sophisticated measure of insulin sensitivity and a broad range of risk factors. Cross-sectional analysis of an occupational cohort using regression and factor analyses was performed. Subjects were 472 apparently healthy white men. The main outcome measures were insulin sensitivity, S(I), by minimal model analysis of the intravenous glucose tolerance test plus liver function and hematologic variables, including the inflammation indices, leukocyte count, and erythrocyte sedimentation rate. The S(I) correlated independently with serum gamma-glutamyl transferase (GGT), aspartate transaminase, and alkaline phosphatase activities; blood pressure; leukocyte count; and erythrocyte sedimentation rate (P < .01). On factor analysis, the factor that explained the greatest proportion of the variance (56.7%) included, in decreasing order of factor loading, triglycerides, S(I) (negative), body mass index, high-density lipoprotein cholesterol (negative), insulin, uric acid, and GGT activity (loadings >0.40). Mean arterial pressure was not a feature (loading 0.29), neither were indices of subclinical inflammation. In apparently healthy men, blood pressure and indices of subclinical inflammation do not cluster with other insulin resistance-related risk factors, despite correlating with insulin sensitivity. In contrast, both GGT activity and uric acid concentrations correlated with insulin sensitivity and co-associated with insulin resistance-related risk factors and are therefore components of a true risk factor cluster. PMID:18702943

  9. Estimated insulin sensitivity predicts regression of albuminuria in Type 1 diabetes

    PubMed Central

    Bjornstad, P.; Maahs, D. M.; Johnson, R. J.; Rewers, M.; Snell-Bergeon, J. K.

    2014-01-01

    Aim To test the hypothesis that greater baseline insulin sensitivity would predict regression of albuminuria over 6 years in adults with Type 1 diabetes. Method We enrolled 81 people aged 30–48 years with albuminuria at baseline in the present study and re-examined them 6 years later. Urinary albumin excretion rate was measured and albuminuria was defined as urinary albumin excretion rate ≥20 µg/min. Regression of albuminuria was defined as normoalbuminuria (urinary albumin excretion rate <20µg/min) at follow-up. Predictors of regression of albuminuria were examined in stepwise logistic regression. The variables age, diabetes duration, sex, serum uric acid, HbA1c, systolic blood pressure, LDL cholesterol, HDL cholesterol, BMI, baseline albumin excretion rate, estimated insulin sensitivity at baseline, change in estimated insulin sensitivity from baseline to follow-up and angiotensinconverting enzyme inhibitor/angiotensin receptor blocker use were considered for inclusion in the model. Results Estimated insulin sensitivity was significantly higher at both baseline (4.6±1.2 vs 3.4±1.7; P=0.002) and follow-up (5.2±1.9 vs. 3.5±1.7; P<0.0001) in people who had regression of albuminuria vs those who did not. HbA1c (odds ratio 0.4, 95% CI 0.2–0.8; P=0.006), estimated insulin sensitivity (odds ratio 2.5, 95% CI 1.3–4.9; P=0.006) at baseline and change in estimated insulin sensitivity from baseline to follow-up (odds ratio 2.7, 95% CI 1.4–5.3; P=0.003) were independently associated with regression of albuminuria in a multivariable stepwise model. Conclusions In conclusion, over 6 years, higher baseline estimated insulin sensitivity and change in estimated insulin sensitivity independently predicted regression of albuminuria. Improving insulin sensitivity in people with Type 1 diabetes is a potential therapeutic target to increase rates of regression of albuminuria. PMID:25303233

  10. LOCAL IGF-I ENHANCES THE SENSITIVITY OF MUSCLE PROTEIN SYNTHESIS TO INSULIN

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Skeletal muscle protein synthesis in the immature muscle is highly sensitive to insulin and nutrients. We hypothesized that the sensitivity is due to local IGFs expressed at a significant level by immature muscle. To test the hypothesis, 3-wk-old transgenic mice with high muscle-specific IGF-I expr...

  11. Adipose tissue monomethyl branched chain fatty acids and insulin sensitivity: effects of obesity and weight loss

    PubMed Central

    Su, Xiong; Magkos, Faidon; Zhou, Dequan; Eagon, J. Christopher; Fabbrini, Elisa; Okunade, Adewole L.; Klein, Samuel

    2014-01-01

    Objective An increase in circulating branched-chain amino acids (BCAA) is associated with insulin resistance. Adipose tissue is a potentially important site for BCAA metabolism. We evaluated whether monomethyl branched chain fatty acids (mmBCFA) in adipose tissue, which are likely derived from BCAA catabolism, are associated with insulin sensitivity. Design and Methods Insulin-stimulated glucose disposal was determined by using the hyperinsulinemic-euglycemic clamp procedure with stable isotope glucose tracer infusion, in 9 lean and 9 obese subjects, and in a separate group of 9 obese subjects before and 1 year after Roux-en-Y gastric bypass (RYGB) surgery (38% weight loss). Adipose tissue mmBCFA content was measured in tissue biopsies taken in the basal state. Results Total adipose tissue mmBCFA content was ~30% lower in obese than lean subjects (P = 0.02), and increased by ~65% after weight loss in the RYGB group (P = 0.01). Adipose tissue mmBCFA content correlated positively with skeletal muscle insulin sensitivity (R2 = 35%, P = 0.01, n = 18). Conclusions These results demonstrate a novel association between adipose tissue mmBCFA content and obesity-related insulin resistance. Additional studies are needed to determine whether the association between adipose tissue mmBCFA and muscle insulin sensitivity is causal or a simple association. PMID:25328153

  12. Adipose Cell Size and Regional Fat Deposition as Predictors of Metabolic Response to Overfeeding in Insulin-Resistant and Insulin-Sensitive Humans.

    PubMed

    McLaughlin, Tracey; Craig, Colleen; Liu, Li-Fen; Perelman, Dalia; Allister, Candice; Spielman, Daniel; Cushman, Samuel W

    2016-05-01

    Obesity is associated with insulin resistance, but significant variability exists between similarly obese individuals, pointing to qualitative characteristics of body fat as potential mediators. To test the hypothesis that obese, insulin-sensitive (IS) individuals possess adaptive adipose cell/tissue responses, we measured subcutaneous adipose cell size, insulin suppression of lipolysis, and regional fat responses to short-term overfeeding in BMI-matched overweight/obese individuals classified as IS or insulin resistant (IR). At baseline, IR subjects exhibited significantly greater visceral adipose tissue (VAT), intrahepatic lipid (IHL), plasma free fatty acids, adipose cell diameter, and percentage of small adipose cells. With weight gain (3.1 ± 1.4 kg), IR subjects demonstrated no significant change in adipose cell size, VAT, or insulin suppression of lipolysis and only 8% worsening of insulin-mediated glucose uptake (IMGU). Alternatively, IS subjects demonstrated significant adipose cell enlargement; decrease in the percentage of small adipose cells; increase in VAT, IHL, and lipolysis; 45% worsening of IMGU; and decreased expression of lipid metabolism genes. Smaller baseline adipose cell size and greater enlargement with weight gain predicted decline in IMGU, as did increase in IHL and VAT and decrease in insulin suppression of lipolysis. Weight gain in IS humans causes maladaptive changes in adipose cells, regional fat distribution, and insulin resistance. The correlation between development of insulin resistance and changes in adipose cell size, VAT, IHL, and insulin suppression of lipolysis highlight these factors as potential mediators between obesity and insulin resistance. PMID:26884438

  13. High intensity interval training improves liver and adipose tissue insulin sensitivity

    PubMed Central

    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

  14. Central Administration of Galanin Receptor 1 Agonist Boosted Insulin Sensitivity in Adipose Cells of Diabetic Rats

    PubMed Central

    Zhang, Zhenwen; Fang, Penghua; He, Biao; Guo, Lili; Runesson, Johan; Langel, Ülo; Shi, Mingyi; Zhu, Yan; Bo, Ping

    2016-01-01

    Our previous studies testified the beneficial effect of central galanin on insulin sensitivity of type 2 diabetic rats. The aim of the study was further to investigate whether central M617, a galanin receptor 1 agonist, can benefit insulin sensitivity. The effects of intracerebroventricular administration of M617 on insulin sensitivity and insulin signaling were evaluated in adipose tissues of type 2 diabetic rats. The results showed that central injection of M617 significantly increased plasma adiponectin contents, glucose infusion rates in hyperinsulinemic-euglycemic clamp tests, GLUT4 mRNA expression levels, GLUT4 contents in plasma membranes, and total cell membranes of the adipose cells but reduced the plasma C-reactive protein concentration in nondiabetic and diabetic rats. The ratios of GLUT4 contents were higher in plasma membranes to total cell membranes in both nondiabetic and diabetic M617 groups than each control. In addition, the central administration of M617 enhanced the ratios of pAkt/Akt and pAS160/AS160, but not phosphorylative cAMP response element-binding protein (pCREB)/CREB in the adipose cells of nondiabetic and diabetic rats. These results suggest that excitation of central galanin receptor 1 facilitates insulin sensitivity via activation of the Akt/AS160 signaling pathway in the fat cells of type 2 diabetic rats. PMID:27127795

  15. Anti-Hyperglycemic and Insulin Sensitizer Effects of Turmeric and Its Principle Constituent Curcumin

    PubMed Central

    Ghorbani, Zeinab; Hekmatdoost, Azita; Mirmiran, Parvin

    2014-01-01

    Context: Turmeric is obtained from the plant Curcuma longa L; its major constituent, curcumin, is a polyphenol with multiple effects which can modulate some signaling pathways. Evidence Acquisition: Insulin resistance is a major risk factor for chronic diseases such as type 2 diabetes, atherosclerotic, metabolic syndrome and cardiovascular disease. In addition, Insulin resistance in peripheral tissue is one of the most important reasons of hyperglycemia which can cause global or systemic effects. The present study reviewed studies published in PubMed from 1998 to 2013, indicating the role of curcumin in attenuation of many pathophysiological processes involved in development and progression of hyperglycemia and insulin resistance. Results: Curcumin can reduce blood glucose level by reducing the hepatic glucose production, suppression of hyperglycemia-induced inflammatory state, stimulation of glucose uptake by up-regulation of GLUT4, GLUT2 and GLUT3 genes expressions, activation of AMP kinase, promoting the PPAR ligand-binding activity, stimulation of insulin secretion from pancreatic tissues, improvement in pancreatic cell function, and reduction of insulin resistance. Conclusions: Curcumin has antihyperglycemic and insulin sensitizer effects. Thereby, more studies evaluating the effects of curcumin on hyperglycemic state and insulin resistance in related disorders such as diabetes are recommended. PMID:25745485

  16. Modulation of Insulin Sensitivity of Hepatocytes by the Pharmacological Downregulation of Phospholipase D

    PubMed Central

    Babenko, Nataliya A.; Kharchenko, Vitalina S.

    2015-01-01

    Background. The role of phospholipase D (PLD) as a positive modulator of glucose uptake activation by insulin in muscle and adipose cells has been demonstrated. The role of PLD in the regulation of glucose metabolism by insulin in the primary hepatocytes has been determined in this study. Methods. For this purpose, we studied effects of inhibitors of PLD on glucose uptake and glycogen synthesis stimulation by insulin. To determine the PLD activity, the method based on determination of products of transphosphatidylation reaction, phosphatidylethanol or phosphatidylbutanol, was used. Results. Inhibition of PLD by a general antagonist (1-butanol) or specific inhibitor, halopemide, or N-hexanoylsphingosine, or by cellular ceramides accumulated in doxorubicin-treated hepatocytes decreased insulin-stimulated glucose metabolism. Doxorubicin-induced hepatocytes resistance to insulin action could be abolished by inhibition of ceramide production. Halopemide could nullify this effect. Addition of propranolol, as well as inhibitors of phosphatidylinositol 3-kinase (PI3-kinase) (wortmannin, LY294002) or suppressors of Akt phosphorylation/activity, luteolin-7-O-glucoside or apigenin-7-O-glucoside, to the culture media could block cell response to insulin action. Conclusion. PLD plays an important role in the insulin signaling in the hepatocytes. PLD is activated downstream of PI3-kinase and Akt and is highly sensitive to ceramide content in the liver cells. PMID:26089893

  17. Proteasome inhibitors, including curcumin, improve pancreatic β-cell function and insulin sensitivity in diabetic mice

    PubMed Central

    Weisberg, S; Leibel, R; Tortoriello, D V

    2016-01-01

    Background: Type 2 diabetes stems from obesity-associated insulin resistance, and in the genetically susceptible, concomitant pancreatic β-cell failure can occur, which further exacerbates hyperglycemia. Recent work by our group and others has shown that the natural polyphenol curcumin attenuates the development of insulin resistance and hyperglycemia in mouse models of hyperinsulinemic or compensated type 2 diabetes. Although several potential downstream molecular targets of curcumin exist, it is now recognized to be a direct inhibitor of proteasome activity. We now show that curcumin also prevents β-cell failure in a mouse model of uncompensated obesity-related insulin resistance (Leprdb/db on the Kaliss background). Results: In this instance, dietary supplementation with curcumin prevented hyperglycemia, increased insulin production and lean body mass, and prolonged lifespan. In addition, we show that short-term in vivo treatment with low dosages of two molecularly distinct proteasome inhibitors celastrol and epoxomicin reverse hyperglycemia in mice with β-cell failure by increasing insulin production and insulin sensitivity. Conclusions: These studies suggest that proteasome inhibitors may prove useful for patients with diabetes by improving both β-cell function and relieving insulin resistance. PMID:27110686

  18. Insulin sensitizers in treatment of nonalcoholic fatty liver disease: Systematic review

    PubMed Central

    Chavez-Tapia, Norberto C; Barrientos-Gutierrez, Tonatiuh; Tellez-Ávila, Felix I; Sánchez-Ávila, Francisco; Montaño-Reyes, Maria Antonieta; Uribe, Misael

    2006-01-01

    AIM: To summarize the evidence available for the clinical effectiveness of insulin sensitizers in the treatment of nonalcoholic fatty liver disease (NAFLD) systematically. METHODS: Relevant articles were located using computer-assisted searches of Medline (1966-March 2006), EMBASE (1988-March 2006), CINAHL (1982-March 2003), Educational Resource Information Center (1966-March 2006), Library, Information Science & Technology Abstracts (1967-March 2006), Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects (1994-2006), dissertations in ProQuest and FirstSearch databases. Manual searches were made in the abstracts from meetings of the American Gastroenterological Association (1999-2006), and the American Association for the Study of Liver Diseases (2003-2005). Studies were retrieved using the following selection criteria: (1) clinical trials using insulin sensitizers in subjects with NAFLD, (2) adult patients, (3) published as full manuscripts or abstracts, and (4) English, Spanish, German, and French languages only. Data were abstracted independently by two reviewers following standardized procedures. A face-to-face comparison of data was conducted to ensure the completeness and reliability of the abstraction process. RESULTS: Nine studies were included, six using metformin and three using thiazolidinediones. Only two studies were placebo-controlled trials. The median sample size for all studies was 18 subjects. In the placebo-controlled trials, metformin improved insulin resistance markers and liver function tests, but not histological scores. In the single-arm trials, metformin and thiazolidinediones improved insulin resistance markers and liver function tests, and beneficial histological changes were reported. There is limited high-quality information available from which to draw categorical conclusions about the clinical use of insulin sensitizers in NAFLD. CONCLUSION: Current information indicates that the use of insulin

  19. Decrease in the plasma von Willebrand factor concentration following glucose ingestion: the role of insulin sensitivity.

    PubMed

    von Känel, R; Nelesen, R A; Le, D T; Ziegler, M G; Dimsdale, J E

    2001-12-01

    Elevated plasma von Willebrand factor (vWF) concentration is thought to be associated with increased prevalence of cardiovascular events in the insulin resistance syndrome. We examined the effects of oral glucose challenge and accompanying metabolic and hemodynamic changes on vWF levels with respect to insulin sensitivity. Forty normotensive and hypertensive subjects (mean age +/- SD, 40 +/- 5 years) underwent a standard oral glucose tolerance test (OGTT). Plasma vWF antigen, glucose, insulin, catecholamines, and hemodynamics were measured at rest, and at 30, 60, 90, and 120 minutes after glucose intake. Insulin sensitivity was determined by the insulin sensitivity index (ISI(0,120)). Resting plasma vWF concentration was associated with screening systolic blood pressure (BP) (r =.43, P =.005). There were time effects for all variables of interest. While vWF antigen (P =.044), epinephrine (P =.003), and diastolic BP (P =.001) decreased after glucose challenge, norepinephrine (P =.009), systolic BP (P =.022), and heart rate (P <.001) increased. Decline in vWF (area under the curve) was associated with decrease in epinephrine (r =.46, P =.004) and with screening systolic BP (r =.45, P =.004). However, neither resting plasma vWF levels nor vWF decrease following glucose ingestion were significantly associated with the ISI(0,120.) The plasma vWF concentration decreases following glucose ingestion. While mechanisms underlying this phenomenon may relate to sympathetic nervous system function, they seem not related to insulin sensitivity. Endothelial dysfunction such as caused by hypertension rather than metabolic dysregulation per se may underlie the elevated plasma vWF concentration found with insulin resistance. PMID:11735092

  20. The AMPK activator R419 improves exercise capacity and skeletal muscle insulin sensitivity in obese mice

    PubMed Central

    Marcinko, Katarina; Bujak, Adam L.; Lally, James S.V.; Ford, Rebecca J.; Wong, Tammy H.; Smith, Brennan K.; Kemp, Bruce E.; Jenkins, Yonchu; Li, Wei; Kinsella, Todd M.; Hitoshi, Yasumichi; Steinberg, Gregory R.

    2015-01-01

    Objective Skeletal muscle AMP-activated protein kinase (AMPK) is important for regulating glucose homeostasis, mitochondrial content and exercise capacity. R419 is a mitochondrial complex-I inhibitor that has recently been shown to acutely activate AMPK in myotubes. Our main objective was to examine whether R419 treatment improves insulin sensitivity and exercise capacity in obese insulin resistant mice and whether skeletal muscle AMPK was important for mediating potential effects. Methods Glucose homeostasis, insulin sensitivity, exercise capacity, and electron transport chain content/activity were examined in wildtype (WT) and AMPK β1β2 muscle-specific null (AMPK-MKO) mice fed a high-fat diet (HFD) with or without R419 supplementation. Results There was no change in weight gain, adiposity, glucose tolerance or insulin sensitivity between HFD-fed WT and AMPK-MKO mice. In both HFD-fed WT and AMPK-MKO mice, R419 enhanced insulin tolerance, insulin-stimulated glucose disposal, skeletal muscle 2-deoxyglucose uptake, Akt phosphorylation and glucose transporter 4 (GLUT4) content independently of alterations in body mass. In WT, but not AMPK-MKO mice, R419 improved treadmill running capacity. Treatment with R419 increased muscle electron transport chain content and activity in WT mice; effects which were blunted in AMPK-MKO mice. Conclusions Treatment of obese mice with R419 improved skeletal muscle insulin sensitivity through a mechanism that is independent of skeletal muscle AMPK. R419 also increases exercise capacity and improves mitochondrial function in obese WT mice; effects that are diminished in the absence of skeletal muscle AMPK. These findings suggest that R419 may be a promising therapy for improving whole-body glucose homeostasis and exercise capacity. PMID:26413470

  1. Gene and MicroRNA Expression Responses to Exercise; Relationship with Insulin Sensitivity

    PubMed Central

    McLean, Carrie S.; Mielke, Clinton; Cordova, Jeanine M.; Langlais, Paul R.; Bowen, Benjamin; Miranda, Danielle; Coletta, Dawn K.; Mandarino, Lawrence J.

    2015-01-01

    Background Healthy individuals on the lower end of the insulin sensitivity spectrum also have a reduced gene expression response to exercise for specific genes. The goal of this study was to determine the relationship between insulin sensitivity and exercise-induced gene expression in an unbiased, global manner. Methods and Findings Euglycemic clamps were used to measure insulin sensitivity and muscle biopsies were done at rest and 30 minutes after a single acute exercise bout in 14 healthy participants. Changes in mRNA expression were assessed using microarrays, and miRNA analysis was performed in a subset of 6 of the participants using sequencing techniques. Following exercise, 215 mRNAs were changed at the probe level (Bonferroni-corrected P<0.00000115). Pathway and Gene Ontology analysis showed enrichment in MAP kinase signaling, transcriptional regulation and DNA binding. Changes in several transcription factor mRNAs were correlated with insulin sensitivity, including MYC, r=0.71; SNF1LK, r=0.69; and ATF3, r= 0.61 (5 corrected for false discovery rate). Enrichment in the 5’-UTRs of exercise-responsive genes suggested regulation by common transcription factors, especially EGR1. miRNA species of interest that changed after exercise included miR-378, which is located in an intron of the PPARGC1B gene. Conclusions These results indicate that transcription factor gene expression responses to exercise depend highly on insulin sensitivity in healthy people. The overall pattern suggests a coordinated cycle by which exercise and insulin sensitivity regulate gene expression in muscle. PMID:25984722

  2. Endurance training improves insulin sensitivity and body composition in prostate cancer patients treated with androgen deprivation therapy.

    PubMed

    Hvid, Thine; Winding, Kamilla; Rinnov, Anders; Dejgaard, Thomas; Thomsen, Carsten; Iversen, Peter; Brasso, Klaus; Mikines, Kari J; van Hall, Gerrit; Lindegaard, Birgitte; Solomon, Thomas P J; Pedersen, Bente K

    2013-10-01

    Insulin resistance and changes in body composition are side effects of androgen deprivation therapy (ADT) given to prostate cancer patients. The present study investigated whether endurance training improves insulin sensitivity and body composition in ADT-treated prostate cancer patients. Nine men undergoing ADT for prostate cancer and ten healthy men with normal testosterone levels underwent 12 weeks of endurance training. Primary endpoints were insulin sensitivity (euglycemic-hyperinsulinemic clamps with concomitant glucose-tracer infusion) and body composition (dual-energy X-ray absorptiometry and magnetic resonance imaging). The secondary endpoint was systemic inflammation. Statistical analysis was carried out using two-way ANOVA. Endurance training increased VO2max (ml(O2)/min per kg) by 11 and 13% in the patients and controls respectively (P<0.0001). The patients and controls demonstrated an increase in peripheral tissue insulin sensitivity of 14 and 11% respectively (P<0.05), with no effect on hepatic insulin sensitivity (P=0.32). Muscle protein content of GLUT4 (SLC2A4) and total AKT (AKT1) was also increased in response to the training (P<0.05 and P<0.01 respectively). Body weight (P<0.0001) and whole-body fat mass (FM) (P<0.01) were reduced, while lean body mass (P=0.99) was unchanged. Additionally, reductions were observed in abdominal (P<0.01), subcutaneous (P<0.05), and visceral (P<0.01) FM amounts. The concentrations of plasma markers of systemic inflammation were unchanged in response to the training. No group × time interactions were observed, except for thigh intermuscular adipose tissue (IMAT) (P=0.01), reflecting a significant reduction in the amount of IMAT in the controls (P<0.05) not observed in the patients (P=0.64). In response to endurance training, ADT-treated prostate cancer patients exhibited improved insulin sensitivity and body composition to a similar degree as eugonadal men. PMID:23744766

  3. Glucose homeostasis and insulin sensitivity in growth hormone-transgenic mice: a cross-sectional analysis.

    PubMed

    Boparai, Ravneet K; Arum, Oge; Khardori, Romesh; Bartke, Andrzej

    2010-10-01

    In contrast to its stimulatory effects on musculature, bone, and organ development, and its lipolytic effects, growth hormone (GH) opposes insulin effects on glucose metabolism. Chronic GH overexposure is thought to result in insulin insensitivity and decreased blood glucose homeostatic control. Yet, despite the importance of this concept for basic biology, as well as human conditions of GH excess or deficiency, no systematic assessment of the impact of GH over- expression on glucose homeostasis and insulin sensitivity has been conducted. We report that male and female adult GH transgenic mice have enhanced glucose tolerance compared to littermate controls and this effect is not dependent on age or on the particular heterologous GH transgene used. Furthermore, increased glucose-stimulated insulin secretion, augmented insulin sensitivity, and muted gluconeogenesis were also observed in bovine GH overexpressing mice. These results show that markedly increased systemic GH concentration in GH-transgenic mice exerts unexpected beneficial effects on glucose homeostasis, presumably via a compensatory increase in insulin release. The counterintuitive nature of these results challenges previously held presumptions of the physiology of these mice and other states of GH overexpression or suppression. In addition, they pose intriguing queries about the relationships between GH, endocrine control of metabolism, and aging. PMID:20707609

  4. Beneficial impact of crocetin, a carotenoid from saffron, on insulin sensitivity in fructose-fed rats.

    PubMed

    Xi, Liang; Qian, Zhiyu; Xu, Guanglin; Zheng, Shuguo; Sun, Sai; Wen, Na; Sheng, Liang; Shi, Yun; Zhang, Yabing

    2007-01-01

    Crocetin, a unique carotenoid with potent antioxidative and anti-inflammatory activities, is a major ingredient of saffron which is used as an important spice and food colorant in various parts of the world. In the present study, the effect of crocetin on insulin resistance and its related abnormalities induced by high-fructose diet were investigated in male Wistar rats. Compared to the control rats fed on normal laboratory diet, fructose-fed rats developed a series of pathological changes including insulin resistance, hyperinsulinemia, dyslipidemia and hypertension. Although having no evident effect on the body weight, fructose feeding caused a marked increase in the weight of epididymal white adipose tissue. Furthermore, a significant reduction in the expression of both protein and mRNA of adiponectin (an insulin-sensitizing adipocytokine) was observed, whereas those of tumor necrosis factor (TNF)-alpha and leptin were enhanced in epididymal white adipose tissue in fructose-fed rats. These disorders were effectively normalized in crocetin-treated rats. Crocetin was also demonstrated here to alleviate free fatty acid (FFA)-induced insulin insensitivity and dysregulated mRNA expression of adiponectin, TNF-alpha and leptin in primary cultured rat adipocytes. These findings suggest the possibility of crocetin treatment as a preventive strategy of insulin resistance and related diseases. The favorable impact on adiponectin, TNF-alpha and leptin expression in white adipose tissue may be involved in the improvement of insulin sensitivity observed in crocetin-treated rats. PMID:16713230

  5. Differentiation of the insulin-sensitive glucose transporter in 3T3-L1 adipocytes

    SciTech Connect

    Frost, S.C.; Baly, D.L.; Cushman, S.W.; Lane, M.D.; Simpson, I.A.

    1986-05-01

    3T3-L1 fibroblasts differentiate in culture to resemble adipocytes both morphologically and biochemically. Insulin-sensitive glucose transport, as measured by 2-deoxy-(1-/sup 14/C)- glucose uptake in the undifferentiated cell is small (2X). In contrast, the rate of glucose transport in fully differentiated cells is elevated 15-fold over basal in the presence of insulin. To determine if this is due to an increase in the number of transporters/cell or accessibility to the transporters, the number of transporters was measured in subcellular fractions over differentiation using a /sup 3/H-cytochalasin B binding assay. The increase in the rate of insulin-sensitive glucose transport directly parallels an increase in the number of transporters which reside in an insulin-responsive intracellular compartment. This observation was confirmed by identifying the transporters by immunoblotting using an antibody generated against the human erythrocyte transporter. The molecular weight of this transporter increases over differentiation from a single band of 40kDa to a heterogeneous triplet of 40, 44 and 48kDa. These data suggest that the transporter undergoes differential processing and that the functional, insulin-responsive transporter may be different from the insulin-insensitive (basal) transporter.

  6. Insulin sensitivity regulates autonomic control of heart rate variation independent of body weight in normal subjects.

    PubMed

    Bergholm, R; Westerbacka, J; Vehkavaara, S; Seppälä-Lindroos, A; Goto, T; Yki-Järvinen, H

    2001-03-01

    It is unclear whether insulin sensitivity independent of body weight regulates control of heart rate variation (HRV) by the autonomic nervous system. Insulin action on whole-body glucose uptake (M-value) and heart rate variability were measured in 21 normal men. The subjects were divided into 2 groups [normally insulin sensitive (IS, 8.0 +/- 0.4 mg/kg.min) and less insulin sensitive (IR, 5.1 +/- 0.3 mg/kg.min)] based on their median M-value (6.2 mg/kg x min). Spectral power analysis of heart rate variability was performed in the basal state and every 30 min during the insulin infusion. The IS and IR groups were comparable, with respect to age (27 +/- 2 vs. 26 +/- 2 yr), body mass index (22 +/- 1 vs. 23 +/- 1 kg/m(2)), body fat (13 +/- 1 vs. 13 +/- 1%), systolic (121 +/- 16 vs. 117 +/- 14 mm Hg) and diastolic (74 +/- 11 vs. 73 +/- 11 mm Hg) blood pressures, and fasting plasma glucose (5.4 +/- 0.1 vs. 5.5 +/- 0.1 mmol/L) concentrations. Fasting plasma insulin was significantly higher in the IR (30 +/- 4 pmol/L) than in the IS (17 +/- 3 pmol/L, P < 0.05) group. In the IS group, insulin significantly increased the normalized low-frequency (LFn) component, a measure of predominantly sympathetic nervous system activity, from 36 +/- 5 to 48 +/- 4 normalized units (nu; 0 vs. 30-120 min, P < 0.001); whereas the normalized high-frequency (HFn) component, a measure of vagal control of HRV, decreased from 66 +/- 9 to 48 +/- 5 nu (P < 0.001). No changes were observed in either the normalized LF component [35 +/- 5 vs. 36 +/- 2 nu, not significant (NS)] or the normalized HF component (52 +/- 6 vs. 51 +/- 4 nu, NS) in the IR group. The ratio LF/HF, a measure of sympathovagal balance, increased significantly in the IS group (0.92 +/- 0.04 vs. 1.01 +/- 0.04, P < 0.01) but remained unchanged in the IR group (0.91 +/- 0.04 vs. 0.92 +/- 0.03, NS). Heart rate and systolic and diastolic blood pressures remained unchanged during the insulin infusion in both groups. We conclude that

  7. Cattle temperament influences metabolism: metabolic response to glucose tolerance and insulin sensitivity tests in beef steers.

    PubMed

    Burdick Sanchez, N C; Carroll, J A; Broadway, P R; Hughes, H D; Roberts, S L; Richeson, J T; Schmidt, T B; Vann, R C

    2016-07-01

    Cattle temperament, defined as the reactivity of cattle to humans or novel environments, can greatly influence several physiological systems in the body, including immunity, stress, and most recently discovered, metabolism. Greater circulating concentrations of nonesterified fatty acids (NEFAs) found in temperamental cattle suggest that temperamental cattle are metabolically different than calm cattle. Further, elevated NEFA concentrations have been reported to influence insulin sensitivity. Therefore, the objective of this study was to determine whether cattle temperament would influence the metabolic response to a glucose tolerance test (GTT) and insulin sensitivity test (IST). Angus-cross steers (16 calm and 15 temperamental; 216 ± 6 kg BW) were selected based on temperament score measured at weaning. On day 1, steers were moved into indoor stanchions to allow measurement of individual ad libitum feed intake. On day 6, steers were fitted with indwelling rectal temperature probes and jugular catheters. At 9 AM on day 7, steers received the GTT (0.5-mL/kg BW of a 50% dextrose solution), and at 2 PM on day 7, steers received the IST (2.5 IU bovine insulin/kg BW). Blood samples were collected and serum isolated at -60, -45, -30, -15, 0, 10, 20, 30, 45, 60, 90, 120, and 150 min relative to each challenge. Serum was stored at -80°C until analyzed for cortisol, glucose, NEFA, and blood urea nitrogen concentrations. All variables changed over time (P < 0.01). For the duration of the study, temperamental steers maintained greater (P < 0.01) serum NEFA and less (P ≤ 0.01) serum blood urea nitrogen and insulin sensitivity (calculated using Revised Quantitative Insulin Sensitivity Check Index) compared with calm steers. During the GTT, temperamental steers had greater (P < 0.01) serum glucose, yet decreased (P = 0.03) serum insulin and (P < 0.01) serum insulin: serum glucose compared to calm cattle. During the IST, temperamental steers had greater (P < 0.01) serum

  8. Chronic hyperinsulinemia reduces insulin sensitivity and metabolic functions of brown adipocyte.

    PubMed

    Rajan, Sujith; Shankar, Kripa; Beg, Muheeb; Varshney, Salil; Gupta, Abhishek; Srivastava, Ankita; Kumar, Durgesh; Mishra, Raj K; Hussain, Zakir; Gayen, Jiaur R; Gaikwad, Anil N

    2016-09-01

    The growing pandemics of diabetes have become a real threat to world economy. Hyperinsulinemia and insulin resistance are closely associated with the pathophysiology of type 2 diabetes. In pretext of brown adipocytes being considered as the therapeutic strategy for the treatment of obesity and insulin resistance, we have tried to understand the effect of hyperinsulinemia on brown adipocyte function. We here with for the first time report that hyperinsulinemia-induced insulin resistance in brown adipocyte is also accompanied with reduced insulin sensitivity and brown adipocyte characteristics. CI treatment decreased expression of brown adipocyte-specific markers (such as PRDM16, PGC1α, and UCP1) and mitochondrial content as well as activity. CI-treated brown adipocytes showed drastic decrease in oxygen consumption rate (OCR) and spare respiratory capacity. Morphological study indicates increased accumulation of lipid droplets in CI-treated brown adipocytes. We have further validated these findings in vivo in C57BL/6 mice implanted with mini-osmotic insulin pump for 8weeks. CI treatment in mice leads to increased body weight gain, fat mass and impaired glucose intolerance with reduced energy expenditure and insulin sensitivity. CI-treated mice showed decreased BAT characteristics and function. We also observed increased inflammation and ER stress markers in BAT of CI-treated animals. The above results conclude that hyperinsulinemia has deleterious effect on brown adipocyte function, making it susceptible to insulin resistance. Thus, the above findings have greater implication in designing approaches for the treatment of insulin resistance and diabetes via recruitment of brown adipocytes. PMID:27340034

  9. Effects of ambient temperature on glucose tolerance and insulin sensitivity test outcomes in normal and obese C57 male mice.

    PubMed

    Dudele, Anete; Rasmussen, Gitte Marie; Mayntz, David; Malte, Hans; Lund, Sten; Wang, Tobias

    2015-05-01

    Mice are commonly used as animal models to study human metabolic diseases, but experiments are typically performed at room temperature, which is far below their thermoneutral zone and is associated with elevated heart rate, food intake, and energy expenditure. We set out to study how ambient temperature affects glucose tolerance and insulin sensitivity in control and obese male mice. Adult male C57BL/6J mice were housed at room temperature (23°C) for 6 weeks and fed either control or high fat diet. They were then fasted for 6 h before glucose or insulin tolerance tests were performed at 15, 20, 25, or 30°C. To ensure that behavioral thermoregulation did not counterbalance the afflicted ambient temperatures, oxygen consumption was determined on mice with the same thermoregulatory opportunities as during the tests. Decreasing ambient temperatures increased oxygen consumption and body mass loss during fasting in both groups. Mice fed high fat diet had improved glucose tolerance at 30°C and increased levels of fasting insulin followed by successive decrease of fasting glucose. However, differences between control and high-fat diet mice were present at all temperatures. Ambient temperature did not affect glucose tolerance in control group and insulin tolerance in either of the groups. Ambient temperature affects glucose metabolism in mice and this effect is phenotype specific. PMID:25991720

  10. Effects of ambient temperature on glucose tolerance and insulin sensitivity test outcomes in normal and obese C57 male mice

    PubMed Central

    Dudele, Anete; Rasmussen, Gitte Marie; Mayntz, David; Malte, Hans; Lund, Sten; Wang, Tobias

    2015-01-01

    Mice are commonly used as animal models to study human metabolic diseases, but experiments are typically performed at room temperature, which is far below their thermoneutral zone and is associated with elevated heart rate, food intake, and energy expenditure. We set out to study how ambient temperature affects glucose tolerance and insulin sensitivity in control and obese male mice. Adult male C57BL/6J mice were housed at room temperature (23°C) for 6 weeks and fed either control or high fat diet. They were then fasted for 6 h before glucose or insulin tolerance tests were performed at 15, 20, 25, or 30°C. To ensure that behavioral thermoregulation did not counterbalance the afflicted ambient temperatures, oxygen consumption was determined on mice with the same thermoregulatory opportunities as during the tests. Decreasing ambient temperatures increased oxygen consumption and body mass loss during fasting in both groups. Mice fed high fat diet had improved glucose tolerance at 30°C and increased levels of fasting insulin followed by successive decrease of fasting glucose. However, differences between control and high-fat diet mice were present at all temperatures. Ambient temperature did not affect glucose tolerance in control group and insulin tolerance in either of the groups. Ambient temperature affects glucose metabolism in mice and this effect is phenotype specific. PMID:25991720

  11. Transient hypoxia reprograms differentiating adipocytes for enhanced insulin sensitivity and triglyceride accumulation

    PubMed Central

    Lu, Hongyun; Gao, Zhanguo; Zhao, Zhiyun; Weng, Jianping; Ye, Jianping

    2015-01-01

    Objective To investigate the impact of transient (2-4 h) hypoxia on metabolic reprogramming of adipocytes. Methods The impact of transient hypoxia on metabolic reprogramming was investigated in 3T3-L1 cells before and after differentiation. Glucose uptake, fatty acid oxidation, lipolysis, and mitochondria were examined to determine the hypoxia effects. Preadipocytes were exposed to transient hypoxia (4h/day) in the course of differentiation. Insulin sensitivity and TG accumulation was examined in the cells at the end of differentiation to determine the reprogramming effects. AMPK activity and gene expression were determined by quantitative RT-PCR and Western blotting in search for mechanism of the reprogramming. Results In acute response to hypoxia, adipocytes exhibited an increase in insulin-dependent and -independent glucose uptake. Fatty acid β-oxidation and pyruvate dehydrogenase (PDH) activity were decreased. Multiple exposures of differentiating adipocytes to transient hypoxia enhanced insulin signaling, TG accumulation, expression of antioxidant genes in differentiated adipocytes in the absence of hypoxia. The metabolic memory was associated with elevated AMPK activity and gene expression (GLUT1, PGC-1α, PPARγ, SREBP, NRF-1, ESRRα, LPL). The enhanced insulin sensitivity was blocked by an AMPK inhibitor. Conclusions Repeated exposure of differentiating adipocytes to transient hypoxia is able to reprogram the cells for increased TG accumulation and enhanced insulin sensitivity. The metabolic alterations were observed in post-differentiated cells under normoxia. The reprogramming involves AMPK activation and gene expression in the metabolic pathways in cytosol and mitochondria. PMID:26219415

  12. Association of oxidative status and insulin sensitivity in periparturient dairy cattle: an observational study.

    PubMed

    Abuelo, A; Hernández, J; Benedito, J L; Castillo, C

    2016-04-01

    Post-parturient insulin resistance (IR) is a common feature in all mammalian animals. However, in dairy cows, it can be exacerbated because of high milk yield, leading to excessive negative energy balance, which is related with increased disease incidence, reduced milk production and worsened reproductive performance. IR has been extensively investigated in humans suffering from diabetes mellitus. In these subjects, it is known that oxidative stress (OS) plays a causative role in the onset of IR. Although OS occurs in transitional dairy cattle, there are yet no studies that investigated the association between IR and OS in dairy cattle. Therefore, the aim of this study was to investigate whether there is a relationship between OS and IR in dairy cattle. Serum samples were taken repeatedly from 22 dairy cows from 2 months prior to the expected calving date to 2 months after calving and were analysed for markers of metabolic and redox balance. Surrogate indices of insulin sensitivity were also calculated. Generalised linear mixed models revealed an effect of the oxidative status on peripheral insulin concentration and on indices of insulin sensitivity. Hence, field trials should investigate the effectiveness of antioxidant therapy on insulin sensitivity in peripheral tissues during the transition period of dairy cattle. PMID:26174108

  13. Receptor for Advanced Glycation End Products Regulates Adipocyte Hypertrophy and Insulin Sensitivity in Mice

    PubMed Central

    Monden, Masayo; Koyama, Hidenori; Otsuka, Yoshiko; Morioka, Tomoaki; Mori, Katsuhito; Shoji, Takuhito; Mima, Yohei; Motoyama, Koka; Fukumoto, Shinya; Shioi, Atsushi; Emoto, Masanori; Yamamoto, Yasuhiko; Yamamoto, Hiroshi; Nishizawa, Yoshiki; Kurajoh, Masafumi; Yamamoto, Tetsuya; Inaba, Masaaki

    2013-01-01

    Receptor for advanced glycation end products (RAGE) has been shown to be involved in adiposity as well as atherosclerosis even in nondiabetic conditions. In this study, we examined mechanisms underlying how RAGE regulates adiposity and insulin sensitivity. RAGE overexpression in 3T3-L1 preadipocytes using adenoviral gene transfer accelerated adipocyte hypertrophy, whereas inhibitions of RAGE by small interfering RNA significantly decrease adipocyte hypertrophy. Furthermore, double knockdown of high mobility group box-1 and S100b, both of which are RAGE ligands endogenously expressed in 3T3-L1 cells, also canceled RAGE-medicated adipocyte hypertrophy, implicating a fundamental role of ligands–RAGE ligation. Adipocyte hypertrophy induced by RAGE overexpression is associated with suppression of glucose transporter type 4 and adiponectin mRNA expression, attenuated insulin-stimulated glucose uptake, and insulin-stimulated signaling. Toll-like receptor (Tlr)2 mRNA, but not Tlr4 mRNA, is rapidly upregulated by RAGE overexpression, and inhibition of Tlr2 almost completely abrogates RAGE-mediated adipocyte hypertrophy. Finally, RAGE−/− mice exhibited significantly less body weight, epididymal fat weight, epididymal adipocyte size, higher serum adiponectin levels, and higher insulin sensitivity than wild-type mice. RAGE deficiency is associated with early suppression of Tlr2 mRNA expression in adipose tissues. Thus, RAGE appears to be involved in mouse adipocyte hypertrophy and insulin sensitivity, whereas Tlr2 regulation may partly play a role. PMID:23011593

  14. The effect of exercise training combined with PPARγ agonist on skeletal muscle glucose uptake and insulin sensitivity in induced diabetic obese Zucker rats

    PubMed Central

    2016-01-01

    [Purpose] Exercise training with PPARγ agonist is expected to increase glucose uptake and improve insulin sensitivity in skeletal muscle of patients with diabetes. However, its mechanisms to effect glucose uptake and insulin sensitivity in skeletal muscle are unclear. [Methods] The mechanism of action was determined by co-treatment with PPARγ agonist- rosiglitazone and exercise training in streptozotocin induced-diabetic obese Zucker rats. Exercise training was carried out for 6 weeks (swimming, 1 h/day, 5 times/week, 5% weight/g, 32±1℃) with rosiglitazone treatment (3mg/kg/day, 6weeks). [Results] Glucose uptake and insulin sensitivity was decreased in diabetic than normal animals. Exercise training and rosiglitazone treatment respectively increased the expression of PPAR(peroxisome proliferators-activated receptor)-α, -β/δ, -γ, PGC-1α(PPAR-γ coactivator-1α), adiponectin, GLUT-4(glucose transportor-4) and p-AMPK-α2(phospho-AMP activated protein kinase-α2) in EDL and SOL of diabetic, as compared to normal animals. Interestingly, training combined with rosiglitazone significantly increased glucose uptake and insulin sensitivity, which resulted in high expression of all molecules in diabetic than all other groups. [Conclusion] These results indicated that exercise training combined with rosiglitazone might mediate regulation of glucose uptake and insulin sensitivity in skeletal muscle. Therefore, exercise training combined with rosiglitazone may be recommended as complementary therapies for diabetes. PMID:27508153

  15. Insulin sensitizes FGF21 in glucose and lipid metabolisms via activating common AKT pathway.

    PubMed

    Yu, Dan; Ye, Xianlong; Wu, Qiang; Li, Shujie; Yang, Yongbi; He, Jinjiao; Liu, Yunye; Zhang, Xiaoyu; Yuan, Qingyan; Liu, Mingyao; Li, Deshan; Ren, Guiping

    2016-06-01

    Previous studies reveal that fibroblast growth factor 21 (FGF21) sensitizes insulin to achieve a synergy in regulating glucose metabolism. Here, we report that insulin sensitizes FGF21 in regulating both glucose and lipid metabolisms. db/db diabetic mice were subcutaneously administrated once a day for 6 weeks. Effective dose of insulin (1 U) could control blood glucose level of the db/db mice for maximum of 2 h, increased the body weight of the db/db mice and did not improve serum lipid parameters. In contrast, effective dose of FGF21 (0.5 mg/kg) could maintain blood glucose of the db/db mice at normal level for at least 24 h, repressed the weight gain of the mice and significantly improved lipid parameters. Ineffective doses of FGF21 (0.125 mg/kg) and insulin had no effect on blood glucose level of the db/db mice after 24 h administration, body weight or lipid parameters. However, combination of the two ineffective doses could maintain blood glucose level of the db/db mice for at least 24 h, suppressed weight gain and significantly improved lipid parameters. These results suggest that insulin sensitizes FGF21 in regulating both glucose and lipid metabolism. The results aimed to study the molecular basis of FGF21 sensitization indicates that combination of the two ineffective doses increased the mRNA expression of glut1, glut4, β-Klotho, sirt1, pgc-1α, ucp-1 and AKT phosphorylation, decreased fasn. The results demonstrate that insulin sensitizes FGF21 through elevating the phosphorylation of common gene Akt and amplifying FGF21 downstream signaling, including increasing expression of glut1 sirt1, pgc-1α, ucp-1, and decreasing fasn expression. In summary, we reports herein for the first time that insulin sensitizes FGF21 to achieve a synergy in regulating glucose and lipid metabolism. Along with previous studies, we conclude that the synergistic effect between FGF21 and insulin is realized through mutual sensitization. PMID:26607153

  16. Association of obesity risk SNPs in PCSK1 with insulin sensitivity and proinsulin conversion

    PubMed Central

    2010-01-01

    Background Prohormone convertase 1 is involved in maturation of peptides. Rare mutations in gene PCSK1, encoding this enzyme, cause childhood obesity and abnormal glucose homeostasis with elevated proinsulin concentrations. Common single nucleotide polymorphisms (SNPs) within this gene, rs6232 and rs6235, are associated with obesity. We studied whether these SNPs influence the prediabetic traits insulin resistance, β-cell dysfunction, or glucose intolerance. Methods We genotyped 1498 German subjects for SNPs rs6232 and rs6235 within PCSK1. The subjects were metabolically characterized by oral glucose tolerance test with glucose, insulin, proinsulin, and C-peptide measurements. A subgroup of 512 subjects underwent a hyperinsulinemic-euglycemic clamp. Results The minor allele frequencies were 25.8% for SNP rs6235 and 6.0% for rs6232. After adjustment for sex and age, we found no association of SNPs rs6235 and rs6232 with BMI or other weight-related traits (all p ≥ 0.07). Both minor alleles, adjusted for sex, age, BMI and insulin sensitivity were associated with elevated AUCproinsulin and AUCproinsulin/AUCinsulin (rs6235: padditive model ≤ 0.009, effect sizes 8/8%, rs6232: pdominant model ≤ 0.01, effect sizes 10/21%). Insulin secretion was not affected by the variants (different secretion parameters, all p ≥ 0.08). The minor allele of SNP rs6232 was additionally associated with 15% higher OGTT-derived and 19% higher clamp-derived insulin sensitivity (pdom ≤ 0.0047), 4.5% lower HOMAIR (pdom = 0.02) and 3.5% lower 120-min glucose (pdom = 0.0003) independently of BMI and proinsulin conversion. SNP rs6235 was not associated with parameters of glucose metabolism. Conclusions Like rare mutations in PCSK1, the more common variants tested determine glucose-stimulated proinsulin conversion, but not insulin secretion. In addition, rs6232, encoding the amino acid exchange N221D, influences insulin sensitivity and glucose homeostasis. PMID:20534142

  17. Transfer of intestinal microbiota from lean donors increases insulin sensitivity in individuals with metabolic syndrome.

    PubMed

    Vrieze, Anne; Van Nood, Els; Holleman, Frits; Salojärvi, Jarkko; Kootte, Ruud S; Bartelsman, Joep F W M; Dallinga-Thie, Geesje M; Ackermans, Mariette T; Serlie, Mireille J; Oozeer, Raish; Derrien, Muriel; Druesne, Anne; Van Hylckama Vlieg, Johan E T; Bloks, Vincent W; Groen, Albert K; Heilig, Hans G H J; Zoetendal, Erwin G; Stroes, Erik S; de Vos, Willem M; Hoekstra, Joost B L; Nieuwdorp, Max

    2012-10-01

    Alterations in intestinal microbiota are associated with obesity and insulin resistance. We studied the effects of infusing intestinal microbiota from lean donors to male recipients with metabolic syndrome on the recipients' microbiota composition and glucose metabolism. Subjects were assigned randomly to groups that were given small intestinal infusions of allogenic or autologous microbiota. Six weeks after infusion of microbiota from lean donors, insulin sensitivity of recipients increased (median rate of glucose disappearance changed from 26.2 to 45.3 μmol/kg/min; P < .05) along with levels of butyrate-producing intestinal microbiota. Intestinal microbiota might be developed as therapeutic agents to increase insulin sensitivity in humans; www.trialregister.nl; registered at the Dutch Trial Register (NTR1776). PMID:22728514

  18. Antidiabetic Property of Symplocos cochinchinensis Is Mediated by Inhibition of Alpha Glucosidase and Enhanced Insulin Sensitivity

    PubMed Central

    Antu, Kalathookunnel Antony; Riya, Mariam Philip; Mishra, Arvind; Anilkumar, Karunakaran S.; Chandrakanth, Chandrasekharan K.; Tamrakar, Akhilesh K.; Srivastava, Arvind K.; Raghu, K. Gopalan

    2014-01-01

    The study is designed to find out the biochemical basis of antidiabetic property of Symplocos cochinchinensis (SC), the main ingredient of ‘Nisakathakadi’ an Ayurvedic decoction for diabetes. Since diabetes is a multifactorial disease, ethanolic extract of the bark (SCE) and its fractions (hexane, dichloromethane, ethyl acetate and 90% ethanol) were evaluated by in vitro methods against multiple targets relevant to diabetes such as the alpha glucosidase inhibition, glucose uptake, adipogenic potential, oxidative stress, pancreatic beta cell proliferation, inhibition of protein glycation, protein tyrosine phosphatase-1B (PTP-1B) and dipeptidyl peptidase-IV (DPP-IV). Among the extracts, SCE exhibited comparatively better activity like alpha glucosidase inhibition (IC50 value-82.07±2.10 µg/mL), insulin dependent glucose uptake (3 fold increase) in L6 myotubes, pancreatic beta cell regeneration in RIN-m5F (3.5 fold increase) and reduced triglyceride accumulation (22% decrease) in 3T3L1 cells, protection from hyperglycemia induced generation of reactive oxygen species in HepG2 cells (59.57% decrease) with moderate antiglycation and PTP-1B inhibition. Chemical characterization by HPLC revealed the superiority of SCE over other extracts due to presence and quantity of bioactives (beta-sitosterol, phloretin 2′glucoside, oleanolic acid) in addition to minerals like magnesium, calcium, potassium, sodium, zinc and manganese. So SCE has been subjected to oral sucrose tolerance test to evaluate its antihyperglycemic property in mild diabetic and diabetic animal models. SCE showed significant antihyperglycemic activity in in vivo diabetic models. We conclude that SC mediates the antidiabetic activity mainly via alpha glucosidase inhibition, improved insulin sensitivity, with moderate antiglycation and antioxidant activity. PMID:25184241

  19. Serum Resistin Levels Are Associated with Adiposity and Insulin Sensitivity in Obese Hispanic Subjects

    PubMed Central

    Nieva-Vazquez, Adriana; Torres-Rasgado, Enrique; López-López, José G.; Romero, Jose R.

    2014-01-01

    Abstract Background and Aims: Resistin is involved in the development of obesity and insulin resistance (IR) in mice and may play a similar role in humans through mechanisms that remain unresolved. The objective of this study was to characterize the relationship between resistin levels in obese subjects with and without IR among Hispanic subjects. Material and Methods: A cross-sectional study was performed on 117 nondiabetic Hispanic subjects of both genders that were allocated into three study groups: A control group (n=47) of otherwise healthy individuals in metabolic balance, a group with obesity (OB) (n=36), and a group with obesity and IR (OB-IR) (n=34). Anthropometric and clinical characterization was carried out, and resistin levels were determined by enzyme-linked immunosorbent assay (ELISA). Results: We found that resistin levels were higher in OB and OB-IR groups when compared to the control group (1331.79±142.15 pg/mL, 1266.28±165.97 pg/mL vs. 959.21±171.43 pg/mL; P<0.05), an effect that was not confounded by age (control, 34.04±10.00 years; OB, 37.30±10.78 years; and OB-IR, 35.67±10.15 years). In addition, we observed a significant correlation (P<0.001) between resistin levels and higher adiposity and insulin sensitivity (IS) in our cohort. Conclusions: Our results suggest that higher resistin levels are associated with higher adiposity and lower IS among obese Hispanic subjects. PMID:24266722

  20. Rosiglitazone-Mediated Effects on Skeletal Muscle Gene Expression Correlate with Improvements in Insulin Sensitivity in Individuals with HIV-Insulin Resistance

    PubMed Central

    Mynarcik, Dennis C.; McNurlan, Margaret A.; Melendez, Mark M.; Vosswinkel, James A.; Gelato, Marie C.

    2011-01-01

    Rosiglitazone, an agonist of peroxisome proliferator activated receptor (PPARγ), improves insulin sensitivity by increasing insulin-stimulated glucose uptake into muscle tissue. This study was undertaken to assess changes in expression of PPAR-regulated genes in muscle tissue following treatment of HIV-associated insulin resistance with rosiglitazone. Muscle gene expression was assessed in twenty-two seronegative HIV subjects (control), 21 HIV-infected individuals with normal insulin sensitivity (HIV-IS) and 19 HIV-infected individuals with insulin resistance (HIV-IR). A subset of the HIV-IR group (N = 10) were re-evaluated 12 weeks after treatment with 8 mg/d of rosiglitazone. The HIV-IR group's rosiglitazone-mediated improvement in insulin sensitivity was highly correlated with increased expression of PPARγ and carnitine palmitoyl transferase-1 (CPT-1), (r = 0.87, P < .001) and (r = 0.95, P < .001), respectively. The changes in PPARγ expression were also correlated with the changes in CPT1 expression (r = 0.75, P = .009). The results suggest that rosiglitazone; may have a direct effect on muscle tissue to improve insulin sensitivity. PMID:21559208

  1. Rosiglitazone-Mediated Effects on Skeletal Muscle Gene Expression Correlate with Improvements in Insulin Sensitivity in Individuals with HIV-Insulin Resistance.

    PubMed

    Mynarcik, Dennis C; McNurlan, Margaret A; Melendez, Mark M; Vosswinkel, James A; Gelato, Marie C

    2011-01-01

    Rosiglitazone, an agonist of peroxisome proliferator activated receptor (PPARγ), improves insulin sensitivity by increasing insulin-stimulated glucose uptake into muscle tissue. This study was undertaken to assess changes in expression of PPAR-regulated genes in muscle tissue following treatment of HIV-associated insulin resistance with rosiglitazone. Muscle gene expression was assessed in twenty-two seronegative HIV subjects (control), 21 HIV-infected individuals with normal insulin sensitivity (HIV-IS) and 19 HIV-infected individuals with insulin resistance (HIV-IR). A subset of the HIV-IR group (N = 10) were re-evaluated 12 weeks after treatment with 8 mg/d of rosiglitazone. The HIV-IR group's rosiglitazone-mediated improvement in insulin sensitivity was highly correlated with increased expression of PPARγ and carnitine palmitoyl transferase-1 (CPT-1), (r = 0.87, P < .001) and (r = 0.95, P < .001), respectively. The changes in PPARγ expression were also correlated with the changes in CPT1 expression (r = 0.75, P = .009). The results suggest that rosiglitazone; may have a direct effect on muscle tissue to improve insulin sensitivity. PMID:21559208

  2. Resistance exercise increase lean body mass and improves basal and hepatic insulin sensitivity in obese adolescents

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Little is known about the metabolic effects of resistance exercise, for instance, weight lifting. We studied whether a resistance exercise program improves insulin sensitivity and glucose metabolism in sedentary obese adolescents. Elevn obese subjects (15.7 +/- 0.4 year; 35.4 +/- 0.8 kg/m2; 41.3 +/-...

  3. Phylloquinone intake is associated with greater insulin sensitivity and glycemic status in adult men and women

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Limited published evidence suggests that vitamin K may have a beneficial role in glucose homeostasis. No observational data exist on the associations between vitamin K intake and insulin sensitivity. The objective of this study was to examine cross-sectional associations between self-reported phyl...

  4. Metabolomic profiling of amino acids and beta-cell function relative to insulin sensitivity in youth

    Technology Transfer Automated Retrieval System (TEKTRAN)

    In longitudinal studies of adults, elevated amino acid (AA) concentrations predicted future type 2 diabetes mellitus (T2DM). The aim of the present investigation was to examine whether increased plasma AA concentrations are associated with impaired beta-cell function relative to insulin sensitivity ...

  5. Effects of delayed gastric emptying on postprandial glucose kinetics, insulin sensitivity, and β-cell function

    PubMed Central

    Hinshaw, Ling; Schiavon, Michele; Mallad, Ashwini; Man, Chiara Dalla; Basu, Rita; Bharucha, Adil. E.; Cobelli, Claudio; Carter, Rickey E.; Basu, Ananda

    2014-01-01

    Controlling meal-related glucose excursions continues to be a therapeutic challenge in diabetes mellitus. Mechanistic reasons for this need to be understood better to develop appropriate therapies. To investigate delayed gastric emptying effects on postprandial glucose turnover, insulin sensitivity, and β-cell responsivity and function, as a feasibility study prior to studying patients with type 1 diabetes, we used the triple tracer technique C-peptide and oral minimal model approach in healthy subjects. A single dose of 30 μg of pramlintide administered at the start of a mixed meal was used to delay gastric emptying rates. With delayed gastric emptying rates, peak rate of meal glucose appearance was delayed, and rate of endogenous glucose production (EGP) was lower. C-peptide and oral minimal models enabled the assessments of β-cell function, insulin sensitivity, and β-cell responsivity simultaneously. Delayed gastric emptying induced by pramlintide improved total insulin sensitivity and decreased total β-cell responsivity. However, β-cell function as measured by total disposition index did not change. The improved whole body insulin sensitivity coupled with lower rate of appearance of EGP with delayed gastric emptying provides experimental proof of the importance of evaluating pramlintide in artificial endocrine pancreas approaches to reduce postprandial blood glucose variability in patients with type 1 diabetes. PMID:25074985

  6. Aerobic exercise increases peripheral and hepatic insulin sensitivity in sedentary adolescents

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The increasing prevalence of obesity and its consequences is a serious public health concern. The present study was undertaken to determine whether a controlled aerobic exercise program (without weight loss) improves insulin sensitivity and glucose metabolism in sedentary adolescents. Twenty nine p...

  7. Enhanced Energy Expenditure, Glucose Utilization, and Insulin Sensitivity in VAMP8 Null Mice

    PubMed Central

    Zong, Haihong; Wang, Cheng-Chun; Vaitheesvaran, Bhavapriya; Kurland, Irwin J.; Hong, Wanjin; Pessin, Jeffrey E.

    2011-01-01

    OBJECTIVE Previous studies have demonstrated that the VAMP8 protein plays a complex role in the control of granule secretion, transport vesicle trafficking, phagocytosis, and endocytosis. The present study was aimed to investigate the role of VAMP8 in mediating GLUT4 trafficking and therefore insulin action in mice. RESEARCH DESIGN AND METHODS Physiological parameters were measured using Oxymax indirect calorimetry system in 12-week-old VAMP8 null mice. Dynamic analysis of glucose homeostasis was assessed using euglycemic–hyperinsulinemic clamp coupled with tracer radioactively labeled 2-deoxyglucose. Insulin stimulated GLUT4 protein expressions on muscle cell surface were examined by immunofluorescence microscopy. RESULTS VAMP8 null mice display reduced adiposity with increased energy expenditure despite normal food intake and reduced spontaneous locomotor activity. In parallel, the VAMP8 null mice also had fasting hypoglycemia (84 ± 11 vs. 115 ± 4) and enhanced glucose tolerance with increased insulin sensitivity due to increases in both basal and insulin-stimulated glucose uptake in skeletal muscle (0.19 ± 0.04 vs. 0.09 ± 0.01 mmol/kg/min during basal, 0.6 ± 0.04 vs. 0.31 ± 0.06 mmol/kg/min during clamp in red-gastrocnemius muscle, P < 0.05). Consistent with a role for VAMP8 in the endocytosis of the insulin-responsive GLUT4, sarcolemma GLUT4 protein levels were increased in both the basal and insulin-stimulated states without any significant change in the total amount of GLUT4 protein or related facilitative glucose transporters present in skeletal muscle, GLUT1, GLUT3, and GLUT11. CONCLUSIONS These data demonstrate that, in the absence of VAMP8, the relative subcellular distribution of GLUT4 is altered, resulting in increased sarcolemma levels that can account for increased glucose clearance and insulin sensitivity. PMID:20876717

  8. Insulin-Sensitizing Effects of Omega-3 Fatty Acids: Lost in Translation?

    PubMed Central

    Lalia, Antigoni Z.; Lanza, Ian R.

    2016-01-01

    Omega-3 polyunsaturated fatty acids (n-3 PUFA) of marine origin, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), have been long studied for their therapeutic potential in the context of type 2 diabetes, insulin resistance, and glucose homeostasis. Glaring discordance between observations in animal and human studies precludes, to date, any practical application of n-3 PUFA as nutritional therapeutics against insulin resistance in humans. Our objective in this review is to summarize current knowledge and provide an up-to-date commentary on the therapeutic value of EPA and DHA supplementation for improving insulin sensitivity in humans. We also sought to discuss potential mechanisms of n-3 PUFA action in target tissues, in specific skeletal muscle, based on our recent work, as well as in liver and adipose tissue. We conducted a literature search to include all preclinical and clinical studies performed within the last two years and to comment on representative studies published earlier. Recent studies support a growing consensus that there are beneficial effects of n-3 PUFA on insulin sensitivity in rodents. Observational studies in humans are encouraging, however, the vast majority of human intervention studies fail to demonstrate the benefit of n-3 PUFA in type 2 diabetes or insulin-resistant non-diabetic people. Nevertheless, there are still several unanswered questions regarding the potential impact of n-3 PUFA on metabolic function in humans. PMID:27258299

  9. MicroRNA-26a regulates insulin sensitivity and metabolism of glucose and lipids

    PubMed Central

    Fu, Xianghui; Dong, Bingning; Tian, Yan; Lefebvre, Philippe; Meng, Zhipeng; Wang, Xichun; Pattou, François; Han, Weidong; Wang, Xiaoqiong; Lou, Fang; Jove, Richard; Staels, Bart; Moore, David D.; Huang, Wendong

    2015-01-01

    Type 2 diabetes (T2D) is characterized by insulin resistance and increased hepatic glucose production, yet the molecular mechanisms underlying these abnormalities are poorly understood. MicroRNAs (miRs) are a class of small, noncoding RNAs that have been implicated in the regulation of human diseases, including T2D. miR-26a is known to play a critical role in tumorigenesis; however, its function in cellular metabolism remains unknown. Here, we determined that miR-26a regulates insulin signaling and metabolism of glucose and lipids. Compared with lean individuals, overweight humans had decreased expression of miR-26a in the liver. Moreover, miR-26 was downregulated in 2 obese mouse models compared with control animals. Global or liver-specific overexpression of miR-26a in mice fed a high-fat diet improved insulin sensitivity, decreased hepatic glucose production, and decreased fatty acid synthesis, thereby preventing obesity-induced metabolic complications. Conversely, silencing of endogenous miR-26a in conventional diet–fed mice impaired insulin sensitivity, enhanced glucose production, and increased fatty acid synthesis. miR-26a targeted several key regulators of hepatic metabolism and insulin signaling. These findings reveal miR-26a as a regulator of liver metabolism and suggest miR-26a should be further explored as a potential target for the treatment of T2D. PMID:25961460

  10. Abatacept improves whole-body insulin sensitivity in rheumatoid arthritis: an observational study.

    PubMed

    Ursini, Francesco; Russo, Emilio; Letizia Hribal, Marta; Mauro, Daniele; Savarino, Francesca; Bruno, Caterina; Tripolino, Cesare; Rubino, Mariangela; Naty, Saverio; Grembiale, Rosa Daniela

    2015-05-01

    Rheumatoid arthritis (RA) is characterized by increased insulin resistance, a well-known risk factor for diabetes and cardiovascular diseases. The aim of the present study was to evaluate the effect of abatacept on insulin sensitivity in RA patients with moderate to severe disease despite treatment with methotrexate. Fifteen RA patients were recruited for the present study. Patients were evaluated at time 0 and after 6 months of the treatment with i.v. abatacept at the dosage recommended for weight range. Evaluation included oral glucose tolerance test (OGTT) at both time points. Insulin sensitivity was estimated with insulin sensitivity index (ISI) by Matsuda, a measure of whole-body insulin sensitivity. ISI significantly increased after the treatment with abatacept from 3.7 ± 2.6 to 5.0 ± 3.2 (P = 0.003) with a mean difference of 1.23. Analysis of glucose and insulin values during OGTT revealed a reduction of both glucose (303.9 ± 73.4 mg/dL min versus 269.2 ± 69.5 mg/dL min, P = 0.009) and insulin (208.4 ± 119.7 mg/dL min versus 158.0 ± 95.3 mg/dL min, P = 0.01) area under the curves (AUCs). Accordingly also glycated hemoglobin significantly improved (5.5 ± 0.4% versus 5.3 ± 0.3%, P = 0.04). No significant differences were found for measures of β-cell function insulinogenic index (1.11 ± 1.19 versus 1.32 ± 0.82, P = 0.77) and oral disposition index (2.0 ± 5.4 versus 6.0 ± 6.0, P = 0.25). Treatment with abatacept seems to be able to improve whole-body insulin sensitivity in RA patients without affecting β-cell function. PMID:26020396

  11. Insulin receptor binding motif tagged with IgG4 Fc (Yiminsu) works as an insulin sensitizer to activate Akt signaling in hepatocytes.

    PubMed

    Wang, J; Zou, T; Yang, H X; Gong, Y Z; Xie, X J; Liu, H Y; Liao, D F

    2015-01-01

    Insulin resistance is a key feature of obesity and type 2 diabetes mellitus (T2DM). Interaction of insulin with the insulin receptor (IR) leads to both its auto-phosphorylation and phosphorylation of tyrosine residues on the IR substrate (IRS) proteins, initiating the activation of intracellular signaling cascades. The metabolic effects of IRS are known to be mediated through pathways involving phosphatidyl-inositol 3-kinase (PI-3K), which result in the activation of Akt signaling. The C-terminal region of the IR ectodomain is required to facilitate the conformational changes that are required for high-affinity binding to insulin. Furthermore, the CH2 and CH3 domains in the Fc fragments of immunoglobulins are responsible for their binding to the Fc receptor, which triggers transcytosis. In this study, we created a fusion peptide of the C-terminal end of the human IR ectodomain with the IgG4 Fc fragment, including an intervening polyG fragment to ensure enough space for insulin binding. We named this new peptide "Yiminsu", meaning an insulin sensitizer. The results of our analyses show that Yiminsu significantly facilitates insulin signaling via the activation of Akt in hepatocytes in a dose- and time-dependent manner. Further studies are required to determine whether Yiminsu can act as an insulin sensitizer. PMID:26345813

  12. Inhibition of Src homology 2 domain-containing phosphatase 1 increases insulin sensitivity in high-fat diet-induced insulin-resistant mice.

    PubMed

    Krüger, Janine; Wellnhofer, Ernst; Meyborg, Heike; Stawowy, Philipp; Östman, Arne; Kintscher, Ulrich; Kappert, Kai

    2016-03-01

    Insulin resistance plays a crucial role in the development of type 2 diabetes. Insulin receptor signalling is antagonized and tightly controlled by protein tyrosine phosphatases (PTPs). However, the precise role of the PTP src homology 2 domain-containing phosphatase 1 (SHP-1) in insulin resistance has not been explored. Male C57BL/6J mice were fed a high-fat diet (HFD, 60% kcal from fat), to induce insulin resistance, or a low-fat diet (LFD, 10% kcal from fat) for 10 weeks. Afterwards, HFD-fed mice were pharmacologically treated with the SHP-1 (Ptpn6) inhibitor sodium stibogluconate and the broad spectrum pan-PTP inhibitor bis(maltolato)oxovanadium(IV) (BMOV). Both inhibitors ameliorated the metabolic phenotype, as evidenced by reduced body weight, improved insulin sensitivity and glucose tolerance, which was not due to altered PTP gene expression. In parallel, phosphorylation of the insulin receptor and of the insulin signalling key intermediate Akt was enhanced, and both PTP inhibitors and siRNA-mediated SHP-1 downregulation resulted in an increased glucose uptake in vitro. Finally, recombinant SHP-1 was capable of dephosphorylating the ligand-induced tyrosine-phosphorylated insulin receptor. These results indicate a central role of SHP-1 in insulin signalling during obesity, and SHP-1 inhibition as a potential therapeutic approach in metabolic diseases. PMID:27047746

  13. Earlier Menarche Is Associated with Lower Insulin Sensitivity and Increased Adiposity in Young Adult Women

    PubMed Central

    Wilson, Dyanne A.; Derraik, José G. B.; Rowe, Deborah L.; Hofman, Paul L.; Cutfield, Wayne S.

    2015-01-01

    Objective We aimed to assess whether age at menarche was associated with insulin sensitivity in young adult women. Methods We studied 54 healthy young women aged 20–30 years. Participants were grouped according to age at menarche: Early (≤11.0 years; n=13), Average (>12.0 and ≤13.0 years; n=28), and Late (≥14.0 years, n=13). Primary outcome was insulin sensitivity measured using intravenous glucose tolerance tests and Bergman’s minimal model. Body composition was assessed using whole-body dual-energy X-ray absorptiometry. Results Earlier menarche was associated with lower insulin sensitivity (p=0.015). There was also a continuous increase in adiposity with younger age at menarche, which was associated with increased weight (p=0.001), BMI (p=0.002), total body fat (p=0.049), and truncal fat (p=0.020). Stratified analyses showed that insulin sensitivity in Early women (5.5 x10-4·min-1(mU/l)) was lower than in Average (8.0 x10-4·min-1(mU/l), p=0.021) and Late (8.6 x10-4·min-1(mU/l), p=0.033) groups. Early women (weight=66.1 kg; BMI=24.1 kg/m2) were considerably heavier and fatter than Average (59.0 kg, p=0.004; 21.4 kg/m2, p=0.002) and Late (57.0 kg, p=0.001; 20.8 kg/m2, p=0.0009) women. Conclusions Early menarche is associated with lower insulin sensitivity and increased adiposity in young adulthood, potentially increasing the risk of type 2 diabetes and the metabolic syndrome later in life. PMID:26061526

  14. Insulin

    NASA Technical Reports Server (NTRS)

    2004-01-01

    The manipulation of organic materials--cells, tissues, and even living organisms--offers many exciting possibilities for the future from organic computers to improved aquaculture. Commercial researchers are using the microgravity environment to produce large near perfect protein crystals Research on insulin has yielded crystals that far surpass the quality of insulin crystals grown on the ground. Using these crystals industry partners are working to develop new and improved treatments for diabetes. Other researchers are exploring the possibility of producing antibiotics using plant cell cultures which could lead to both orbital production and the improvement of ground-based antibiotic production.

  15. Importance of the high-molecular-mass isoform of adiponectin in improved insulin sensitivity with rosiglitazone treatment in HIV disease.

    PubMed

    Qurashi, Saima; Mynarcik, Dennis C; McNurlan, Margaret A; Ahn, Hongshik; Ferris, Robert; Gelato, Marie C

    2008-09-01

    The present study was designed to investigate the relationship of isoforms of adiponectin to insulin sensitivity in subjects with HIV-associated insulin resistance in response to treatment with the thiazolidinedione, rosiglitazone. The two isoforms of adiponectin, HMW (high-molecular-mass) and LMW (low-molecular-mass), were separated by sucrose-gradient-density centrifugation. The amount of adiponectin in gradient fractions was determined by ELISA. Peripheral insulin sensitivity (Rd) was determined with hyperinsulinaemic-euglycaemic clamp, whereas hepatic sensitivity [HOMA (Homoeostasis Model Assessment) %S] was based on basal glucose and insulin values. Treatment with rosiglitazone for 3 months resulted in a significant improvement in the index of hepatic insulin sensitivity (86.4+/-15% compared with 139+/-23; P=0.007) as well as peripheral insulin sensitivity (4.04+/-0.23 compared with 6.17+/-0.66 mg of glucose/kg of lean body mass per min; P<0.001). Improvement in HOMA was associated with increased levels of HMW adiponectin (r=0.541, P=0.045), but not LMW adiponectin. The present study suggests that the HMW isoform of adiponectin is important in the regulation of rosiglitazone-mediated improvement in insulin sensitivity in individuals with HIV-associated insulin resistance, particularly in the liver. PMID:18254722

  16. Arg287Gln VARIANT OF EPHX2 AND EPOXYEICOSATRIENOIC ACIDS ARE ASSOCIATED WITH INSULIN SENSITIVITY IN HUMANS

    PubMed Central

    Ramirez, Claudia E.; Shuey, Megan M.; Milne, Ginger L.; Gilbert, Kimberly; Hui, Nian; Yu, Chang; Luther, James M.; Brown, Nancy J.

    2014-01-01

    Epoxyeicosatrienoic acids (EETs) protect against the development of insulin resistance in rodents. EETs are hydrolyzed to less biologically active diols by soluble epoxide hydrolase (encoded for by EPHX2). Functional variants of EPHX2 encode for enzymes with increased (Lys55Arg) or decreased (Arg287Gln) hydrolase activity. This study tested the hypothesis that variants of EPHX2 are associated with insulin sensitivity or secretion in humans. Subjects participating in metabolic phenotyping studies were genotyped. Eighty-five subjects underwent hyperglycemic clamps. There was no relationship between the Lys55Arg genotype and insulin sensitivity or secretion. In contrast, the EPHX2 287Gln variant was associated with higher insulin sensitivity index (p=0.019 controlling for body mass index and metabolic syndrome). Also, there was an interactive effect of EPHX2 Arg287Gln genotype and body mass index on insulin sensitivity index (p=0.029). There was no relationship between EPHX2 Arg287Gln genotype and acute or late-phase glucose-stimulated insulin secretion, but disposition index was higher in 287Gln carriers compared with Arg/Arg (p=0.022). Plasma EETs correlated with insulin sensitivity index (r=0.64, p=0.015 for total EETs) and were decreased in the metabolic syndrome. A genetic variant that results in decreased soluble epoxide hydrolase activity is associated with increased insulin sensitivity, as are higher EETs. PMID:25173047

  17. A Functional Variant of the Dimethylarginine Dimethylaminohydrolase-2 Gene Is Associated with Insulin Sensitivity

    PubMed Central

    Andreozzi, Francesco; Presta, Ivan; Mannino, Gaia Chiara; Scarpelli, Daniela; Di Silvestre, Sara; Di Pietro, Natalia; Succurro, Elena; Sciacqua, Angela; Pandolfi, Assunta; Consoli, Agostino; Hribal, Marta Letizia; Perticone, Francesco; Sesti, Giorgio

    2012-01-01

    Background Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of endothelial nitric oxide synthase, which was associated with insulin resistance. Dimethylarginine dimethylaminohydrolase (DDAH) is the major determinant of plasma ADMA. Examining data from the DIAGRAM+ (Diabetes Genetics Replication And Meta-analysis), we identified a variant (rs9267551) in the DDAH2 gene nominally associated with type 2 diabetes (P = 3×10−5). Methodology/Principal Findings initially, we assessed the functional impact of rs9267551 in human endothelial cells (HUVECs), observing that the G allele had a lower transcriptional activity resulting in reduced expression of DDAH2 and decreased NO production in primary HUVECs naturally carrying it. We then proceeded to investigate whether this variant is associated with insulin sensitivity in vivo. To this end, two cohorts of nondiabetic subjects of European ancestry were studied. In sample 1 (n = 958) insulin sensitivity was determined by the insulin sensitivity index (ISI), while in sample 2 (n = 527) it was measured with a euglycemic-hyperinsulinemic clamp. In sample 1, carriers of the GG genotype had lower ISI than carriers of the C allele (67±33 vs.79±44; P = 0.003 after adjusting for age, gender, and BMI). ADMA levels were higher in subjects carrying the GG genotype than in carriers of the C allele (0.68±0.14 vs. 0.57±0.14 µmol/l; P = 0.04). In sample 2, glucose disposal was lower in GG carriers as compared with C carriers (9.3±4.1 vs. 11.0±4.2 mg×Kg−1 free fat mass×min−1; P = 0.009). Conclusions/Significance A functional polymorphism of the DDAH2 gene may confer increased risk for type 2 diabetes by affecting insulin sensitivity throughout increased ADMA levels. PMID:22558392

  18. Diet and exercise interventions reduce intrahepatic fat content and improve insulin sensitivity in obese older adults.

    PubMed

    Shah, Krupa; Stufflebam, Abby; Hilton, Tiffany N; Sinacore, David R; Klein, Samuel; Villareal, Dennis T

    2009-12-01

    Both obesity and aging increase intrahepatic fat (IHF) content, which leads to nonalcoholic fatty liver disease (NAFLD) and metabolic abnormalities such as insulin resistance. We evaluated the effects of diet and diet in conjunction with exercise on IHF content and associated metabolic abnormalities in obese older adults. Eighteen obese (BMI >or=30 kg/m(2)) older (>or=65 years old) adults completed a 6-month clinical trial. Participants were randomized to diet (D group; n = 9) or diet + exercise (D+E group; n = 9). Primary outcome was IHF quantified by magnetic resonance spectroscopy (MRS). Secondary outcomes included insulin sensitivity (assessed by oral glucose tolerance), body composition (assessed by dual-energy X-ray absorptiometry), physical function (VO(2 peak) and strength), glucose, lipids, and blood pressure (BP). Body weight (D: -9 +/- 1%, D+E: -10 +/- 2%, both P < 0.05) and fat mass (D: -13 +/- 3%, D+E -16 +/- 3%, both P < 0.05) decreased in both groups but there was no difference between groups. IHF decreased to a similar extent in both groups (D: -46 +/- 11%, D+E: -45 +/- 8%, both P < 0.05), which was accompanied by comparable improvements in insulin sensitivity (D: 66 +/- 25%, D+E: 68 +/- 28%, both P < 0.05). The relative decreases in IHF correlated directly with relative increases in insulin sensitivity index (ISI) (r = -0.52; P < 0.05). Improvements in VO(2 peak), strength, plasma triglyceride (TG), and low-density lipoprotein-cholesterol concentration, and diastolic BP occurred in the D+E group (all P < 0.05) but not in the D group. Diet with or without exercise results in significant decreases in IHF content accompanied by considerable improvements in insulin sensitivity in obese older adults. The addition of exercise to diet therapy improves physical function and other obesity- and aging-related metabolic abnormalities. PMID:19390517

  19. Out of the blue: the spectral sensitivity of hummingbird hawkmoths.

    PubMed

    Telles, Francismeire Jane; Lind, Olle; Henze, Miriam Judith; Rodríguez-Gironés, Miguel Angel; Goyret, Joaquin; Kelber, Almut

    2014-06-01

    The European hummingbird hawkmoth Macroglossum stellatarum is a diurnal nectar forager like the honeybee, and we expect similarities in their sensory ecology. Using behavioural tests and electroretinograms (ERGs), we studied the spectral sensitivity of M. stellatarum. By measuring ERGs in the dark-adapted eye and after adaptation to green light, we determined that M. stellatarum has ultraviolet (UV), blue and green receptors maximally sensitive at 349, 440 and 521 nm, and confirmed that green receptors are most frequent in the retina. To determine the behavioural spectral sensitivity (action spectrum) of foraging moths, we trained animals to associate a disk illuminated with spectral light, with a food reward, and a dark disk with no reward. While the spectral positions of sensitivity maxima found in behavioural tests agree with model predictions based on the ERG data, the sensitivity to blue light was 30 times higher than expected. This is different from the honeybee but similar to earlier findings in the crepuscular hawkmoth Manduca sexta. It may indicate that the action spectrum of foraging hawkmoths does not represent their general sensory capacity. We suggest that the elevated sensitivity to blue light is related to the innate preference of hawkmoths for blue flowers. PMID:24553915

  20. Sensitive detection of human insulin using a designed combined pore approach.

    PubMed

    Lei, Chang; Noonan, Owen; Jambhrunkar, Siddharth; Qian, Kun; Xu, Chun; Zhang, Jun; Nouwens, Amanda; Yu, Chengzhong

    2014-06-25

    A unique combined pore approach to the sensitive detection of human insulin is developed. Through a systematic study to understand the impact of pore size and surface chemistry of nanoporous materials on their enrichment and purification performance, the advantages of selected porous materials are integrated to enhance detection sensitivity in a unified two-step process. In the first purification step, a rationally designed large pore material (ca. 100 nm in diameter) is chosen to repel the interferences from nontarget molecules. In the second enrichment step, a hydrophobically modified mesoporous material with a pore size of 5 nm is selected to enrich insulin molecules. A low detection limit of 0.05 ng mL(-1) in artificial urine is achieved by this advanced approach, similar to most antibody-based analysis protocols. This designer approach is efficient and low cost, and thus has great potential in the sensitive detection of biomolecules in complex biological systems. PMID:24599559

  1. Steatosis and insulin resistance in hepatitis C: a way out for the virus?

    PubMed

    Del Campo, José A; Romero-Gómez, Manuel

    2009-10-28

    The hepatitis C virus (HCV) induces lipid accumulation in vitro and in vivo. The pathogenesis of steatosis is due to both viral and host factors. Viral steatosis is mostly reported in patients with genotype 3a, whereas metabolic steatosis is often associated with genotype 1 and metabolic syndrome. Several molecular mechanisms responsible for steatosis have been associated with the HCV core protein, which is able to induce gene expression and activity of sterol regulatory element binding protein 1 (SREBP1) and peroxisome proliferator-activated receptor gamma (PPARgamma), increasing the transcription of genes involved in hepatic fatty acid synthesis. Steatosis has been also implicated in viral replication. In infected cells, HCV core protein is targeted to lipid droplets which serve as intracellular storage organelles. These studies have shown that lipid droplets are essential for virus assembly. Thus, HCV promotes steatosis as an efficient mechanism for stable viral replication. Chronic HCV infection can also induce insulin resistance. In patients with HCV, insulin resistance is more strongly associated with viral load than visceral obesity. HCV seems to lead to insulin resistance through interference of intracellular insulin signalling by HCV proteins, mainly, the serine phosphorylation of insulin receptor-1 (IRS-1) and impairment of the downstream Akt signalling pathway. The HCV core protein interferes with in vitro insulin signalling by genotype-specific mechanisms, where the role of suppressor of cytokine signal 7 (SOCS-7) in genotype 3a and mammalian target of rapamycin (mTOR) in genotype 1 in IRS-1 downregulation play key roles. Steatosis and insulin resistance have been associated with fibrosis progression and a reduced rate of sustained response to peginterferon plus ribavirin. PMID:19859993

  2. Effects of ovariectomy and intrinsic aerobic capacity on tissue-specific insulin sensitivity.

    PubMed

    Park, Young-Min; Rector, R Scott; Thyfault, John P; Zidon, Terese M; Padilla, Jaume; Welly, Rebecca J; Meers, Grace M; Morris, Matthew E; Britton, Steven L; Koch, Lauren G; Booth, Frank W; Kanaley, Jill A; Vieira-Potter, Victoria J

    2016-02-01

    High-capacity running (HCR) rats are protected against the early (i.e., ∼ 11 wk postsurgery) development of ovariectomy (OVX)-induced insulin resistance (IR) compared with low-capacity running (LCR) rats. The purpose of this study was to utilize the hyperinsulinemic euglycemic clamp to determine whether 1) HCR rats remain protected from OVX-induced IR when the time following OVX is extended to 27 wk and 2) tissue-specific glucose uptake differences are responsible for the protection in HCR rats under sedentary conditions. Female HCR and LCR rats (n = 40; aged ∼ 22 wk) randomly received either OVX or sham (SHM) surgeries and then underwent the clamp 27 wk following surgeries. [3-(3)H]glucose was used to determine glucose clearance, whereas 2-[(14)C]deoxyglucose (2-DG) was used to assess glucose uptake in skeletal muscle, brown adipose tissue (BAT), subcutaneous white adipose tissue (WAT), and visceral WAT. OVX decreased the glucose infusion rate and glucose clearance in both lines, but HCR had better insulin sensitivity than LCR (P < 0.05). In both lines, OVX significantly reduced glucose uptake in soleus and gastrocnemius muscles; however, HCR showed ∼ 40% greater gastrocnemius glucose uptake compared with LCR (P < 0.05). HCR also exhibited greater glucose uptake in BAT and visceral WAT compared with LCR (P < 0.05), yet these tissues were not affected by OVX in either line. In conclusion, OVX impairs insulin sensitivity in both HCR and LCR rats, likely driven by impairments in insulin-mediated skeletal muscle glucose uptake. HCR rats have greater skeletal muscle, BAT, and WAT insulin-mediated glucose uptake, which may aid in protection against OVX-associated insulin resistance. PMID:26646101

  3. Changes of insulin sensitivity and secretion after bariatric/metabolic surgery.

    PubMed

    Mingrone, Geltrude; Cummings, David E

    2016-07-01

    Type 2 diabetes (T2D) is classically characterized by failure of pancreatic β-cell function and insulin secretion to compensate for a prevailing level of insulin resistance, typically associated with visceral obesity. Although this is usually a chronic, progressive disease in which delay of end-organ complications is the primary therapeutic goal for medical and behavioral approaches, several types of bariatric surgery, especially those that include intestinal bypass components, exert powerful antidiabetes effects to yield remission of T2D in most cases. It has become increasingly clear that in addition to the known benefits of acute caloric restriction and chronic weight loss to ameliorate T2D, bariatric/metabolic operations also engage a variety of weight-independent mechanisms to improve glucose homeostasis, enhancing insulin sensitivity and secretion to varying degrees depending on the specific operation. In this paper, we review the effects of Roux-en-Y gastric bypass, biliopancreatic diversion, and vertical sleeve gastrectomy on the primary determinants of glucose homeostasis: insulin sensitivity, insulin secretion, and, to the lesser extent that it is known, insulin-independent glucose disposal. A full understanding of these effects should help optimize surgical and device-based designs to provide maximal antidiabetes impact, and it holds the promise to identify targets for possible novel diabetes pharmacotherapeutics. These insights also contribute to the conceptual rationale for use of bariatric operations as "metabolic surgery," employed primarily to treat T2D, including among patients not obese enough to qualify for surgery based on traditional criteria related to high body mass index. PMID:27568471

  4. Bezafibrate Improves Insulin Sensitivity and Metabolic Flexibility in STZ-Induced Diabetic Mice.

    PubMed

    Franko, Andras; Huypens, Peter; Neschen, Susanne; Irmler, Martin; Rozman, Jan; Rathkolb, Birgit; Neff, Frauke; Prehn, Cornelia; Dubois, Guillaume; Baumann, Martina; Massinger, Rebecca; Gradinger, Daniel; Przemeck, Gerhard K H; Repp, Birgit; Aichler, Michaela; Feuchtinger, Annette; Schommers, Philipp; Stöhr, Oliver; Sanchez-Lasheras, Carmen; Adamski, Jerzy; Peter, Andreas; Prokisch, Holger; Beckers, Johannes; Walch, Axel K; Fuchs, Helmut; Wolf, Eckhard; Schubert, Markus; Wiesner, Rudolf J; Hrabě de Angelis, Martin

    2016-09-01

    Bezafibrate (BEZ), a pan activator of peroxisome proliferator-activated receptors (PPARs), has been generally used to treat hyperlipidemia for decades. Clinical trials with type 2 diabetes patients indicated that BEZ also has beneficial effects on glucose metabolism, although the underlying mechanisms of these effects remain elusive. Even less is known about a potential role for BEZ in treating type 1 diabetes. Here we show that BEZ markedly improves hyperglycemia and glucose and insulin tolerance in mice with streptozotocin (STZ)-induced diabetes, an insulin-deficient mouse model of type 1 diabetes. BEZ treatment of STZ mice significantly suppressed the hepatic expression of genes that are annotated in inflammatory processes, whereas the expression of PPAR and insulin target gene transcripts was increased. Furthermore, BEZ-treated mice also exhibited improved metabolic flexibility as well as an enhanced mitochondrial mass and function in the liver. Finally, we show that the number of pancreatic islets and the area of insulin-positive cells tended to be higher in BEZ-treated mice. Our data suggest that BEZ may improve impaired glucose metabolism by augmenting hepatic mitochondrial performance, suppressing hepatic inflammatory pathways, and improving insulin sensitivity and metabolic flexibility. Thus, BEZ treatment might also be useful for patients with impaired glucose tolerance or diabetes. PMID:27284107

  5. Fibroblast Growth Factor 21 Improves Insulin Sensitivity and Synergizes with Insulin in Human Adipose Stem Cell-Derived (hASC) Adipocytes

    PubMed Central

    Lee, Darwin V.; Li, Dongmei; Yan, Qingyun; Zhu, Yimin; Goodwin, Bryan; Calle, Roberto; Brenner, Martin B.; Talukdar, Saswata

    2014-01-01

    Fibroblast growth factor 21 (FGF21) has evolved as a major metabolic regulator, the pharmacological administration of which causes weight loss, insulin sensitivity and glucose control in rodents and humans. To understand the molecular mechanisms by which FGF21 exerts its metabolic effects, we developed a human in vitro model of adipocytes to examine crosstalk between FGF21 and insulin signaling. Human adipose stem cell-derived (hASC) adipocytes were acutely treated with FGF21 alone, insulin alone, or in combination. Insulin signaling under these conditions was assessed by measuring tyrosine phosphorylation of insulin receptor (InsR), insulin receptor substrate-1 (IRS-1), and serine 473 phosphorylation of Akt, followed by a functional assay using 14C-2-deoxyglucose [14C]-2DG to measure glucose uptake in these cells. FGF21 alone caused a modest increase of glucose uptake, but treatment with FGF21 in combination with insulin had a synergistic effect on glucose uptake in these cells. The presence of FGF21 also effectively lowered the insulin concentration required to achieve the same level of glucose uptake compared to the absence of FGF21 by 10-fold. This acute effect of FGF21 on insulin signaling was not due to IR, IGF-1R, or IRS-1 activation. Moreover, we observed a substantial increase in basal S473-Akt phosphorylation by FGF21 alone, in contrast to the minimal shift in basal glucose uptake. Taken together, our data demonstrate that acute co-treatment of hASC-adipocytes with FGF21 and insulin can result in a synergistic improvement in glucose uptake. These effects were shown to occur at or downstream of Akt, or separate from the canonical insulin signaling pathway. PMID:25365322

  6. The effects of acute exercise on serum adiponectin and resistin levels and their relation to insulin sensitivity in overweight males.

    PubMed

    Jamurtas, A Z; Theocharis, V; Koukoulis, G; Stakias, N; Fatouros, I G; Kouretas, D; Koutedakis, Y

    2006-05-01

    The purpose of this study was to investigate the effects of a submaximal aerobic exercise bout on adiponectin and resistin levels as well as insulin sensitivity, until 48 h post-exercise in healthy overweight males. Nine subjects performed an exercise bout at an intensity corresponding to approximately 65% of their maximal oxygen consumption for 45 min. Adiponectin, resistin, cortisol, insulin, glucose and insulin sensitivity were measured prior to exercise, immediately after exercise as well as 24 and 48 h after exercise. Data were analyzed using repeated measures ANOVA while Pearson's correlations were performed to identify possible relationship among the assessed variables. There were no significant differences for adiponectin (microg ml(-1)) [pre, 3.61(0.73); post, 3.15(0.43); 24 h, 3.15(0.81); 48 h, 3.37(0.76)] or resistin (ng ml(-1)) [pre, 0.19(0.03); post, 0.13(0.03); 24 h, 0.23(0.04); 48 h, 0.23(0.03)] across time. Insulin sensitivity increased and insulin concentration decreased significantly only immediately after exercise. Furthermore, no significant correlations were observed among the variables assessed except for the expected between insulin level and insulin sensitivity. These results indicate that a submaximal aerobic workout does not result in significant changes in adiponectin and resistin up to 48 h post-exercise. Furthermore, it appears that adiponectin or resistin is not associated with insulin sensitivity. PMID:16525810

  7. Blood pressure is reduced and insulin sensitivity increased in glucose-intolerant, hypertensive subjects after 15 days of consuming high-polyphenol dark chocolate.

    PubMed

    Grassi, Davide; Desideri, Giovambattista; Necozione, Stefano; Lippi, Cristina; Casale, Raffaele; Properzi, Giuliana; Blumberg, Jeffrey B; Ferri, Claudio

    2008-09-01

    Flavanols from chocolate appear to increase nitric oxide bioavailability, protect vascular endothelium, and decrease cardiovascular disease (CVD) risk factors. We sought to test the effect of flavanol-rich dark chocolate (FRDC) on endothelial function, insulin sensitivity, beta-cell function, and blood pressure (BP) in hypertensive patients with impaired glucose tolerance (IGT). After a run-in phase, 19 hypertensives with IGT (11 males, 8 females; 44.8 +/- 8.0 y) were randomized to receive isocalorically either FRDC or flavanol-free white chocolate (FFWC) at 100 g/d for 15 d. After a wash-out period, patients were switched to the other treatment. Clinical and 24-h ambulatory BP was determined by sphygmometry and oscillometry, respectively, flow-mediated dilation (FMD), oral glucose tolerance test, serum cholesterol and C-reactive protein, and plasma homocysteine were evaluated after each treatment phase. FRDC but not FFWC ingestion decreased insulin resistance (homeostasis model assessment of insulin resistance; P < 0.0001) and increased insulin sensitivity (quantitative insulin sensitivity check index, insulin sensitivity index (ISI), ISI(0); P < 0.05) and beta-cell function (corrected insulin response CIR(120); P = 0.035). Systolic (S) and diastolic (D) BP decreased (P < 0.0001) after FRDC (SBP, -3.82 +/- 2.40 mm Hg; DBP, -3.92 +/- 1.98 mm Hg; 24-h SBP, -4.52 +/- 3.94 mm Hg; 24-h DBP, -4.17 +/- 3.29 mm Hg) but not after FFWC. Further, FRDC increased FMD (P < 0.0001) and decreased total cholesterol (-6.5%; P < 0.0001), and LDL cholesterol (-7.5%; P < 0.0001). Changes in insulin sensitivity (Delta ISI - Delta FMD: r = 0.510, P = 0.001; Delta QUICKI - Delta FMD: r = 0.502, P = 0.001) and beta-cell function (Delta CIR(120) - Delta FMD: r = 0.400, P = 0.012) were directly correlated with increases in FMD and inversely correlated with decreases in BP (Delta ISI - Delta 24-h SBP: r = -0.368, P = 0.022; Delta ISI - Delta 24-h DBP r = -0.384, P = 0.017). Thus, FRDC

  8. The Effect of Regular Exercise on Insulin Sensitivity in Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis.

    PubMed

    Way, Kimberley L; Hackett, Daniel A; Baker, Michael K; Johnson, Nathan A

    2016-08-01

    The purpose of this study was to examine the effect of regular exercise training on insulin sensitivity in adults with type 2 diabetes mellitus (T2DM) using the pooled data available from randomised controlled trials. In addition, we sought to determine whether short-term periods of physical inactivity diminish the exercise-induced improvement in insulin sensitivity. Eligible trials included exercise interventions that involved ≥3 exercise sessions, and reported a dynamic measurement of insulin sensitivity. There was a significant pooled effect size (ES) for the effect of exercise on insulin sensitivity (ES, -0.588; 95% confidence interval [CI], -0.816 to -0.359; P<0.001). Of the 14 studies included for meta-analyses, nine studies reported the time of data collection from the last exercise bout. There was a significant improvement in insulin sensitivity in favour of exercise versus control between 48 and 72 hours after exercise (ES, -0.702; 95% CI, -1.392 to -0.012; P=0.046); and this persisted when insulin sensitivity was measured more than 72 hours after the last exercise session (ES, -0.890; 95% CI, -1.675 to -0.105; P=0.026). Regular exercise has a significant benefit on insulin sensitivity in adults with T2DM and this may persist beyond 72 hours after the last exercise session. PMID:27535644

  9. The Effect of Regular Exercise on Insulin Sensitivity in Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis

    PubMed Central

    Hackett, Daniel A.; Baker, Michael K.

    2016-01-01

    The purpose of this study was to examine the effect of regular exercise training on insulin sensitivity in adults with type 2 diabetes mellitus (T2DM) using the pooled data available from randomised controlled trials. In addition, we sought to determine whether short-term periods of physical inactivity diminish the exercise-induced improvement in insulin sensitivity. Eligible trials included exercise interventions that involved ≥3 exercise sessions, and reported a dynamic measurement of insulin sensitivity. There was a significant pooled effect size (ES) for the effect of exercise on insulin sensitivity (ES, –0.588; 95% confidence interval [CI], –0.816 to –0.359; P<0.001). Of the 14 studies included for meta-analyses, nine studies reported the time of data collection from the last exercise bout. There was a significant improvement in insulin sensitivity in favour of exercise versus control between 48 and 72 hours after exercise (ES, –0.702; 95% CI, –1.392 to –0.012; P=0.046); and this persisted when insulin sensitivity was measured more than 72 hours after the last exercise session (ES, –0.890; 95% CI, –1.675 to –0.105; P=0.026). Regular exercise has a significant benefit on insulin sensitivity in adults with T2DM and this may persist beyond 72 hours after the last exercise session. PMID:27535644

  10. NEU3 sialidase as a marker of insulin sensitivity: Regulation by fatty acids.

    PubMed

    Lipina, Christopher; Nardi, Francesca; Grace, Helen; Hundal, Harinder S

    2015-09-01

    The plasma membrane-associated enzyme NEU3 sialidase functions to cleave sialic acid residues from the ganglioside GM3 thereby promoting its degradation, and has been implicated in the modulation of insulin action. Herein, we report for the first time that impaired insulin sensitivity in skeletal muscle and liver of obese Zucker fatty rats and aged C57BL/6 mice coincides with reduced NEU3 protein abundance. In addition, high fat feeding was found to significantly reduce NEU3 protein in white adipose tissue of rats. Notably, we also demonstrate the ability of the fatty acids palmitate and oleate to repress and induce NEU3 protein in L6 myotubes, concomitant with their insulin desensitising and enhancing effects, respectively. Moreover, we show that the palmitate-driven loss in NEU3 protein is mediated, at least in part, by intracellular ceramide synthesis but does not involve the proteasomal pathway. Strikingly, we further reveal that protein kinase B (PKB/Akt) acts as a key positive modulator of NEU3 protein abundance. Together, our findings implicate NEU3 as a potential biomarker of insulin sensitivity, and provide novel mechanistic insight into the regulation of NEU3 expression. PMID:26022181

  11. Alterations of Mitochondrial Function and Insulin Sensitivity in Human Obesity and Diabetes Mellitus.

    PubMed

    Koliaki, Chrysi; Roden, Michael

    2016-07-17

    Mitochondrial function refers to a broad spectrum of features such as resting mitochondrial activity, (sub)maximal oxidative phosphorylation capacity (OXPHOS), and mitochondrial dynamics, turnover, and plasticity. The interaction between mitochondria and insulin sensitivity is bidirectional and varies depending on tissue, experimental model, methodological approach, and features of mitochondrial function tested. In human skeletal muscle, mitochondrial abnormalities may be inherited (e.g., lower mitochondrial content) or acquired (e.g., impaired OXPHOS capacity and plasticity). Abnormalities ultimately lead to lower mitochondrial functionality due to or resulting in insulin resistance and type 2 diabetes mellitus. Similar mechanisms can also operate in adipose tissue and heart muscle. In contrast, mitochondrial oxidative capacity is transiently upregulated in the liver of obese insulin-resistant humans with or without fatty liver, giving rise to oxidative stress and declines in advanced fatty liver disease. These data suggest a highly tissue-specific interaction between insulin sensitivity and oxidative metabolism during the course of metabolic diseases in humans. PMID:27146012

  12. Solvent mediated microstructures and release behavior of insulin from pH-sensitive nanoparticles.

    PubMed

    Wu, Zhi Min; Guo, Xin Dong; Zhang, Li Juan; Jiang, Wei; Ling, Li; Qian, Yu; Chen, Yun

    2012-06-01

    The insulin loaded nanoparticles composed of poly (lactic-co-glycolic acid) (PLGA) and hydroxypropyl methylcellulose phthalate (HP55) were prepared via the emulsions solvent diffusion method with two different solvents, namely, DMSO and acetone/water. The microstructures of the nanoparticles were studied by the solubility parameters theory, DSC, FTIR, and the nitrogen adsorption technique. Phase-separated PLGA domains were observed from the nanoparticles prepared with both types of solvents. Mesopores were observed from the nanoparticles prepared with DMSO as the solvent and almost did not exist with acetone/water. An in vitro drug release study showed that the pH-sensitivity of nanoparticles was not only attributed to the pH-dependent dissolubility of HP55 but also to the internal microstructure. The formation of mesopores accelerated the release of insulin, leading to no obvious pH-sensitivity of the nanoparticles prepared with DMSO. However, for the nanoparticles prepared with acetone/water, the release of insulin was pH-dependent. The results demonstrated that solvents played an important role in affecting the microstructures of nanoparticles, which influenced markedly the insulin release behavior. PMID:22356870

  13. Beneficial Impact of Sleep Extension on Fasting Insulin Sensitivity in Adults with Habitual Sleep Restriction

    PubMed Central

    Leproult, Rachel; Deliens, Gaétane; Gilson, Médhi; Peigneux, Philippe

    2015-01-01

    Study Objectives: A link between sleep loss and increased risk for the development of diabetes is now well recognized. The current study investigates whether sleep extension under real-life conditions is a feasible intervention with a beneficial impact on glucose metabolism in healthy adults who are chronically sleep restricted. Design: Intervention study. Participants: Sixteen healthy non-obese volunteers (25 [23, 27.8] years old, 3 men). Intervention: Two weeks of habitual time in bed followed by 6 weeks during which participants were instructed to increase their time in bed by one hour per day. Measurements and Results: Continuous actigraphy monitoring and daily sleep logs during the entire study. Glucose and insulin were assayed on a single morning blood sample at the end of habitual time in bed and at the end of sleep extension. Home polysomnography was performed during one weekday of habitual time in bed and after 40 days of sleep extension. Sleep time during weekdays increased (mean actigraphic data: +44 ± 34 minutes, P < 0.0001; polysomnographic data: +49 ± 68 minutes, P = 0.014), without any significant change during weekends. Changes from habitual time in bed to the end of the intervention in total sleep time correlated with changes in glucose (r = +0.53, P = 0.041) and insulin levels (r = −0.60, P = 0.025), as well as with indices of insulin sensitivity (r = +0.76, P = 0.002). Conclusions: In healthy adults who are chronically sleep restricted, a simple low cost intervention such as sleep extension is feasible and is associated with improvements in fasting insulin sensitivity. Citation: Leproult R, Deliens G, Gilson M, Peigneux P. Beneficial impact of sleep extension on fasting insulin sensitivity in adults with habitual sleep restriction. SLEEP 2015;38(5):707–715. PMID:25348128

  14. Shorter Sleep Duration is Associated with Decreased Insulin Sensitivity in Healthy White Men

    PubMed Central

    Wong, Patricia M.; Manuck, Stephen B.; DiNardo, Monica M.; Korytkowski, Mary; Muldoon, Matthew F.

    2015-01-01

    Study Objective: Short sleep has been linked to increased risk for type 2 diabetes and incident cardiovascular disease and acute sleep restriction impairs insulin-mediated glucose disposal. Here, we examined whether indices of glucose metabolism vary with naturally occurring differences in sleep duration. Design and Measures: Subjects were midlife, nondiabetic community volunteers (N = 224; mean age 44.5 ± 6.6 y [range: 30–54]; 52% female; 89% white). Laboratory measures of insulin sensitivity (Si) and acute secretion (AIRg), glucose effectiveness (Sg), and disposition index (Di) were obtained from a 180-min, intravenous glucose tolerance test. Results: Shorter self-reported sleep duration (in hours) was associated with lower Si (P = 0.043), although an interaction of sleep duration with participant race (β = −0.81, P = 0.002) showed this association significant only in whites. Moreover, sex-stratified analyses revealed that shorter sleep duration predicted lower Si in white men (β = 0.29, P = 0.003) but not in white women (P = 0.22). Findings were similar for AIRg. The relationship between sleep duration and AIRg was moderated by race as well as sex, such that shorter sleep duration associated with greater insulin release only in white men (β = −0.28, P = 0.004). Sleep duration was unrelated to Sg and Di (P's > 0.05). Conclusions: Our findings suggest that shorter sleep duration may impair insulin sensitivity and beta-cell function in nondiabetic white men, possibly contributing to later type 2 diabetes and cardiovascular disease. Citation: Wong PM, Manuck SB, DiNardo MM, Korytkowski M, Muldoon MF. Shorter sleep duration is associated with decreased insulin sensitivity in healthy white men. SLEEP 2015;38(2):223–231. PMID:25325485

  15. Activation of G proteins by GIV-GEF is a pivot point for insulin resistance and sensitivity

    PubMed Central

    Ma, Gary S.; Lopez-Sanchez, Inmaculada; Aznar, Nicolas; Kalogriopoulos, Nicholas; Pedram, Shabnam; Midde, Krishna; Ciaraldi, Theodore P.; Henry, Robert R.; Ghosh, Pradipta

    2015-01-01

    Insulin resistance (IR) is a metabolic disorder characterized by impaired insulin signaling and cellular glucose uptake. The current paradigm for insulin signaling centers upon the insulin receptor (InsR) and its substrate IRS1; the latter is believed to be the sole conduit for postreceptor signaling. Here we challenge that paradigm and show that GIV/Girdin, a guanidine exchange factor (GEF) for the trimeric G protein Gαi, is another major hierarchical conduit for the metabolic insulin response. By virtue of its ability to directly bind InsR, IRS1, and phosphoinositide 3-kinase, GIV serves as a key hub in the immediate postreceptor level, which coordinately enhances the metabolic insulin response and glucose uptake in myotubes via its GEF function. Site-directed mutagenesis or phosphoinhibition of GIV-GEF by the fatty acid/protein kinase C-theta pathway triggers IR. Insulin sensitizers reverse phosphoinhibition of GIV and reinstate insulin sensitivity. We also provide evidence for such reversible regulation of GIV-GEF in skeletal muscles from patients with IR. Thus GIV is an essential upstream component that couples InsR to G-protein signaling to enhance the metabolic insulin response, and impairment of such coupling triggers IR. We also provide evidence that GIV-GEF serves as therapeutic target for exogenous manipulation of physiological insulin response and reversal of IR in skeletal muscles. PMID:26378251

  16. Activation of G proteins by GIV-GEF is a pivot point for insulin resistance and sensitivity.

    PubMed

    Ma, Gary S; Lopez-Sanchez, Inmaculada; Aznar, Nicolas; Kalogriopoulos, Nicholas; Pedram, Shabnam; Midde, Krishna; Ciaraldi, Theodore P; Henry, Robert R; Ghosh, Pradipta

    2015-11-15

    Insulin resistance (IR) is a metabolic disorder characterized by impaired insulin signaling and cellular glucose uptake. The current paradigm for insulin signaling centers upon the insulin receptor (InsR) and its substrate IRS1; the latter is believed to be the sole conduit for postreceptor signaling. Here we challenge that paradigm and show that GIV/Girdin, a guanidine exchange factor (GEF) for the trimeric G protein Gαi, is another major hierarchical conduit for the metabolic insulin response. By virtue of its ability to directly bind InsR, IRS1, and phosphoinositide 3-kinase, GIV serves as a key hub in the immediate postreceptor level, which coordinately enhances the metabolic insulin response and glucose uptake in myotubes via its GEF function. Site-directed mutagenesis or phosphoinhibition of GIV-GEF by the fatty acid/protein kinase C-theta pathway triggers IR. Insulin sensitizers reverse phosphoinhibition of GIV and reinstate insulin sensitivity. We also provide evidence for such reversible regulation of GIV-GEF in skeletal muscles from patients with IR. Thus GIV is an essential upstream component that couples InsR to G-protein signaling to enhance the metabolic insulin response, and impairment of such coupling triggers IR. We also provide evidence that GIV-GEF serves as therapeutic target for exogenous manipulation of physiological insulin response and reversal of IR in skeletal muscles. PMID:26378251

  17. Higher omega-3 index is associated with increased insulin sensitivity and more favourable metabolic profile in middle-aged overweight men.

    PubMed

    Albert, Benjamin B; Derraik, José G B; Brennan, Christine M; Biggs, Janene B; Smith, Greg C; Garg, Manohar L; Cameron-Smith, David; Hofman, Paul L; Cutfield, Wayne S

    2014-01-01

    We assessed whether omega-3 index (red blood cell concentrations of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)) was associated with insulin sensitivity and other metabolic outcomes in 47 overweight men aged 46.5 ± 5.1 years. Participants were assessed twice, 16 weeks apart. Insulin sensitivity was assessed by the Matsuda method from an oral glucose tolerance test. Linear associations were examined; stratified analyses were carried out with participants separated according to the omega-3 index: lower tertiles (LOI; n = 31) and highest tertile (HOI; n = 16). Increasing omega-3 index was correlated with higher insulin sensitivity (r = 0.23; p = 0.025), higher disposition index (r = 0.20; p = 0.054), and lower CRP concentrations (r = -0.39; p < 0.0001). Insulin sensitivity was 43% higher in HOI than in LOI men (Matsuda index 6.83 vs 4.78; p = 0.009). Similarly, HOI men had disposition index that was 70% higher (p = 0.013) and fasting insulin concentrations 25% lower (p = 0.038). HOI men displayed lower nocturnal systolic blood pressure (-6.0 mmHg; p = 0.025) and greater systolic blood pressure dip (14.7 vs 10.8%; p = 0.039). Men in the HOI group also had lower concentrations of CRP (41% lower; p = 0.033) and free fatty acids (21% lower, p = 0.024). In conclusion, higher omega-3 index is associated with increased insulin sensitivity and a more favourable metabolic profile in middle-aged overweight men. PMID:25331725

  18. Cardiorespiratory Fitness and Insulin Sensitivity in Overweight or Obese Subjects May Be Linked Through Intrahepatic Lipid Content

    PubMed Central

    Haufe, Sven; Engeli, Stefan; Budziarek, Petra; Utz, Wolfgang; Schulz-Menger, Jeanette; Hermsdorf, Mario; Wiesner, Susanne; Otto, Christoph; Haas, Verena; de Greiff, Armin; Luft, Friedrich C.; Boschmann, Michael; Jordan, Jens

    2010-01-01

    OBJECTIVE Low cardiorespiratory fitness (CRF) predisposes one to cardiovascular disease and type 2 diabetes in part independently of body weight. Given the close relationship between intrahepatic lipid content (IHL) and insulin sensitivity, we hypothesized that the direct relationship between fitness and insulin sensitivity may be explained by IHL. RESEARCH DESIGN AND METHODS We included 138 overweight to obese, otherwise healthy subjects (aged 43.6 ± 8.9 years, BMI 33.8 ± 4 kg/m2). Body composition was estimated by bioimpedance analyses. Abdominal fat distribution, intramyocellular, and IHL were assessed by magnetic resonance spectroscopy and tomography. Incremental exercise testing was performed to estimate an individual's CRF. Insulin sensitivity was determined during an oral glucose tolerance test. RESULTS For all subjects, CRF was related to insulin sensitivity (r = 0.32, P < 0.05), IHL (r = −0.27, P < 0.05), and visceral (r = −0.25, P < 0.05) and total fat mass (r = −0.32, P < 0.05), but not to intramyocellular lipids (r = −0.08, NS). Insulin sensitivity correlated significantly with all fat depots. In multivariate regression analyses, independent predictors of insulin sensitivity were IHL, visceral fat, and fitness (r2 = −0.43, P < 0.01, r2 = −0.34, and r2 = 0.29, P < 0.05, respectively). However, the positive correlation between fitness and insulin sensitivity was abolished after adjustment for IHL (r = 0.16, NS), whereas it remained significant when adjusted for visceral or total body fat. Further, when subjects were grouped into high versus low IHL, insulin sensitivity was higher in those subjects with low IHL, irrespective of fitness levels. CONCLUSIONS Our study suggests that the positive effect of increased CRF on insulin sensitivity in overweight to obese subjects may be mediated indirectly through IHL reduction. PMID:20357364

  19. A single night of partial sleep loss impairs fasting insulin sensitivity but does not affect cephalic phase insulin release in young men.

    PubMed

    Cedernaes, Jonathan; Lampola, Lauri; Axelsson, Emil K; Liethof, Lisanne; Hassanzadeh, Sara; Yeganeh, Adine; Broman, Jan-Erik; Schiöth, Helgi B; Benedict, Christian

    2016-02-01

    The present study sought to investigate whether a single night of partial sleep deprivation (PSD) would alter fasting insulin sensitivity and cephalic phase insulin release (CPIR) in humans. A rise in circulating insulin in response to food-related sensory stimulation may prepare tissues to break down ingested glucose, e.g. by stimulating rate-limiting glycolytic enzymes. In addition, given insulin's anorexigenic properties once it reaches the brain, the CPIR may serve as an early peripheral satiety signal. Against this background, in the present study 16 men participated in two separate sessions: one night of PSD (4.25 h sleep) versus one night of full sleep (8.5 h sleep). In the morning following each sleep condition, subjects' oral cavities were rinsed with a 1-molar sucrose solution for 45 s, preceded and followed by blood sampling for repeated determination of plasma glucose and serum insulin concentrations (-3, +3, +5, +7, +10 and +20 min). Our main result was that PSD, compared with full sleep, was associated with significantly higher peripheral insulin resistance, as indicated by a higher fasting homeostasis model assessment of insulin resistance index (+16%, P = 0.025). In contrast, no CPIR was observed in any of the two sleep conditions. Our findings indicate that a single night of PSD is already sufficient to impair fasting insulin sensitivity in healthy men. In contrast, brief oral cavity rinsing with sucrose solution did not change serum insulin concentrations, suggesting that a blunted CPIR is an unlikely mechanism through which acute sleep loss causes metabolic perturbations during morning hours in humans. PMID:26361380

  20. Artemisia extracts activate PPARγ, promote adipogenesis, and enhance insulin sensitivity in adipose tissue of obese mice

    PubMed Central

    Richard, Allison J.; Burris, Thomas P.; Sanchez-Infantes, David; Wang, Yongjun; Ribnicky, David M.; Stephens, Jacqueline M.

    2014-01-01

    Objective Studies have shown that the inability of adipose tissue to properly expand during the obese state or respond to insulin can lead to metabolic dysfunction. Artemisia is a diverse group of plants that has a history of medicinal use. This study examines the ability of ethanolic extracts of Artemisia scoparia (SCO) and Artemisia santolinifolia (SAN) to modulate adipocyte development in cultured adipocytes and white adipose tissue (WAT) function in vivo using a mouse model of diet-induced obesity. Research Design & Procedures Adipogenesis was assessed using Oil Red O staining and immunoblotting. A nuclear receptor specificity assay was used to examine the specificity of SCO- and SAN-induced PPARγ activation. C57BL/6J mice, fed a high-fat diet, were gavaged with saline, SCO, or SAN for 2 weeks. Whole-body insulin sensitivity was examined using insulin tolerance tests. WAT depots were assessed via immunoblotting for markers of insulin action and adipokine production. Results We established that SCO and SAN were highly specific activators of PPARγ and did not activate other nuclear receptors. After a one-week daily gavage, SCO- and SAN-treated mice had lower insulin-induced glucose disposal rates than control mice. At the end of the 2-week treatment period, SCO- and SAN-treated mice had enhanced insulin-responsive Akt serine-473 phosphorylation and significantly decreased MCP-1 levels in visceral WAT relative to control mice; these differences were depot specific. Moreover, plasma adiponectin levels were increased following SCO treatment. Conclusion Overall, these studies demonstrate that extracts from two Artemisia species can have metabolically favorable effects on adipocytes and WAT. PMID:24985103

  1. Trigonella foenum-graecum water extract improves insulin sensitivity and stimulates PPAR and γ gene expression in high fructose-fed insulin-resistant rats

    PubMed Central

    Mohammadi, Abbas; Gholamhosseinian, Ahmad; Fallah, Hossein

    2016-01-01

    Background: Insulin resistance is the main defect associated with the metabolic syndrome. In obesity, the decreased adiponectin levels and elevation of plasma-free fatty acids are the main factors associated with insulin resistance. In this study, we evaluated the effect of trigonella foenum-graecum (TFG) extract on insulin sensitivity in high fructose-fed insulin-resistant rats. Materials and Methods: Experimental rats were fed with a high fructose diet for eight weeks. After the first six weeks, the animals were treated with trigonella foenum-graecum extract or pioglitazone for two weeks. Serum glucose, triglycerides, cholesterol, and HDL-c were measured. The insulin and adiponectin levels were assayed by the enzyme-linked immunosorbent assay (ELISA), and Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) was calculated. The plasma-free fatty acid profile was obtained by gas chromatography. PPARγ and GLUT4 gene expression were assessed by real-time polymerase chain reaction (PCR) and western blotting. Results: In the trigonella foenum-graecum- extract treated group the following results were obtained: Insulin (49.02 ± 6.93 pmol/L), adiponectin (7.1 ± 0.64 μg/ml), and triglycerides (110.3 ± 16.7 mg/dl), which were significantly different and improved compared to the control group (insulin (137 ± 34 pmol/l), adiponectin (3.9 ± 0.15 μg/ml), glucose (187 ± 15 mg/dl), and triglycerides (217 ± 18 mg/dl). Also the PPARγ gene expression was significantly increased compared to the control group. Conclusion: This study demonstrates the beneficial effects of trigonella foenum-graecum extract on insulin resistance in rats fed on a high-fructose diet. At least three mechanisms are involved, including direct insulin-like effect, increase in adiponectin levels, and PPARγ protein expression. PMID:27110551

  2. No effect of bicarbonate treatment on insulin sensitivity and glucose control in non-diabetic older adults

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Chronic mild metabolic acidosis is common among older adults, and limited evidence suggests that it may contribute to insulin resistance and type 2 diabetes. This analysis was conducted to determine whether bicarbonate supplementation, an alkalinizing treatment, improves insulin sensitivity or gluco...

  3. Adiponectin Gene Variants are Associated with Insulin Sensitivity in Response to Dietary Fat Consumption in Caucasian Men

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Adiponectin (adipoQ) gene variants have been associated with type 2 diabetes mellitus and insulin resistance. Our aim was to examine whether the presence of several polymorphisms at the adipoQ gene locus (211391 G . A, 211377C.G, 45 T.G, and 276 G.T) influences the insulin sensitivity to dietary fat...

  4. Type 2 diabetes in youth: Are there racial differences in beta-cell responsiveness relative to insulin sensitivity?

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Non-diabetic African American (AA) youth have an upregulated insulin secretion relative to insulin sensitivity (IS) compared with their American White (AW) peers. We investigated if similar racial differences exist in youth with T2DM. Fourteen AAs and 14 AWs T2DM adolescents underwent evaluation of ...

  5. Identification of Adipokine Clusters Related to Parameters of Fat Mass, Insulin Sensitivity and Inflammation

    PubMed Central

    Flehmig, Gesine; Scholz, Markus; Klöting, Nora; Fasshauer, Mathias; Tönjes, Anke; Stumvoll, Michael; Youn, Byung-Soo; Blüher, Matthias

    2014-01-01

    In obesity, elevated fat mass and ectopic fat accumulation are associated with changes in adipokine secretion, which may link obesity to inflammation and the development of insulin resistance. However, relationships among individual adipokines and between adipokines and parameters of obesity, glucose metabolism or inflammation are largely unknown. Serum concentrations of 20 adipokines were measured in 141 Caucasian obese men (n = 67) and women (n = 74) with a wide range of body weight, glycemia and insulin sensitivity. Unbiased, distance-based hierarchical cluster analyses were performed to recognize patterns among adipokines and their relationship with parameters of obesity, glucose metabolism, insulin sensitivity and inflammation. We identified two major adipokine clusters related to either (1) body fat mass and inflammation (leptin, ANGPTL3, DLL1, chemerin, Nampt, resistin) or insulin sensitivity/hyperglycemia, and lipid metabolism (vaspin, clusterin, glypican 4, progranulin, ANGPTL6, GPX3, RBP4, DLK1, SFRP5, BMP7, adiponectin, CTRP3 and 5, omentin). In addition, we found distinct adipokine clusters in subgroups of patients with or without type 2 diabetes (T2D). Logistic regression analyses revealed ANGPTL6, DLK1, Nampt and progranulin as strongest adipokine correlates of T2D in obese individuals. The panel of 20 adipokines predicted T2D compared to a combination of HbA1c, HOMA-IR and fasting plasma glucose with lower sensitivity (78% versus 91%) and specificity (76% versus 94%). Therefore, adipokine patterns may currently not be clinically useful for the diagnosis of metabolic diseases. Whether adipokine patterns are relevant for the predictive assessment of intervention outcomes needs to be further investigated. PMID:24968098

  6. Transcriptional control of insulin-sensitive glucose carrier Glut4 expression in adipose tissue cells.

    PubMed

    Penkov, D N; Akopyan, Zh A; Kochegura, T N; Egorov, A D

    2016-03-01

    In search for new targets for obesity treatment, we have studied the effect of several transcription factors on the conversion of murine preadipocytes from the 3T3-L1 cell line into adipocytes. We have found that knockdown of Prep1 gene expression affects adipogenic differentiation and results in significant increase in the insulin-sensitive glucose carrier Glut4 gene expression. PMID:27193720

  7. Chromium picolinate improves insulin sensitivity in obese subjects with polycystic ovary syndrome.

    PubMed

    Lydic, Michael L; McNurlan, Margaret; Bembo, Shirley; Mitchell, Lina; Komaroff, Eugene; Gelato, Marie

    2006-07-01

    Trivalent chromium (1000 microg), as chromium picolinate, given without change in diet or activity level, caused a 38% mean improvement in glucose disposal rate in five obese subjects with polycystic ovary syndrome who were tested with a euglycemic hyperinsulinemic clamp technique. This suggests that chromium picolinate, an over-the-counter dietary product, may be useful as an insulin sensitizer in the treatment of polycystic ovary syndrome. PMID:16730719

  8. Jerusalem artichoke and chungkookjang additively improve insulin secretion and sensitivity in diabetic rats.

    PubMed

    Yang, Hye Jeong; Kwon, Dae Young; Kim, Min Jung; Kang, Suna; Kim, Da Sol; Park, Sunmin

    2012-01-01

    Jerusalem artichoke (Helianthus tuberosus Linne, HTL) and chungkookjang (CKJ; fermented soybeans) both modulate energy and glucose metabolism. However, the mechanism and their additive effects are unknown. We investigated whether the consumption of HTL and CKJ altered insulin sensitivity, insulin secretion capacity and β-cell survival in type 2 diabetic animals. Rats were divided into partially pancreatectomized (Px) diabetic rats, and sham operated non-diabetic control rats and all fed high fat diets. Diabetic rats were sub-divided into an untreated diabetic control group and those fed 5% HTL, 5% CKJ or 5% HTL+5% CKJ for 8 weeks. HTL+CKJ treatment reduced visceral fat without modulating energy intake compared to the diabetic-control. Glucose tolerance was improved in an ascending order of diabetic-control, CKJ, HTL, HTL+CKJ, and normal-control, but by different mechanisms. CKJ and CKJ+HTL, but not HTL, increased first and second phase insulin secretion in comparison to the diabetic-control at hyperglycemic clamp. However, glucose infusion rates (mg/kg bw/min) were increased by and CKJ+HTL (13.5), but not HTL (9.4) or CKJ (9.5) alone, and HTL and CKJ+ HTL decreased hepatic glucose compared to diabetic-control during the hyperinsulinemic euglycemic study and were associated with decreased triglyceride accumulation and increased glycogen storage. The improved hepatic insulin sensitivity by HTL and CKJ+HTL was explained by potentiated insulin signaling (tyrosine phosphorylation of insulin receptor substrate 2→phosphorylation of Akt) and phosphorylation of AMPK→phosphorykation of acetyl Co carboxlase in comparison to diabetic-control and decreased PEPCK expression. Absolute β-cell mass was increased by CKJ (23.4mg) and CKJ+HTL (26.3 mg) by increasing proliferation compared to the diabetic-control (21.26 mg). Although HTL lowered β-cell apoptosis, it did not increase β-cell mass (20.8 mg). In conclusions, HTL and CKJ enhanced glucose tolerance in different

  9. Jerusalem artichoke and chungkookjang additively improve insulin secretion and sensitivity in diabetic rats

    PubMed Central

    2012-01-01

    Jerusalem artichoke (Helianthus tuberosus Linne, HTL) and chungkookjang (CKJ; fermented soybeans) both modulate energy and glucose metabolism. However, the mechanism and their additive effects are unknown. We investigated whether the consumption of HTL and CKJ altered insulin sensitivity, insulin secretion capacity and β-cell survival in type 2 diabetic animals. Rats were divided into partially pancreatectomized (Px) diabetic rats, and sham operated non-diabetic control rats and all fed high fat diets. Diabetic rats were sub-divided into an untreated diabetic control group and those fed 5% HTL, 5% CKJ or 5% HTL+5% CKJ for 8 weeks. HTL+CKJ treatment reduced visceral fat without modulating energy intake compared to the diabetic-control. Glucose tolerance was improved in an ascending order of diabetic-control, CKJ, HTL, HTL+CKJ, and normal-control, but by different mechanisms. CKJ and CKJ+HTL, but not HTL, increased first and second phase insulin secretion in comparison to the diabetic-control at hyperglycemic clamp. However, glucose infusion rates (mg/kg bw/min) were increased by and CKJ+HTL (13.5), but not HTL (9.4) or CKJ (9.5) alone, and HTL and CKJ+ HTL decreased hepatic glucose compared to diabetic-control during the hyperinsulinemic euglycemic study and were associated with decreased triglyceride accumulation and increased glycogen storage. The improved hepatic insulin sensitivity by HTL and CKJ+HTL was explained by potentiated insulin signaling (tyrosine phosphorylation of insulin receptor substrate 2→phosphorylation of Akt) and phosphorylation of AMPK→phosphorykation of acetyl Co carboxlase in comparison to diabetic-control and decreased PEPCK expression. Absolute β-cell mass was increased by CKJ (23.4mg) and CKJ+HTL (26.3 mg) by increasing proliferation compared to the diabetic-control (21.26 mg). Although HTL lowered β-cell apoptosis, it did not increase β-cell mass (20.8 mg). In conclusions, HTL and CKJ enhanced glucose tolerance in different

  10. Laforin and malin knockout mice have normal glucose disposal and insulin sensitivity

    PubMed Central

    DePaoli-Roach, Anna A.; Segvich, Dyann M.; Meyer, Catalina M.; Rahimi, Yasmeen; Worby, Carolyn A.; Gentry, Matthew S.; Roach, Peter J.

    2012-01-01

    Lafora disease is a fatal, progressive myoclonus epilepsy caused in ∼90% of cases by mutations in the EPM2A or EPM2B genes. Characteristic of the disease is the formation of Lafora bodies, insoluble deposits containing abnormal glycogen-like material in many tissues, including neurons, muscle, heart and liver. Because glycogen is important for glucose homeostasis, the aberrant glycogen metabolism in Lafora disease might disturb whole-body glucose handling. Indeed, Vernia et al. [Vernia, S., Heredia, M., Criado, O., Rodriguez de Cordoba, S., Garcia-Roves, P.M., Cansell, C., Denis, R., Luquet, S., Foufelle, F., Ferre, P. et al. (2011) Laforin, a dual-specificity phosphatase involved in Lafora disease, regulates insulin response and whole-body energy balance in mice. Hum. Mol. Genet., 20, 2571–2584] reported that Epm2a−/− mice had enhanced glucose disposal and insulin sensitivity, leading them to suggest that laforin, the Epm2a gene product, is involved in insulin signaling. We analyzed 3-month- and 6–7-month-old Epm2a−/− mice and observed no differences in glucose tolerance tests (GTTs) or insulin tolerance tests (ITTs) compared with wild-type mice of matched genetic background. At 3 months, Epm2b−/− mice also showed no differences in GTTs and ITTs. In the 6–7-month-old Epm2a−/− mice, there was no evidence for increased insulin stimulation of the phosphorylation of Akt, GSK-3 or S6 in skeletal muscle, liver and heart. From metabolic analyses, these animals were normal with regard to food intake, oxygen consumption, energy expenditure and respiratory exchange ratio. By dual-energy X-ray absorptiometry scan, body composition was unaltered at 3 or 6–7 months of age. Echocardiography showed no defects of cardiac function in Epm2a−/− or Epm2b−/− mice. We conclude that laforin and malin have no effect on whole-body glucose metabolism and insulin sensitivity, and that laforin is not involved in insulin signaling. PMID:22186021

  11. Effect of confinement in small space flight size cages on insulin sensitivity of exercise-trained rats

    NASA Technical Reports Server (NTRS)

    Mondon, C. E.; Dolkas, C. B.; Reaven, G. M.

    1983-01-01

    The effect of confinement in small cages (simulating the size to be used in future space Shuttle missions) on insulin sensitivity was studied in rats having an increased insulin sensitivity due to exercise training prior to confinement. Oral glucose tolerance tests (OGTT) were given to both control and exercise-trained rats before and after placement in the small cages for 7 days. The insulin resistance was assessed by the product of the area of the insulin and glucose curves of the OGTT (IG index). Results show that the values obtained before confinement were one-half as high in exercise-trained rats as those in control rats, reflecting an increased sensitivity to insulin with exercise training. After 7 days confinement, the IG index was found to be not significantly different from initial values for both control and exercise-trained rats. These findings suggest that increased insulin sensitivity in exercise-trained rats persists 7 days after cessation of running activity. The data also indicate that exercise training, before flight, may be beneficial in minimizing the loss of insulin sensitivity expected with decreased use of gravity dependent muscles during exposure to hypogravity in space flight.

  12. Interaction of growth hormone receptor/binding protein gene disruption and caloric restriction for insulin sensitivity and attenuated aging.

    PubMed

    Arum, Oge; Saleh, Jamal; Boparai, Ravneet; Turner, Jeremy; Kopchick, John; Khardori, Romesh; Bartke, Andrzej

    2014-01-01

    The correlation of physiological sensitivity to insulin ( vis-à-vis glycemic regulation) and longevity is extensively established, creating a justifiable gerontological interest on whether insulin sensitivity is causative, or even predictive, of some or all phenotypes of slowed senescence (including longevity). The growth hormone receptor/ binding protein gene-disrupted (GHR-KO) mouse is the most extensively investigated insulin-sensitive, attenuated aging model. It was reported that, in a manner divergent from similar mutants, GHR-KO mice fail to respond to caloric restriction (CR) by altering their insulin sensitivity. We hypothesized that maximized insulin responsiveness is what causes GHR-KO mice to exhibit a suppressed survivorship response to dietary (including caloric) restriction; and attempted to refute this hypothesis by assessing the effects of CR on GHR-KO mice for varied slow-aging-associated phenotypes. In contrast to previous reports, we found GHR-KO mice on CR to be less responsive than their ad libitum (A.L.) counterparts to the hypoglycemia-inducing effects of insulin. Further, CR had negligible effects on the metabolism or cognition of GHR-KO mice. Therefore, our data suggest that the effects of CR on the insulin sensitivity of GHR-KO mice do not concur with the effects of CR on the aging of GHR-KO mice. PMID:25789159

  13. Impairment of vesicular ATP release affects glucose metabolism and increases insulin sensitivity

    PubMed Central

    Sakamoto, Shohei; Miyaji, Takaaki; Hiasa, Miki; Ichikawa, Reiko; Uematsu, Akira; Iwatsuki, Ken; Shibata, Atsushi; Uneyama, Hisayuki; Takayanagi, Ryoichi; Yamamoto, Akitsugu; Omote, Hiroshi; Nomura, Masatoshi; Moriyama, Yoshinori

    2014-01-01

    Neuroendocrine cells store ATP in secretory granules and release it along with hormones that may trigger a variety of cellular responses in a process called purinergic chemical transmission. Although the vesicular nucleotide transporter (VNUT) has been shown to be involved in vesicular storage and release of ATP, its physiological relevance in vivo is far less well understood. In Vnut knockout (Vnut−/−) mice, we found that the loss of functional VNUT in adrenal chromaffin granules and insulin granules in the islets of Langerhans led to several significant effects. Vesicular ATP accumulation and depolarization-dependent ATP release were absent in the chromaffin granules of Vnut−/− mice. Glucose-responsive ATP release was also absent in pancreatic β-cells in Vnut−/− mice, while glucose-responsive insulin secretion was enhanced to a greater extent than that in wild-type tissue. Vnut−/− mice exhibited improved glucose tolerance and low blood glucose upon fasting due to increased insulin sensitivity. These results demonstrated an essential role of VNUT in vesicular storage and release of ATP in neuroendocrine cells in vivo and suggest that vesicular ATP and/or its degradation products act as feedback regulators in catecholamine and insulin secretion, thereby regulating blood glucose homeostasis. PMID:25331291

  14. Thecal cell sensitivity to luteinizing hormone and insulin in polycystic ovarian syndrome.

    PubMed

    Cadagan, David; Khan, Raheela; Amer, Saad

    2016-03-01

    This study examined whether a defect of steroid synthesis in ovarian theca cells may lead to the development of PCOS, through contributions to excess androgen secretion. Polycystic ovarian syndrome (PCOS) is one of the leading causes of infertility worldwide affecting around 1 in 10 of women of a reproductive age. One of the fundamental abnormalities in this syndrome is the presence of hormonal irregularities, including hyperandrogenemia, hyperinsulinemia and hypersecretion of luteinizing hormone (LH). Studies suggest that insulin treatment increases progesterone and androstenedione secretion in PCOS theca cells when compared to insulin treated normal theca cells. Furthermore the augmented effects of LH and insulin have been seen to increase ovarian androgen synthesis in non-PCOS theca cultures whilst also increasing the expression of steroidogenic enzymes specific to the PI3-K pathway. Our examination of primary thecal cultures showed an increase in both the expression of the steroidogenic enzyme CYP17 and androgen secretion in PCOS theca cells under basal conditions, when compared to non-PCOS cells. This was increased significantly under treatments of LH and insulin combined. Our results support the previous reported hypothesis that a dysfunction may exist within the PI3-K pathway. Specifically, that sensitivity exists to physiological symptoms including hyperinsulinemia and hyper secretion of LH found in PCOS through co-stimulation. The impact of these findings may allow the development of a therapeutic target in PCOS. PMID:26952754

  15. Impairment of vesicular ATP release affects glucose metabolism and increases insulin sensitivity.

    PubMed

    Sakamoto, Shohei; Miyaji, Takaaki; Hiasa, Miki; Ichikawa, Reiko; Uematsu, Akira; Iwatsuki, Ken; Shibata, Atsushi; Uneyama, Hisayuki; Takayanagi, Ryoichi; Yamamoto, Akitsugu; Omote, Hiroshi; Nomura, Masatoshi; Moriyama, Yoshinori

    2014-01-01

    Neuroendocrine cells store ATP in secretory granules and release it along with hormones that may trigger a variety of cellular responses in a process called purinergic chemical transmission. Although the vesicular nucleotide transporter (VNUT) has been shown to be involved in vesicular storage and release of ATP, its physiological relevance in vivo is far less well understood. In Vnut knockout (Vnut(-/-)) mice, we found that the loss of functional VNUT in adrenal chromaffin granules and insulin granules in the islets of Langerhans led to several significant effects. Vesicular ATP accumulation and depolarization-dependent ATP release were absent in the chromaffin granules of Vnut(-/-) mice. Glucose-responsive ATP release was also absent in pancreatic β-cells in Vnut(-/-) mice, while glucose-responsive insulin secretion was enhanced to a greater extent than that in wild-type tissue. Vnut(-/-) mice exhibited improved glucose tolerance and low blood glucose upon fasting due to increased insulin sensitivity. These results demonstrated an essential role of VNUT in vesicular storage and release of ATP in neuroendocrine cells in vivo and suggest that vesicular ATP and/or its degradation products act as feedback regulators in catecholamine and insulin secretion, thereby regulating blood glucose homeostasis. PMID:25331291

  16. Effect of losartan and atenolol on insulin sensitivity in nondiabetic hypertensive patients

    PubMed Central

    Bharati, Sandesh Madhukar; Singh, Nishith

    2016-01-01

    Objective: To study the effects of losartan and atenolol on glucometabolic parameters in nondiabetic hypertensive patients. Materials and Methods: In a prospective, open-label, parallel group study, nondiabetic patients with mild to moderate hypertension were randomized to either losartan (titrated from 50 to 100 mg/day, n = 20) or atenolol (titrated from 25 mg to 100 mg/day, n = 20) for period of 24 weeks. At baseline, 12 and 24 weeks fasting plasma glucose (FPG), fasting plasma insulin (FPI), homeostasis model assessment for insulin resistance (HOMA-IR) apart from lipid parameters, mean systolic, and diastolic blood pressures levels were determined. Results: At the end of study, losartan significantly (P < 0.05) reduced FPG, FPI, and HOMA-IR compared to atenolol and baseline. While atenolol increased the HOMA-IR levels significantly compared to the baseline. Conclusions: Losartan improved the insulin sensitivity while atenolol worsened it. Losartan is better than atenolol for its effects on the glucose-insulin metabolism. PMID:27440952

  17. Insulin sensitivity of muscle protein metabolism is altered in patients with chronic kidney disease and metabolic acidosis

    PubMed Central

    Garibotto, Giacomo; Sofia, Antonella; Russo, Rodolfo; Paoletti, Ernesto; Bonanni, Alice; Parodi, Emanuele L; Viazzi, Francesca; Verzola, Daniela

    2015-01-01

    An emergent hypothesis is that a resistance to the anabolic drive by insulin may contribute to loss of strength and muscle mass in patients with chronic kidney disease (CKD). We tested whether insulin resistance extends to protein metabolism using the forearm perfusion method with arterial insulin infusion in 7 patients with CKD and metabolic acidosis (bicarbonate 19 mmol/l) and 7 control individuals. Forearm glucose balance and protein turnover (2H-phenylalanine kinetics) were measured basally and in response to insulin infused at different rates for 2 h to increase local forearm plasma insulin concentration by approximately 20 and 50 μU/ml. In response to insulin, forearm glucose uptake was significantly increased to a lesser extent (−40%) in patients with CKD than controls. In addition, whereas in the controls net muscle protein balance and protein degradation were decreased by both insulin infusion rates, in patients with CKD net protein balance and protein degradation were sensitive to the high (0.035 mU/kg per min) but not the low (0.01 mU/kg per min) insulin infusion. Besides blunting muscle glucose uptake, CKD and acidosis interfere with the normal suppression of protein degradation in response to a moderate rise in plasma insulin. Thus, alteration of protein metabolism by insulin may lead to changes in body tissue composition which may become clinically evident in conditions characterized by low insulinemia. PMID:26308671

  18. Modeling hepatic insulin sensitivity during a meal: validation against the euglycemic hyperinsulinemic clamp.

    PubMed

    Dalla Man, Chiara; Piccinini, Francesca; Basu, Rita; Basu, Ananda; Rizza, Robert A; Cobelli, Claudio

    2013-04-15

    Recently, we proposed a model describing the suppression of endogenous glucose production (EGP) during a meal. It assumes that EGP suppression depends on glucose concentration and its rate of change and on delayed insulin action. Hepatic insulin sensitivity (S(I)(Lmeal)) can be derived from EGP model parameters. This model was shown to adequately describe EGP profiles measured with multiple tracer techniques; however, S(I)(Lmeal) has never been compared directly with its euglycemic hyperinsulinemic clamp counterpart (S(I)(Lclamp)). To do so, 62 subjects with different degrees of glucose tolerance underwent a triple-tracer mixed meal. Fifty-seven subjects also underwent a labeled ([3-(3)H]glucose) euglycemic hyperinsulinemic clamp. From the triple-tracer meal data, virtually model-independent estimates of EGP were obtained using the tracer-to-tracee clamp technique, and the EGP model was identified in each subject. Model fit was satisfactory, and S(I)(Lmeal) was estimated with good precision. Correlation between S(I)(Lclamp) and S(I)(Lmeal) was good (r = 0.72, P < 0.001); however, S(I)(Lmeal) was lower than S(I)(Lclamp) (4.60 ± 0.64 vs. 8.73 ± 1.07 10(-4) dl·kg(-1)·min(-1) per μU/ml, P < 0.01). This difference may be due to different ranges of insulin explored during the two tests (ΔI(clamp) = 15.60 ± 1.61 vs. ΔI(meal)= 83.37 ± 10.71 μU/ml) as well as steady- vs. non-steady-state glucose and insulin profiles. In conclusion, the new EGP model provides an estimate of hepatic insulin sensitivity during a meal that is in good agreement with that derived in the same individuals with a hyperinsulinemic clamp. When used in conjunction with the minimal model, the approach potentially enables estimation of hepatic insulin sensitivity from a single-tracer labeled meal or oral glucose tolerance test. PMID:23443923

  19. Prostaglandin A2 enhances cellular insulin sensitivity via a mechanism that involves the orphan nuclear receptor NR4A3.

    PubMed

    Zhu, X; Walton, R G; Tian, L; Luo, N; Ho, S-R; Fu, Y; Garvey, W T

    2013-03-01

    We have previously reported that members of the NR4A family of orphan nuclear receptors can augment insulin's ability to stimulate glucose transport in adipocytes. In the current study, we endeavored to test for an insulin-sensitizing effect in muscle cells and to identify a potential transactivator. Lentiviral constructs were used to engineer both hyperexpression and shRNA silencing of NR4A3 in C2C12 myocytes. The NR4A3 hyper-expression construct led to a significant increase in glucose transport rates in the presence of maximal insulin while the NR4A3 knock-down exhibited a significant reduction in insulin-stimulated glucose transport rates. Consistently, insulin-mediated AKT phosphorylation was increased by NR4A3 hyperexpression and decreased following shRNA NR4A3 suppression. Then, we examined effects of prostaglandin A2 (PGA2) on insulin action and NR4A3 transactivation. PGA2 augmented insulin-stimulated glucose uptake in C2C12 myocytes and AKT phosphorylation after 12-h treatment, without significant effects on basal transport or basal AKT phosphorylation. More importantly, we demonstrated that PGA2 led to a greater improvement in insulin-stimulated glucose rates in NR4A3 overexpressing C2C12 myocytes, when compared with Lac-Z controls stimulated with insulin and PGA2. Moreover, the sensitizing effect of PGA2 was significantly diminished in NR4A3 knockdown myocytes compared to scramble controls. These results show for the first time that: (i) PGA2 augments insulin action in myocytes as manifested by enhanced stimulation of glucose transport and AKT phosphorylation; and (ii) the insulin sensitizing effect is dependent upon the orphan nuclear receptor NR4A3. PMID:23104421

  20. High-dose Vitamin D Supplementation and Measures of Insulin Sensitivity in Polycystic Ovary Syndrome: a Randomized Controlled Pilot Trial

    PubMed Central

    Raja-Khan, Nazia; Shah, Julie; Stetter, Christy M.; Lott, Mary E.J.; Kunselman, Allen R.; Dodson, William C.; Legro, Richard S.

    2015-01-01

    Objective To determine the effects of high-dose vitamin D on insulin sensitivity in Polycystic Ovary Syndrome (PCOS). Design Randomized placebo-controlled trial. Setting Academic medical center. Patients 28 PCOS women. Interventions Vitamin D3 12,000 International Units or placebo daily for 12 weeks. Main Outcome Measures The primary outcome was quantitative insulin sensitivity check index (QUICKI). Secondary outcomes included glucose and insulin levels during a 75-gram oral glucose tolerance test and blood pressure. Results Twenty-two women completed the study. Compared to placebo, vitamin D significantly increased 25-hydroxyvitamin D (mean (95% confidence interval) in vitamin D group 20.1 (15.7 to 24.5) ng/ml at baseline and 65.7 (52.3 to 79.2) ng/ml at 12 weeks; placebo 22.5 (18.1 to 26.8) ng/ml at baseline and 23.8 (10.4 to 37.2) ng/ml at 12 weeks). There were no significant differences in QUICKI and other measures of insulin sensitivity, however we observed trends towards lower 2-hour insulin and lower 2-hour glucose. We also observed a protective effect of vitamin D on blood pressure. Conclusions In women with PCOS, insulin sensitivity was unchanged with high-dose vitamin D but there was a trend towards decreased 2-hour insulin and a protective effect on blood pressure. Clinical Trial registration number ClinicalTrials.gov Identifier: NCT00907153 PMID:24636395

  1. Serum sphingolipids: relationships to insulin sensitivity and changes with exercise in humans.

    PubMed

    Bergman, Bryan C; Brozinick, Joseph T; Strauss, Allison; Bacon, Samantha; Kerege, Anna; Bui, Hai Hoang; Sanders, Phil; Siddall, Parker; Kuo, Ming Shang; Perreault, Leigh

    2015-08-15

    Ceramides and sphingolipids are a family of lipid molecules that circulate in serum and accumulate in skeletal muscle, promoting insulin resistance. Plasma ceramide and dihydroceramide are related to insulin resistance, yet less is known regarding other ceramide and sphingolipid species. Despite its association with insulin sensitivity, chronic endurance exercise training does not change plasma ceramide and sphingolipid content, with little known regarding a single bout of exercise. We measured basal relationships and the effect of acute exercise (1.5 h at 50% V̇o2 max) and recovery on serum ceramide and sphingolipid content in sedentary obese individuals, endurance-trained athletes, and individuals with type 2 diabetes (T2D). Basal serum C18:0, C20:0, and C24:1 ceramide and C18:0 and total dihydroceramide were significantly higher in T2D and, along with C16:0 ceramide and C18:0 sphingomyelin, correlated positively with insulin resistance. Acute exercise significantly increased serum ceramide, glucosylceramide, and GM3 gangliosides, which largely decreased to basal values in recovery. Sphingosine 1-phosphate and sphingomyelin did not change during exercise but decreased below basal values in recovery. Serum C16:0 and C18:0 ceramide and C18:0 sphingomyelin, but not the total concentrations of either of them, were positively correlated with markers of muscle NF-κB activation, suggesting that specific species activate intracellular inflammation. Interestingly, a subset of sphingomyelin species, notably C14:0, C22:3, and C24:4 species, was positively associated with insulin secretion and glucose tolerance. Together, these data show that unique ceramide and sphingolipid species associate with either protective or deleterious features for diabetes and could provide novel therapeutic targets for the future. PMID:26126684

  2. Proteasome Dysfunction Associated to Oxidative Stress and Proteotoxicity in Adipocytes Compromises Insulin Sensitivity in Human Obesity

    PubMed Central

    Díaz-Ruiz, Alberto; Guzmán-Ruiz, Rocío; Moreno, Natalia R.; García-Rios, Antonio; Delgado-Casado, Nieves; Membrives, Antonio; Túnez, Isaac; El Bekay, Rajaa; Fernández-Real, José M.; Tovar, Sulay; Diéguez, Carlos; Tinahones, Francisco J.; Vázquez-Martínez, Rafael; López-Miranda, José

    2015-01-01

    Abstract Aims: Obesity is characterized by a low-grade systemic inflammatory state and adipose tissue (AT) dysfunction, which predispose individuals to the development of insulin resistance (IR) and metabolic disease. However, a subset of obese individuals, referred to as metabolically healthy obese (MHO) individuals, are protected from obesity-associated metabolic abnormalities. Here, we aim at identifying molecular factors and pathways in adipocytes that are responsible for the progression from the insulin-sensitive to the insulin-resistant, metabolically unhealthy obese (MUHO) phenotype. Results: Proteomic analysis of paired samples of adipocytes from subcutaneous (SC) and omental (OM) human AT revealed that both types of cells are altered in the MUHO state. Specifically, the glutathione redox cycle and other antioxidant defense systems as well as the protein-folding machinery were dysregulated and endoplasmic reticulum stress was increased in adipocytes from IR subjects. Moreover, proteasome activity was also compromised in adipocytes of MUHO individuals, which was associated with enhanced accumulation of oxidized and ubiquitinated proteins in these cells. Proteasome activity was also impaired in adipocytes of diet-induced obese mice and in 3T3-L1 adipocytes exposed to palmitate. In line with these data, proteasome inhibition significantly impaired insulin signaling in 3T3-L1 adipocytes. Innovation: This study provides the first evidence of the occurrence of protein homeostasis deregulation in adipocytes in human obesity, which, together with oxidative damage, interferes with insulin signaling in these cells. Conclusion: Our results suggest that proteasomal dysfunction and impaired proteostasis in adipocytes, resulting from protein oxidation and/or misfolding, constitute major pathogenic mechanisms in the development of IR in obesity. Antioxid. Redox Signal. 23, 597–612. PMID:25714483

  3. Association Between Thyrotropin Levels and Insulin Sensitivity in Euthyroid Obese Adolescents

    PubMed Central

    Javed, Asma; Balagopal, P. Babu; Vella, Adrian; Fischer, Philip R.; Piccinini, Francesca; Dalla Man, Chiara; Cobelli, Claudio; Giesler, Paula D.; Laugen, Jeanette M.

    2015-01-01

    Background: Thyrotropin (TSH) levels display a positive association with body mass index (BMI), and the prevalence of isolated hyperthyrotropinemia is higher in obese adolescents compared to their normal weight controls. However, the metabolic significance of the higher TSH in obese adolescents is less clear. The objective of this study was to determine the relationship between TSH concentrations and insulin sensitivity, lipids, and adipokines in euthyroid, non-diabetic, obese adolescents. Methods: Thirty-six euthyroid, non-diabetic, obese adolescents between the ages of 12 and 18 years underwent a 75 g oral glucose tolerance test. Insulin sensitivity (Si) and pancreatic β-cell function as assessed by disposition index (DI) were measured using the oral glucose minimal model approach. Cholesterol (total, low-density lipoprotein [LDL-C], and high-density lipoprotein [HDL-C]), triglycerides (TG), interleukin-6 (IL-6), total and high molecular weight (HMW) adiponectin, and retinol binding protein-4 (RBP4) were also determined. Associations between measures of thyroid function and Si, DI, lipids, and adipokines were computed using Pearson's correlation coefficient and multiple regression analysis. Results: The mean age of the subjects was 14.3±1.88 years, and the mean BMI was 32.5±4.65 kg/m2; 97% were non-Hispanic white and 47% were male. The mean TSH was 2.7±1.2 mIU/L. Increasing serum TSH was correlated with decreasing Si (log Si) in the entire cohort (p=0.03), but this relationship persisted only in males (p=0.02). The correlation between TSH and Si in males remained significant after adjusting for BMI (p=0.02). There was no correlation between TSH and pancreatic β-cell function as assessed by DI (p=0.48). TSH correlated positively with LDL-C (p=0.04) and IL-6 (p=0.03), but these associations vanished or weakened after adjusting for BMI (LDL-C p-value=0.44; IL-6 p-value=0.07). Conclusions: This study suggests a sex-specific association between TSH and insulin

  4. A Genome-Wide siRNA Screen to Identify Modulators of Insulin Sensitivity and Gluconeogenesis

    PubMed Central

    Yang, Ruojing; Lacson, Raul G.; Castriota, Gino; Zhang, Xiaohua D.; Liu, Yaping; Zhao, Wenqing; Einstein, Monica; Camargo, Luiz Miguel; Qureshi, Sajjad; Wong, Kenny K.; Zhang, Bei B.; Ferrer, Marc; Berger, Joel P.

    2012-01-01

    Background Hepatic insulin resistance impairs insulin’s ability to suppress hepatic glucose production (HGP) and contributes to the development of type 2 diabetes (T2D). Although the interests to discover novel genes that modulate insulin sensitivity and HGP are high, it remains challenging to have a human cell based system to identify novel genes. Methodology/Principal Findings To identify genes that modulate hepatic insulin signaling and HGP, we generated a human cell line stably expressing beta-lactamase under the control of the human glucose-6-phosphatase (G6PC) promoter (AH-G6PC cells). Both beta-lactamase activity and endogenous G6PC mRNA were increased in AH-G6PC cells by a combination of dexamethasone and pCPT-cAMP, and reduced by insulin. A 4-gene High-Throughput-Genomics assay was developed to concomitantly measure G6PC and pyruvate-dehydrogenase-kinase-4 (PDK4) mRNA levels. Using this assay, we screened an siRNA library containing pooled siRNA targeting 6650 druggable genes and identified 614 hits that lowered G6PC expression without increasing PDK4 mRNA levels. Pathway analysis indicated that siRNA-mediated knockdown (KD) of genes known to positively or negatively affect insulin signaling increased or decreased G6PC mRNA expression, respectively, thus validating our screening platform. A subset of 270 primary screen hits was selected and 149 hits were confirmed by target gene KD by pooled siRNA and 7 single siRNA for each gene to reduce G6PC expression in 4-gene HTG assay. Subsequently, pooled siRNA KD of 113 genes decreased PEPCK and/or PGC1alpha mRNA expression thereby demonstrating their role in regulating key gluconeogenic genes in addition to G6PC. Last, KD of 61 of the above 113 genes potentiated insulin-stimulated Akt phosphorylation, suggesting that they suppress gluconeogenic gene by enhancing insulin signaling. Conclusions/Significance These results support the proposition that the proteins encoded by the genes identified in our cell

  5. PPARγ Antagonist Gleevec Improves Insulin Sensitivity and Promotes the Browning of White Adipose Tissue.

    PubMed

    Choi, Sun-Sil; Kim, Eun-Sun; Jung, Ji-Eun; Marciano, David P; Jo, Ala; Koo, Ja Young; Choi, Soo Youn; Yang, Yong Ryoul; Jang, Hyun-Jun; Kim, Eung-Kyun; Park, Jiyoung; Kwon, Hyug Moo; Lee, In Hee; Park, Seung Bum; Myung, Kyung-Jae; Suh, Pann-Ghill; Griffin, Patrick R; Choi, Jang Hyun

    2016-04-01

    Blocking phosphorylation of peroxisome proliferator-activated receptor (PPAR)γ at Ser(273) is one of the key mechanisms for antidiabetes drugs to target PPARγ. Using high-throughput phosphorylation screening, we here describe that Gleevec blocks cyclin-dependent kinase 5-mediated PPARγ phosphorylation devoid of classical agonism as a PPARγ antagonist ligand. In high fat-fed mice, Gleevec improved insulin sensitivity without causing severe side effects associated with other PPARγ-targeting drugs. Furthermore, Gleevec reduces lipogenic and gluconeogenic gene expression in liver and ameliorates inflammation in adipose tissues. Interestingly, Gleevec increases browning of white adipose tissue and energy expenditure. Taken together, the results indicate that Gleevec exhibits greater beneficial effects on both glucose/lipid metabolism and energy homeostasis by blocking PPARγ phosphorylation. These data illustrate that Gleevec could be a novel therapeutic agent for use in insulin resistance and type 2 diabetes. PMID:26740599

  6. Estimating insulin sensitivity from glucose levels only: Use of a non-linear mixed effects approach and maximum a posteriori (MAP) estimation.

    PubMed

    Yates, James W T; Watson, Edmund M

    2013-02-01

    Insulin Sensitivity is an important parameter for the management of Diabetes. It can be derived for a particular patient using data derived from some glucose challenge tests using measured glucose and insulin levels at various times. Whilst a useful approach, deriving insulin sensitivities to inform insulin dosing in other settings such as Intensive Care Units can be more challenging - especially as insulin levels have to be assayed in a laboratory, not at the bedside. This paper investigates an approach to measure insulin sensitivity from glucose levels only. Estimates of mean and between individual parameter variances are used to derive conditional estimates of insulin sensitivity. The method is demonstrated to perform reasonably well, with conditional estimates comparing well with estimates derived from insulin data as well. PMID:22244505

  7. Altered fetal skeletal muscle nutrient metabolism following an adverse in utero environment and the modulation of later life insulin sensitivity.

    PubMed

    Dunlop, Kristyn; Cedrone, Megan; Staples, James F; Regnault, Timothy R H

    2015-01-01

    The importance of the in utero environment as a contributor to later life metabolic disease has been demonstrated in both human and animal studies. In this review, we consider how disruption of normal fetal growth may impact skeletal muscle metabolic development, ultimately leading to insulin resistance and decreased insulin sensitivity, a key precursor to later life metabolic disease. In cases of intrauterine growth restriction (IUGR) associated with hypoxia, where the fetus fails to reach its full growth potential, low birth weight (LBW) is often the outcome, and early in postnatal life, LBW individuals display modifications in the insulin-signaling pathway, a critical precursor to insulin resistance. In this review, we will present literature detailing the classical development of insulin resistance in IUGR, but also discuss how this impaired development, when challenged with a postnatal Western diet, may potentially contribute to the development of later life insulin resistance. Considering the important role of the skeletal muscle in insulin resistance pathogenesis, understanding the in utero programmed origins of skeletal muscle deficiencies in insulin sensitivity and how they may interact with an adverse postnatal environment, is an important step in highlighting potential therapeutic options for LBW offspring born of pregnancies characterized by placental insufficiency. PMID:25685986

  8. Altered Fetal Skeletal Muscle Nutrient Metabolism Following an Adverse In Utero Environment and the Modulation of Later Life Insulin Sensitivity

    PubMed Central

    Dunlop, Kristyn; Cedrone, Megan; Staples, James F.; Regnault, Timothy R.H.

    2015-01-01

    The importance of the in utero environment as a contributor to later life metabolic disease has been demonstrated in both human and animal studies. In this review, we consider how disruption of normal fetal growth may impact skeletal muscle metabolic development, ultimately leading to insulin resistance and decreased insulin sensitivity, a key precursor to later life metabolic disease. In cases of intrauterine growth restriction (IUGR) associated with hypoxia, where the fetus fails to reach its full growth potential, low birth weight (LBW) is often the outcome, and early in postnatal life, LBW individuals display modifications in the insulin-signaling pathway, a critical precursor to insulin resistance. In this review, we will present literature detailing the classical development of insulin resistance in IUGR, but also discuss how this impaired development, when challenged with a postnatal Western diet, may potentially contribute to the development of later life insulin resistance. Considering the important role of the skeletal muscle in insulin resistance pathogenesis, understanding the in utero programmed origins of skeletal muscle deficiencies in insulin sensitivity and how they may interact with an adverse postnatal environment, is an important step in highlighting potential therapeutic options for LBW offspring born of pregnancies characterized by placental insufficiency. PMID:25685986

  9. How does acupuncture affect insulin sensitivity in women with polycystic ovary syndrome and insulin resistance? Study protocol of a prospective pilot study

    PubMed Central

    Zheng, Yanhua; Stener-Victorin, Elisabet; Ng, Ernest H Y; Li, Juan; Wu, Xiaoke; Ma, Hongxia

    2015-01-01

    Introduction Hyperinsulinaemia and insulin resistance (IR) are key features of polycystic ovary syndrome (PCOS) and metabolic syndrome. The effect of 5 weeks of acupuncture treatment has been investigated in a completed prospective pilot trial (Clinicaltrials.gov: NCT01457209), and acupuncture with electrical stimulation applied to insulin-resistant rats with dihydrotestosterone-induced PCOS was shown to improve insulin sensitivity. Therefore, we now aim to conduct a prospective pilot study to evaluate whether using the same acupuncture treatment protocol given over a longer period of time (6 months) than in the previous pilot trial will improve insulin sensitivity in women with PCOS and IR. Our hypothesis is that acupuncture with combined manual and low-frequency electrical stimulation of the needles will improve insulin sensitivity in women with PCOS and IR. Methods/analysis This is a prospective pilot trial. A total of 112 women with PCOS and IR will be recruited and categorised according to their body mass index (BMI) as normal weight (BMI=18.5−23 kg/m2) or as overweight/obese (BMI>23 kg/m2). Acupuncture will be applied three times per week for 6 months at 30 min per treatment. The primary outcome will be the change in insulin sensitivity before and after 6 months of acupuncture treatment, as measured by an oral glucose tolerance test. Ethics/dissemination Ethical approval of this study has been granted from the ethics committee of the First Affiliated Hospital of Guangzhou Medical University (No. 2013039). Written and informed consent will be obtained from each patient before any study procedure is performed, according to good clinical practice. The results of this trial will be disseminated in a peer-reviewed journal and presented at international congresses. Trial registration numbers NCT02026323 and ChiCTR-OCH-13003921. PMID:25941189

  10. Insulin-Stimulated Release of D-Chiro-Inositol-Containing Inositolphosphoglycan Mediator Correlates with Insulin Sensitivity in Women with Polycystic Ovary Syndrome

    PubMed Central

    Cheang, Kai I.; Baillargeon, Jean-Patrice; Essah, Paulina A.; Ostlund, Richard E.; Apridonize, Teimuraz; Islam, Leila; Nestler, John E.

    2008-01-01

    Some actions of insulin are mediated by inositolphosphoglycan mediators. Deficient release of a putative D-chiro-inositol-containing inositolphosphoglycan (DCI-IPG) mediator may contribute to insulin resistance in women with polycystic ovary syndrome (PCOS). Previously we demonstrated that oral DCI supplementation improved ovulation and metabolic parameters in women with PCOS. However, whether oral DCI mediates an increase in the release of the DCI-IPG mediator and an improvement in insulin sensitivity in women with PCOS is unknown. We conducted a randomized controlled trial of DCI supplementation vs. placebo in 11 women with PCOS who were assessed at two-time points, 6 weeks apart. Plasma DCI, DCI-IPG release during OGTT (AUCDCI-IPG) and insulin sensitivity (Si) by FSIVGTT were assessed at baseline and end-of-study. The study was terminated early due to a sudden unavailability of the study drug. However, in all subjects without regard to treatment assignment, there was a positive correlation between the change in AUCDCI-IPG / AUCInsulin ratio and the change in Si during the 6-week period (r=0.69, p=0.02), which remained significant after adjustment for BMI (p=0.022), and after further adjustment for BMI and treatment allocation (p=0.0261). This suggests that in women with PCOS, increased glucose-stimulated DCI-IPG release is significantly correlated with improved insulin sensitivity. The significant relationship between DCI-IPG release and insulin sensitivity suggests that the DCI-IPG mediator may be a target for therapeutic interventions in PCOS. PMID:18803944

  11. Effect of a β-Hydroxyphosphonate Analogue of ʟ-Carnitine on Insulin-Sensitive and Insulin-Resistant 3T3-L1 Adipocytes.

    PubMed

    Avalos-Soriano, Anaguiven; De la Cruz-Cordero, Ricardo; López-Martínez, Francisco Josue; Rosado, Jorge L; Duarte-Vázquez, Miguel Ángel; Garcia-Gasca, Teresa

    2015-01-01

    This study investigated the effect of a β-x200B;hydroxyphosphonate analog of ʟ-carnitine (L-CA) (CAS number: 1220955-x200B;20-3, Component: 1221068-91-2, C12H29NO4PI), (3-Hexanaminium, 1-(dimethoxyphosphinyl)-2-hydroxy-N,N,N,5-x200B;tetramethy-iodide (1:1), (2R, 3S)) on parameters related with type-2 diabetes in an in vitro model. Nontoxic concentrations of L-CA were assayed and compared to commercial ʟ-carnitine effects. L-CA did not affect adipogenesis in normal cells, but an increment of TG accumulation was observed on insulin-resistant adipocytes (80%) when compared with resistant control. L-CA also stimulated glucose analog 2-NBDG uptakes on insulin-resistant adipocytes in a similar way as insulin when compared to insulin-resistant cells. Our results show that the L-CA promoted insulin-like responses on insulin-resistant adipocytes without appreciable pro-adipogenic effect in sensitive adipocytes. PMID:26160659

  12. Improved insulin sensitivity and body fat distribution in HIV-infected patients treated with rosiglitazone: a pilot study.

    PubMed

    Gelato, Marie C; Mynarcik, Dennis C; Quick, Joyce L; Steigbigel, Roy T; Fuhrer, Jack; Brathwaite, Collin E M; Brebbia, John S; Wax, Mark R; McNurlan, Margaret A

    2002-10-01

    The insulin-sensitizing drugs thiazolidinediones (TZDs), such as rosiglitazone, improve insulin sensitivity and also promote adipocyte differentiation in vitro. The authors hypothesized that TZDs might be beneficial to patients with HIV disease to improve insulin sensitivity and the distribution of body fat by increasing peripheral fat. The ability of rosiglitazone (8 mg/d) to improve insulin sensitivity (from hyperinsulinemic-euglycemic clamp) and to improve body fat distribution (determined from computed tomography measurements of visceral adipose tissue [VAT] and subcutaneous adipose tissue [SAT]) was determined in 8 HIV-positive patients. Before treatment, the insulin sensitivity of the patients was reduced to approximately 34% of that in control subjects. The rate of glucose disposal during a hyperinsulinemic-euglycemic clamp (Rd) was 3.8 +/-.4 (SEM) mg glucose/kg lean body mass/min compared with 11.08 +/- 1.1 (p<.001) in healthy age- and body mass index (BMI)-matched control subjects. After rosiglitazone treatment of 6 to 12 weeks, Rd increased to 5.99 +/-.9 (p=.02), an improvement of 59 +/- 22%. SAT increased by 23 +/- 10% (p=.05), and, surprisingly, VAT was decreased by 21 +/- 8% (p=.04) with a trend for increased SAT/VAT that failed to reach statistical significance. There were no significant changes in blood counts, viral loads, or CD4 counts with rosiglitazone treatment. The study demonstrates that rosiglitazone therapy improves insulin resistance and body fat distribution in some patients with HIV disease. PMID:12394794

  13. Adiponectin in mice with altered GH action: links to insulin sensitivity and longevity?

    PubMed

    Lubbers, Ellen R; List, Edward O; Jara, Adam; Sackman-Sala, Lucila; Cordoba-Chacon, Jose; Gahete, Manuel D; Kineman, Rhonda D; Boparai, Ravneet; Bartke, Andrzej; Kopchick, John J; Berryman, Darlene E

    2013-03-01

    Adiponectin is positively correlated with longevity and negatively correlated with many obesity-related diseases. While there are several circulating forms of adiponectin, the high-molecular-weight (HMW) version has been suggested to have the predominant bioactivity. Adiponectin gene expression and cognate serum protein levels are of particular interest in mice with altered GH signaling as these mice exhibit extremes in obesity that are positively associated with insulin sensitivity and lifespan as opposed to the typical negative association of these factors. While a few studies have reported total adiponectin levels in young adult mice with altered GH signaling, much remains unresolved, including changes in adiponectin levels with advancing age, proportion of total adiponectin in the HMW form, adipose depot of origin, and differential effects of GH vs IGF1. Therefore, the purpose of this study was to address these issues using assorted mouse lines with altered GH signaling. Our results show that adiponectin is generally negatively associated with GH activity, regardless of age. Further, the amount of HMW adiponectin is consistently linked with the level of total adiponectin and not necessarily with previously reported lifespan or insulin sensitivity of these mice. Interestingly, circulating adiponectin levels correlated strongly with inguinal fat mass, implying that the effects of GH on adiponectin are depot specific. Interestingly, rbGH, but not IGF1, decreased circulating total and HMW adiponectin levels. Taken together, these results fill important gaps in the literature related to GH and adiponectin and question the frequently reported associations of total and HMW adiponectin with insulin sensitivity and longevity. PMID:23261955

  14. Palmitate stimulates glucose transport in rat adipocytes by a mechanism involving translocation of the insulin sensitive glucose transporter (GLUT4)

    NASA Technical Reports Server (NTRS)

    Hardy, R. W.; Ladenson, J. H.; Henriksen, E. J.; Holloszy, J. O.; McDonald, J. M.

    1991-01-01

    In rat adipocytes, palmitate: a) increases basal 2-deoxyglucose transport 129 +/- 27% (p less than 0.02), b) decreases the insulin sensitive glucose transporter (GLUT4) in low density microsomes and increases GLUT4 in plasma membranes and c) increases the activity of the insulin receptor tyrosine kinase. Palmitate-stimulated glucose transport is not additive with the effect of insulin and is not inhibited by the protein kinase C inhibitors staurosporine and sphingosine. In rat muscle, palmitate: a) does not affect basal glucose transport in either the soleus or epitrochlearis and b) inhibits insulin-stimulated glucose transport by 28% (p less than 0.005) in soleus but not in epitrochlearis muscle. These studies demonstrate a potentially important differential role for fatty acids in the regulation of glucose transport in different insulin target tissues.

  15. pH-sensitive poly(lactide-co-glycolide) nanoparticle composite microcapsules for oral delivery of insulin

    PubMed Central

    Sun, Shaoping; Liang, Na; Yamamoto, Hiromitsu; Kawashima, Yoshiaki; Cui, Fude; Yan, Pengfei

    2015-01-01

    This study proposes a new concept of pH-sensitive poly(lactide-co-glycolide) (PLGA) nanoparticle composite microcapsules for oral delivery of insulin. Firstly, insulin–sodium oleate complex was prepared by the hydrophobic ion pairing method and then encapsulated into PLGA nanoparticles by the emulsion solvent diffusion method. In order to reduce the burst release of insulin from PLGA nanoparticles and deliver insulin to specific gastrointestinal regions, hence to enhance bioavailability of insulin, the PLGA nanoparticles were further encapsulated into Eudragit® FS 30D to prepare PLGA nanoparticle composite microcapsules by organic spray-drying method. The preparation was evaluated in vitro and in vivo, and the absorption mechanism was discussed. The in vitro drug release studies revealed that the drug release was pH dependent, and the in vivo results demonstrated that the formulation of PLGA nanoparticle composite microcapsules was an effective candidate for oral insulin delivery. PMID:25999713

  16. Association of common JAK2 variants with body fat, insulin sensitivity and lipid profile

    PubMed Central

    Ge, Dongliang; Gooljar, Sakina B; Kyriakou, Theodosios; Collins, Laura J; Swaminathan, Ramasamyiyer; Snieder, Harold; Spector, Tim D; O'Dell, Sandra D

    2007-01-01

    The leptin signal is transduced via the JAK2-STAT3 pathway at the leptin receptor. JAK2 also phosphorylates IRS, integral to insulin and leptin action and is required for optimum ABCA1-dependent transport of lipids from cells to apoA-I. We hypothesised that common variation in the JAK2 gene may be associated with body fat, insulin sensitivity and modulation of the serum lipid profile in the general population. Ten tagging SNPs spanning the gene were genotyped in 2760 Caucasian female twin subjects (mean age 47.3±12.6 years) from the St Thomas' UK Adult Twin Registry (Twins UK). Minor allele frequencies were between 0.170 and 0.464. The major allele of rs7849191 was associated with higher central fat (P=0.030), % central fat (P=0.014) and waist circumference (P=0.027) and the major allele of rs3780378 with higher serum apoA (P=0.026), total cholesterol (P=0.014) and LDL cholesterol (P=0.012) and lower triglyceride (P=0.023). However, no associations were significant at a level which took account of multiple testing. Although JAK2 is a critical element in leptin and insulin signalling and has a role in cellular cholesterol transport, we failed to establish associations of common SNPs with relevant phenotypes in this human study. PMID:18239666

  17. Increased fetal myocardial sensitivity to insulin-stimulated glucose metabolism during ovine fetal growth restriction.

    PubMed

    Barry, James S; Rozance, Paul J; Brown, Laura D; Anthony, Russell V; Thornburg, Kent L; Hay, William W

    2016-04-01

    Unlike other visceral organs, myocardial weight is maintained in relation to fetal body weight in intrauterine growth restriction (IUGR) fetal sheep despite hypoinsulinemia and global nutrient restriction. We designed experiments in fetal sheep with placental insufficiency and restricted growth to determine basal and insulin-stimulated myocardial glucose and oxygen metabolism and test the hypothesis that myocardial insulin sensitivity would be increased in the IUGR heart. IUGR was induced by maternal hyperthermia during gestation. Control (C) and IUGR fetal myocardial metabolism were measured at baseline and under acute hyperinsulinemic/euglycemic clamp conditions at 128-132 days gestation using fluorescent microspheres to determine myocardial blood flow. Fetal body and heart weights were reduced by 33% (P = 0.008) and 30% (P = 0.027), respectively. Heart weight to body weight ratios were not different. Basal left ventricular (LV) myocardial blood flow per gram of LV tissue was maintained in IUGR fetuses compared to controls. Insulin increased LV myocardial blood flow by ∼38% (P < 0.01), but insulin-stimulated LV myocardial blood flow in IUGR fetuses was 73% greater than controls. Similar to previous reports testing acute hypoxia, LV blood flow was inversely related to arterial oxygen concentration (r(2 )= 0.71) in both control and IUGR animals. Basal LV myocardial glucose delivery and uptake rates were not different between IUGR and control fetuses. Insulin increased LV myocardial glucose delivery (by 40%) and uptake (by 78%) (P < 0.01), but to a greater extent in the IUGR fetuses compared to controls. During basal and hyperinsulinemic-euglycemic clamp conditions LV myocardial oxygen delivery, oxygen uptake, and oxygen extraction efficiency were not different between groups. These novel results demonstrate that the fetal heart exposed to nutrient and oxygen deprivation from placental insufficiency appears to maintain myocardial energy supply

  18. Dipeptidyl peptidase 4 inhibitor improves brain insulin sensitivity, but fails to prevent cognitive impairment in orchiectomy obese rats.

    PubMed

    Pintana, Hiranya; Pongkan, Wanpitak; Pratchayasakul, Wasana; Chattipakorn, Nipon; Chattipakorn, Siriporn C

    2015-08-01

    It is unclear whether the dipeptidyl peptidase 4 (DPP4) inhibitor can counteract brain insulin resistance, brain mitochondrial dysfunction, impairment of hippocampal synaptic plasticity and cognitive decline in testosterone-deprived obese rats. We hypothesized that DPP4 inhibitor vildagliptin improves cognitive function in testosterone-deprived obese rats by restoring brain insulin sensitivity, brain mitochondrial function and hippocampal synaptic plasticity. Thirty male Wistar rats received either a sham-operated (S, n=6) or bilateral orchiectomy (ORX, n=24). ORX rats were divided into two groups and fed with either a normal diet (ND (NDO)) or a high-fat diet (HFO) for 12 weeks. Then, ORX rats in each dietary group were divided into two subgroups (n=6/subgroup) to receive either a vehicle or vildagliptin (3 mg/kg per day, p.o.) for 4 weeks. After treatment, cognitive function, metabolic parameters, brain insulin sensitivity, hippocampal synaptic plasticity and brain mitochondrial function were determined in each rat. We found that HFO rats exhibited peripheral and brain insulin resistance, brain mitochondrial dysfunction, impaired hippocampal synaptic plasticity and cognitive decline. NDO rats did not develop peripheral and brain insulin resistance. However, impaired hippocampal synaptic plasticity and cognitive decline occurred. Vildagliptin significantly improved peripheral insulin sensitivity, restored brain insulin sensitivity and decreased brain mitochondrial reactive oxygen species production in HFO rats. However, vildagliptin did not restore hippocampal synaptic plasticity and cognitive function in both NDO and HFO rats. These findings suggest that vildagliptin could not counteract the impairment of hippocampal synaptic plasticity and cognitive decline in testosterone-deprived subjects, despite its effects on improved peripheral and brain insulin sensitivity as well as brain mitochondrial function. PMID:26016746

  19. Influence of Apolipoproteins on the Association Between Lipids and Insulin Sensitivity

    PubMed Central

    Baldi, Simona; Bonnet, Fabrice; Laville, Martine; Morgantini, Cecilia; Monti, Lucilla; Hojlund, Kurt; Ferrannini, Ele; Natali, Andrea

    2013-01-01

    OBJECTIVE We evaluated whether the association of insulin sensitivity with HDL cholesterol (HDL) and triglycerides is influenced by major plasma apolipoproteins, as suggested by recent experimental evidence. RESEARCH DESIGN AND METHODS This study included a cross-sectional analysis of the RISC Study, a multicenter European clinical investigation in 1,017 healthy volunteers balanced in sex (women 54%) and age strata (range 30–60 years). Insulin sensitivity (M/I in µmol ⋅ min−1 ⋅ kgFFM−1 ⋅ nM−1) was measured by the clamp technique and apolipoproteins (ApoB, -C3, -A1, and -E) by Multiplex Technology. RESULTS The center-, sex-, and age-adjusted standardized regression coefficients (STDβ) with M/I were similar for HDL and triglycerides (+19.9 ± 1.9 vs. −20.0 ± 2.0, P < 0.0001). Further adjustment for triglycerides (or HDL), BMI, and adiponectin (or nonesterified fatty acid) attenuated the strength of the association of M/I with both HDL (STDβ +6.4 ± 2.3, P < 0.01) and triglycerides (−9.5 ± 2.1, P < 0.001). Neither ApoA1 nor ApoE and ApoB showed any association with M/I independent from plasma HDL cholesterol and triglycerides. ApoC3, in contrast, in both men and women, was positively associated with M/I independently of plasma lipids. A relative enrichment of plasma lipids with ApoC3 is associated with lower body fat percentage and lower plasma alanine amino transferase. CONCLUSIONS Our results suggest that HDL cholesterol modulates insulin sensitivity through a mechanism that is partially mediated by BMI and adiponectin but not by ApoA1. Similarly, the influence of triglycerides on insulin sensitivity is in part mediated by BMI and is unrelated to ApoE or ApoB, but it is significantly modulated by ApoC3, which appears to protect from the negative effect of plasma lipids. PMID:24130363

  20. Association of insulin sensitivity to lipids across the lifespan in people with Type 1 diabetes

    PubMed Central

    Maahs, D. M.; Nadeau, K.; Snell-Bergeon, J. K.; Schauer, I.; Bergman, B.; West, N. A.; Rewers, M.; Daniels, S. R.; Ogden, L. G.; Hamman, R. F.; Dabelea, D.

    2010-01-01

    Aims Insulin resistance and dyslipidaemia both increase cardiovascular risk in Type 1 diabetes. However, little data exist on the associations of insulin resistance to lipids in Type 1 diabetes. Our objective was to explore the associations between insulin resistance (assessed by glucose infusion rate) and lipids in people with Type 1 diabetes and determine whether adiposity and/or average glycaemia influence these associations. Methods Hyperinsulinaemic–euglycaemic clamp studies were performed in 60 subjects with Type 1 diabetes aged 12–19 years (age 15 ± 2 years, 57% female, duration of diabetes 6.3 ± 3.8 years, HbA1c 8.6 ± 1.5%) and 40 subjects with Type 1 diabetes aged 27–61 years (age 45 ± 9 years, 53% female, duration of diabetes 23 ± 8 years, HbA1c 7.5 ± 0.9%). Multiple linear regression models were fit to examine the association between glucose infusion rate and fasting lipid levels with adjustment for possible confounders. Results Lower glucose infusion rate was significantly associated with lower levels of HDL cholesterol in youths with Type 1 diabetes and with higher levels of triglycerides and higher triglyceride/HDL ratio in both youths and adults. The magnitude of the associations between glucose infusion rate and lipid levels translate into interquartile differences of 0.098 mmol/l for HDL cholesterol, 0.17 mmol/l for triglycerides and 1.06 for triglycerides/HDL in the adolescents and 0.20 mmol/l for triglycerides and 1.01 for triglycerides/HDL in the adults. The associations were attenuated and no longer statistically significant by adjustment for adiposity among adults, while adjustment for HbA1c had a small effect in youths and adults. Conclusions Lower insulin sensitivity is associated with a more atherogenic lipid profile in both youths and adults with Type 1 diabetes. PMID:21219421

  1. Insulin secretory defects in polycystic ovary syndrome. Relationship to insulin sensitivity and family history of non-insulin-dependent diabetes mellitus.

    PubMed Central

    Ehrmann, D A; Sturis, J; Byrne, M M; Karrison, T; Rosenfield, R L; Polonsky, K S

    1995-01-01

    The increased prevalence of non-insulin-dependent diabetes mellitus (NIDDM) among women with polycystic ovary syndrome (PCOS) has been ascribed to the insulin resistance characteristic of PCOS. This study was undertaken to determine the role of defects in insulin secretion as well as familial factors to the predisposition to NIDDM seen in PCOS. We studied three groups of women: PCOS with a family history of NIDDM (PCOS FHx POS; n = 11), PCOS without a family history of NIDDM (PCOS FHx NEG; n = 13), and women without PCOS who have a family history of NIDDM (NON-PCOS FHx POS; n = 8). Beta cell function was evaluated during a frequently sampled intravenous glucose tolerance test, by a low dose graded glucose infusion, and by the ability of the beta cell to be entrained by an oscillatory glucose infusion. PCOS FHx POS women were significantly less likely to demonstrate appropriate beta cell compensation for the degree of insulin resistance. The ability of the beta cell to entrain, as judged by the spectral power for insulin secretion rate, was significantly reduced in PCOS FHx POS subjects. In conclusion, a history of NIDDM in a first-degree relative appears to define a subset of PCOS subjects with a greater prevalence of insulin secretory defects. The risk of developing NIDDM imparted by insulin resistance in PCOS may be enhanced by these defects in insulin secretion. PMID:7615824

  2. A liver HIF-2α/IRS2 pathway sensitizes hepatic insulin signaling and is modulated by VEGF inhibition

    PubMed Central

    Taniguchi, Cullen M.; Wiegand, Stanley J.; Anderson, Keith; Chan, Carol W-M.; Mulligan, Kimberly X.; Kuo, David; Yuan, Jenny; Vallon, Mario; Morton, Lori; Lefai, Etienne; Simon, M. Celeste; Maher, Jacquelyn J.; Mithieux, Gilles; Rajas, Fabienne; Annes, Justin; McGuinness, Owen P.; Thurston, Gavin; Giaccia, Amato J.; Kuo, Calvin J.

    2013-01-01

    Insulin initiates diverse hepatic metabolic responses, including gluconeogenic suppression and induction of glycogen synthesis and lipogenesis1,2. The liver possesses a rich sinusoidal capillary network with increased hypoxia and decreased gluconeogenesis in the perivenous zone3. Here, diverse vascular endothelial growth factor (VEGF) inhibitors improved glucose tolerance in normal or diabetic db/db mice, potentiating hepatic insulin signaling, decreasing gluconeogenic gene expression, increasing glycogen storage and suppressing hepatic glucose production (HGP). VEGF inhibition induced hepatic hypoxia via sinusoidal vascular regression and sensitized liver insulin signaling through hypoxia inducible factor-2α (HIF-2α) stabilization. Notably, liver-specific constitutive activation of HIF-2α, but not HIF-1α, was sufficient to augment hepatic insulin signaling via direct and indirect induction of insulin receptor substrate 2 (IRS2), an essential insulin receptor adaptor protein4–6. Further, liver IRS2 was both necessary and sufficient to mediate HIF-2α and VEGF inhibition effects on glucose tolerance and hepatic insulin signaling. These results demonstrate an unsuspected intersection between HIF-2α–mediated hypoxic signaling and hepatic insulin action via IRS2 induction, which can be co-opted by VEGF inhibitors to modulate glucose metabolism. These studies also indicate distinct roles in hepatic metabolism for HIF-1α, which promotes glycolysis7–9, versus HIF-2α, which suppresses gluconeogenesis, and suggest novel treatment approaches for type 2 diabetes mellitus. PMID:24037094

  3. Insulin sensitivity is related to fat oxidation and protein kinase C activity in children with acute burn injury

    PubMed Central

    Cree, Melanie G.; Zwetsloot, Jennifer J.; Herndon, David N.; Newcomer, Bradley R.; Fram, Ricki Y.; Angel, Carlos; Green, Justin M.; Dohm, Gerald L.; Sun, Dayoung; Aarsland, Asle; Wolfe, Robert R.

    2014-01-01

    Objective Impaired fatty acid oxidation occurs with type 2 diabetes and is associated with accumulations of intracellular lipids, which may increase diacylglycerol, stimulate protein kinase C activity and inactivate insulin signaling. Glucose and fat metabolism are altered in burn patients, but have never been related to intracellular lipids or insulin signaling. Methods Thirty children sustaining >40% total body surface area burns were studied acutely with glucose and palmitate tracer infusions and a hyper-insulinemic euglycemic clamp. Muscle triglyceride, diacylglycerol, fatty acyl CoA and insulin signaling were measured. Liver and muscle triglyceride levels were measured with magnetic resonance spectroscopy. Muscle samples from healthy children were controls for diacylglycerol concentrations. Results Insulin sensitivity was reduced and correlated with whole body palmitate β-oxidation (P=0.004). Muscle insulin signaling was not stimulated by hyper-insulinemia. Tissue triglyceride concentrations and activated protein kinase C-β were elevated, whereas the concentration of diacylglycerol was similar to the controls. Free fatty acid profiles of muscle triglyceride did not match diacylglycerol. Conclusions Insulin resistance following burn injury is accompanied by decreased insulin signaling and increased protein kinase C-β activation. The best metabolic predictor of insulin resistance in burned patients was palmitate oxidation. PMID:18535477

  4. Bioactives of Artemisia dracunculus L. enhance insulin sensitivity by modulation of ceramide metabolism in rat skeletal muscle cells

    PubMed Central

    Obanda, Diana N.; Ribnicky, David; Raskin, Ilya; Cefalu, William T.

    2014-01-01

    Objective An increase in ectopic lipids in peripheral tissues has been implicated in attenuating insulin action. The botanical extract of Artemisia dracunculus L. (PMI-5011) improves insulin action, yet the precise mechanism is not known. We sought to determine whether the mechanism by which the bioactive compounds in PMI-5011 improve insulin signaling is through regulation of ceramide metabolism Methods L6 Myotubes were separately preincubated with 250uM palmitic acid with or without PMI-5011 or four bioactive compounds isolated from PMI-5011 and postulated to be responsible for the effect. The effects on insulin signaling, ceramide and glucosylceramide profiles were determined. Results Treatment of L6 myotubes with palmitic acid resulted in increased levels of total ceramides and glucosylceramides, and cell surface expression of gangliosides. Palmitic acid also inhibited insulin-stimulated phosphorylation of protein kinase B/Akt and reduced glycogen accumulation. Bioactives from PMI-5011 had no effect on ceramide formation but one active compound (DMC-2) and its synthetic analogue significantly reduced glucosylceramide accumulation and increased insulin sensitivity via restoration of Akt phosphorylation. Conclusions The observations suggest that insulin sensitization by PMI-5011 is partly mediated through moderation of glycosphingolipid accumulation. PMID:24985108

  5. Sortilin facilitates VLDL-B100 secretion by insulin sensitive McArdle RH7777 cells.

    PubMed

    Sparks, Robert P; Guida, Wayne C; Sowden, Mark P; Jenkins, Jermaine L; Starr, Matthew L; Fratti, Rutilio A; Sparks, Charles E; Sparks, Janet D

    2016-09-16

    Studies examining the relationship between cellular sortilin and VLDL-B100 secretion demonstrate inconsistent results. Current studies explore the possibility that discrepancies may be related to insulin sensitivity. McArdle RH7777 cells (McA cells) cultured under serum enriched conditions lose sensitivity to insulin. Following incubation in serum-free DMEM containing 1% BSA, McA cells become insulin responsive and demonstrate reduced apo B secretion. Current studies indicate that insulin sensitive McA cells express lower cellular sortilin that corresponds with reduction in VLDL-B100 secretion without changes in mRNA of either sortilin or apo B. When sortilin expression is further reduced by siRNA knockdown (KD), there are additional decreases in VLDL-B100 secretion. A crystal structure of human sortilin (hsortilin) identifies two binding sites on the luminal domain for the N- and C-termini of neurotensin (NT). A small organic compound (cpd984) was identified that has strong theoretical binding to the N-terminal site. Both cpd984 and NT bind hsortilin by surface plasmon resonance. In incubations with insulin sensitive McA cells, cpd984 was shown to enhance VLDL-B100 secretion at each level of sortilin KD suggesting cpd984 acted through sortilin in mediating its effect. Current results support a role for sortilin to facilitate VLDL-B100 secretion which is limited to insulin sensitive McA cells. Inconsistent reports of the relationship between VLDL-B100 secretion and sortilin in previous studies may relate to differing functions of sortilin in VLDL-B100 secretion depending upon insulin sensitivity. PMID:27495870

  6. THE EFFECTS OF THE DASH DIET ALONE AND IN COMBINATION WITH EXERCISE AND CALORIC RESTRICTION ON INSULIN SENSITIVITY AND LIPIDS

    PubMed Central

    Blumenthal, James A.; Babyak, Michael A.; Sherwood, Andrew; Craighead, Linda; Lin, Pao-Hwa; Johnson, Julie; Watkins, Lana L.; Wang, Jenny T.; Kuhn, Cynthia; Feinglos, Mark; Hinderliter, Alan

    2010-01-01

    This study examined the effects of the Dietary Approaches to Stop Hypertension (DASH) diet on insulin sensitivity and lipids. In a randomized control trial, 144 overweight (body mass index 25–40) men (N= 47) and women (N= 97) with high blood pressure (130–159/85–99 mm Hg) were randomly assigned to either: (1) DASH diet alone (DASH-A); (2) DASH diet with aerobic exercise and caloric restriction (DASH-WM); or usual diet controls (UC). Body composition, fitness, insulin sensitivity, and fasting lipids were measured before and following 4 months of treatment. Insulin sensitivity was estimated based on glucose and insulin levels in the fasting state and after an oral glucose load. Participants in the DASH-WM condition lost weight (−8.7 [95% CI = −2.0, −9.7] kg,), and exhibited a significant increase in aerobic capacity, while the DASH-A and UC participants maintained their weight (−0.3 [95% CI = −1.2, 0.5] kg and +0.9 [95% CI = 0.0, 1.7] kg, respectively) and had no improvement in exercise capacity. DASH-WM demonstrated lower glucose levels following the oral glucose load, improved insulin sensitivity, and lower total cholesterol and triglycerides compared to both DASH-A and UC, and lower fasting glucose and low-density lipoprotein cholesterol compared to UC; DASH-A participants generally did not differ from UC in these measures. Combining the DASH diet with exercise and weight loss resulted in significant improvements in insulin sensitivity and lipids. Despite clinically significant reductions in blood pressure, the DASH diet alone, without caloric restriction or exercise, resulted in minimal improvements in insulin sensitivity or lipids. PMID:20212264

  7. Improvement in insulin sensitivity following a 1-year lifestyle intervention program in viscerally obese men: contribution of abdominal adiposity.

    PubMed

    Borel, Anne-Laure; Nazare, Julie-Anne; Smith, Jessica; Alméras, Natalie; Tremblay, Angelo; Bergeron, Jean; Poirier, Paul; Després, Jean-Pierre

    2012-02-01

    The objectives of the study were to quantify the effect of a 1-year healthy eating-physical activity/exercise lifestyle modification program on insulin sensitivity in viscerally obese men classified according to their glucose tolerance status and to evaluate the respective contributions of changes in body fat distribution vs changes in cardiorespiratory fitness (CRF) to the improvements in indices of plasma glucose/insulin homeostasis. Abdominally obese, dyslipidemic men (waist circumference ≥90 cm, triglycerides ≥1.69 mmol/L, and/or high-density lipoprotein cholesterol <1.03 mmol/L) were recruited. The 1-year intervention/evaluation was completed by 104 men. Body weight, composition, and fat distribution were assessed by dual-energy x-ray absorptiometry/computed tomography. Cardiorespiratory fitness and cardiometabolic risk profile were measured. After 1 year, insulin sensitivity improved in association with decreases in both visceral (VAT) and subcutaneous adiposity (SAT) as well as with the improvement in CRF, regardless of baseline glucose tolerance. Further analyses were performed according to changes in glucose tolerance status: improvement (group I, n = 39), no change (group N, n = 50), or worsening (group W, n = 15) after 1 year. Groups I and N improved their insulin sensitivity and their CRF, whereas group W did not, while losing less VAT than groups I and N. Multiple regressions showed that reduction in VAT was associated with an improvement in homeostasis model assessment of insulin resistance, whereas reduction in SAT was rather associated with improvement of the insulin sensitivity index of Matsuda. Changes in CRF were not independently associated with changes in indices of plasma glucose/insulin homeostasis. A 1-year lifestyle intervention improved plasma glucose/insulin homeostasis in viscerally obese men, including those with normal glucose tolerance status at baseline. Changes in SAT and VAT but not in CRF appeared to mediate these improvements

  8. Adipocyte-specific blockade of gamma-secretase, but not inhibition of Notch activity, reduces adipose insulin sensitivity

    PubMed Central

    Sparling, David P.; Yu, Junjie; Kim, KyeongJin; Zhu, Changyu; Brachs, Sebastian; Birkenfeld, Andreas L.; Pajvani, Utpal B.

    2015-01-01

    Objective As the obesity pandemic continues to expand, novel molecular targets to reduce obesity-related insulin resistance and Type 2 Diabetes (T2D) continue to be needed. We have recently shown that obesity is associated with reactivated liver Notch signaling, which, in turn, increases hepatic insulin resistance, opening up therapeutic avenues for Notch inhibitors to be repurposed for T2D. Herein, we tested the systemic effects of γ-secretase inhibitors (GSIs), which prevent endogenous Notch activation, and confirmed these effects through creation and characterization of two different adipocyte-specific Notch loss-of-function mouse models through genetic ablation of the Notch transcriptional effector Rbp-Jk (A-Rbpj) and the obligate γ-secretase component Nicastrin (A-Nicastrin). Methods Glucose homeostasis and both local adipose and systemic insulin sensitivity were examined in GSI-treated, A-Rbpj and A-Nicastrin mice, as well as vehicle-treated or control littermates, with complementary in vitro studies in primary hepatocytes and 3T3-L1 adipocytes. Results GSI-treatment increases hepatic insulin sensitivity in obese mice but leads to reciprocal lowering of adipose glucose disposal. While A-Rbpj mice show normal body weight, adipose development and mass and unchanged adipose insulin sensitivity as control littermates, A-Nicastrin mice are relatively insulin-resistant, mirroring the GSI effect on adipose insulin action. Conclusions Notch signaling is dispensable for normal adipocyte function, but adipocyte-specific γ-secretase blockade reduces adipose insulin sensitivity, suggesting that specific Notch inhibitors would be preferable to GSIs for application in T2D. PMID:26909319

  9. The effect of n-3 fatty acids on glucose homeostasis and insulin sensitivity.

    PubMed

    Flachs, P; Rossmeisl, M; Kopecky, J

    2014-01-01

    Type 2 diabetes (T2D) as well as cardiovascular disease (CVD) represent major complications of obesity and associated metabolic disorders (metabolic syndrome). This review focuses on the effects of long-chain n-3 polyunsaturated fatty acids (omega-3) on insulin sensitivity and glucose homeostasis, which are improved by omega-3 in many animal models of metabolic syndrome, but remain frequently unaffected in humans. Here we focus on: (i) mechanistic aspects of omega-3 action, reflecting also our experiments in dietary obese mice; and (ii) recent studies analysing omega-3's effects in various categories of human subjects. Most animal experiments document beneficial effects of omega-3 on insulin sensitivity and glucose metabolism even under conditions of established obesity and insulin resistance. Besides positive results obtained in both cross-sectional and prospective cohort studies on healthy human populations, also some intervention studies in prediabetic subjects document amelioration of impaired glucose homeostasis by omega-3. However, the use of omega-3 to reduce a risk of new-onset diabetes in prediabetic subjects still remains to be further characterized. The results of a majority of clinical trials performed in T2D patients suggest that omega-3 have none or marginal effects on metabolic control, while effectively reducing hypertriglyceridemia in these patients. Despite most of the recent randomized clinical trials do not support the role of omega-3 in secondary prevention of CVD, this issue remains still controversial. Combined interventions using omega-3 and antidiabetic or hypolipidemic drugs should be further explored and considered for treatment of patients with T2D and other diseases. PMID:24564669

  10. Gender Differences in Skeletal Muscle Substrate Metabolism – Molecular Mechanisms and Insulin Sensitivity

    PubMed Central

    Lundsgaard, Anne-Marie; Kiens, Bente

    2014-01-01

    It has become increasingly apparent that substrate metabolism is subject to gender-specific regulation, and the aim of this review is to outline the available evidence of molecular gender differences in glucose and lipid metabolism of skeletal muscle. Female sex has been suggested to have a favorable effect on glucose homeostasis, and the available evidence from hyperinsulinemic–euglycemic clamp studies is summarized to delineate whether there is a gender difference in whole-body insulin sensitivity and in particular insulin-stimulated glucose uptake of skeletal muscle. Whether an eventual higher insulin sensitivity of female skeletal muscle can be related to gender-specific regulation of molecular metabolism will be topic for discussion. Gender differences in muscle fiber type distribution and substrate availability to and in skeletal muscle are highly relevant for substrate metabolism in men and women. In particular, the molecular machinery for glucose and fatty acid oxidative and storage capacities in skeletal muscle and its implications for substrate utilization during metabolic situations of daily living are discussed, emphasizing their relevance for substrate choice in the fed and fasted state, and during periods of physical activity and recovery. Together, handling of carbohydrate and lipids and regulation of their utilization in skeletal muscle have implications for whole-body glucose homeostasis in men and women. 17-β estradiol is the most important female sex hormone, and the identification of estradiol receptors in skeletal muscle has opened for a role in regulation of substrate metabolism. Also, higher levels of circulating adipokines as adiponectin and leptin in women and their implications for muscle metabolism will be considered. PMID:25431568

  11. Beef Fat Enriched with Polyunsaturated Fatty Acid Biohydrogenation Products Improves Insulin Sensitivity Without Altering Dyslipidemia in Insulin Resistant JCR:LA-cp Rats.

    PubMed

    Diane, Abdoulaye; Borthwick, Faye; Mapiye, Cletos; Vahmani, Payam; David, Rolland C; Vine, Donna F; Dugan, Michael E R; Proctor, Spencer D

    2016-07-01

    The main dietary sources of trans fatty acids are partially hydrogenated vegetable oils (PHVO), and products derived from polyunsaturated fatty acid biohydrogenation (PUFA-BHP) in ruminants. Trans fatty acid intake has historically been associated with negative effects on health, generating an anti-trans fat campaign to reduce their consumption. The profiles and effects on health of PHVO and PUFA-BHP can, however, be quite different. Dairy products naturally enriched with vaccenic and rumenic acids have many purported health benefits, but the putative benefits of beef fat naturally enriched with PUFA-BHP have not been investigated. The objective of the present experiment was to determine the effects of beef peri-renal fat (PRF) with differing enrichments of PUFA-BHP on lipid and insulin metabolism in a rodent model of dyslipidemia and insulin resistance (JCR:LA-cp rat). The results showed that 6 weeks of diet supplementation with beef PRF naturally enriched due to flaxseed (FS-PRF) or sunflower-seed (SS-PRF) feeding to cattle significantly improved plasma fasting insulin levels and insulin sensitivity, postprandial insulin levels (only in the FS-PRF) without altering dyslipidemia. Moreover, FS-PRF but not SS-PRF attenuated adipose tissue accumulation. Therefore, enhancing levels of PUFA-BHP in beef PRF with FS feeding may be a useful approach to maximize the health-conferring value of beef-derived fats. PMID:27072368

  12. Dasatinib improves insulin sensitivity and affects lipid metabolism in a patient with chronic myeloid leukaemia.

    PubMed

    Iizuka, Katsumi; Niwa, Hiroyuki; Kato, Takehiro; Takeda, Jun

    2016-01-01

    A 65-year-old woman had been visiting our department for the treatment of type-2 diabetes mellitus since December 2012. Her glycated haemoglobin levels were well controlled (≈5.8% (40 mmol/mol)) by metformin (500 mg). In July 2014, her white cell count increased suddenly to 33 530 cells/μL and she was diagnosed with Ph+ chronic myeloid leukaemia. She was started on dasatinib (100 mg), which immediately normalised plasma levels of WCC. Dasatinib improved the glycaemic index to <6.0% and also improved plasma levels of triglycerides (TGs) and high-density lipoprotein-cholesterol (HDL-c). Levels of low-density lipoprotein-cholesterol were increased but remained within the normal range. The TG:HDL-c ratio and Quantitative Insulin Sensitivity Check Index rapidly improved. Followed by an improvement in insulin sensitivity, plasma levels of adiponectin and leptin were increased. This case study suggests that dasatinib might have positive as well as negative effects on the metabolism of glucose and lipids. PMID:26873919

  13. 5,7-Dihydroxy-6-geranylflavanone improves insulin sensitivity through PPARα/γ dual activation.

    PubMed

    Lee, Woojung; Yoon, Goo; Kim, Min Cheol; Kwon, Hak Cheol; Bae, Gyu-Un; Kim, Yong Kee; Kim, Su-Nam

    2016-05-01

    In the present study, we demonstrate that 5,7-dihydroxy-6-geranylflavanone (DGF) isolated from Amorpha fruticosa (A. fruticosa) is a novel peroxisome proliferator-activated receptor (PPAR)α/γ dual agonist which may be used to improve insulin sensitivity. The extract from A. fruticosa increased the transcriptional activity of both PPARα and PPARγ which was, in part, driven by the active ingredient DGF. Treatment with DGF markedly enhanced the adipogenesis of 3T3-L1 preadipocytes, which was comparable to the effect of the PPARγ agonist, troglitazone. In addition, DGF was found to enhance fatty acid oxidation and glucose utilization through the dual activation of PPARα/γ. In addition treatment with DGF led to an improvement in insulin sensitivity, resulting in enhanced glucose uptake in muscle cells. The findings of our study data suggest that DGF may be used as potential therapeutic agent in the treatment of type 2 diabetes and related metabolic disorders by enhancing glucose and lipid metabolism. PMID:26986637

  14. Temperature-Acclimated Brown Adipose Tissue Modulates Insulin Sensitivity in Humans

    PubMed Central

    Lee, Paul; Smith, Sheila; Linderman, Joyce; Courville, Amber B.; Brychta, Robert J.; Dieckmann, William; Werner, Charlotte D.; Chen, Kong Y.

    2014-01-01

    In rodents, brown adipose tissue (BAT) regulates cold- and diet-induced thermogenesis (CIT; DIT). Whether BAT recruitment is reversible and how it impacts on energy metabolism have not been investigated in humans. We examined the effects of temperature acclimation on BAT, energy balance, and substrate metabolism in a prospective crossover study of 4-month duration, consisting of four consecutive blocks of 1-month overnight temperature acclimation (24°C [month 1] → 19°C [month 2] → 24°C [month 3] → 27°C [month 4]) of five healthy men in a temperature-controlled research facility. Sequential monthly acclimation modulated BAT reversibly, boosting and suppressing its abundance and activity in mild cold and warm conditions (P < 0.05), respectively, independent of seasonal fluctuations (P < 0.01). BAT acclimation did not alter CIT but was accompanied by DIT (P < 0.05) and postprandial insulin sensitivity enhancement (P < 0.05), evident only after cold acclimation. Circulating and adipose tissue, but not skeletal muscle, expression levels of leptin and adiponectin displayed reciprocal changes concordant with cold-acclimated insulin sensitization. These results suggest regulatory links between BAT thermal plasticity and glucose metabolism in humans, opening avenues to harnessing BAT for metabolic benefits. PMID:24954193

  15. Peroxisome proliferator-activated receptor gamma agonists as insulin sensitizers: from the discovery to recent progress.

    PubMed

    Cho, Nobuo; Momose, Yu

    2008-01-01

    An epidemic of metabolic diseases including type 2 diabetes and obesity is undermining the health of people living in industrialized societies. There is an urgent need to develop innovative therapeutics. The peroxisome proliferator-activated receptor gamma (PPARgamma) is one of the ligand-activated transcription factors in the nuclear hormone receptor superfamily and a pivotal regulator of glucose and lipid homeostasis. The discovery of PPARgamma as a target of multimodal insulin sensitizers, represented by thiazolidinediones (TZDs), has attracted remarkable scientific interest and had a great impact on the pharmaceutical industry. With the clinical success of the PPARgamma agonists, pioglitazone (Actos) and rosiglitazone (Avandia), development of novel and potent insulin-sensitizing agents with diverse clinical profiles has been accelerated. Currently, a number of PPARgamma agonists from different chemical classes and with varying pharmacological profiles are being developed. Despite quite a few obstacles to the development of PPAR-related drugs, PPARgamma-targeted agents still hold promise. There are new concepts and encouraging evidence emerging that suggest this class can yield improved anti-diabetic agents. This review covers the discovery of TZDs, provides an overview of PPARgamma including the significance of PPARgamma as a drug target, describes the current status of a wide variety of novel PPARgamma ligands including PPAR dual and pan agonists and selective PPARgamma modulators (SPPARgammaMs), and highlights new approaches for identifying agents targeting PPARgamma in the treatment of type 2 diabetes. PMID:19075761

  16. Enhanced insulin sensitivity in skeletal muscle and liver by physiological overexpression of SIRT6☆

    PubMed Central

    Anderson, Jason G.; Ramadori, Giorgio; Ioris, Rafael M.; Galiè, Mirco; Berglund, Eric D.; Coate, Katie C.; Fujikawa, Teppei; Pucciarelli, Stefania; Moreschini, Benedetta; Amici, Augusto; Andreani, Cristina; Coppari, Roberto

    2015-01-01

    Objective Available treatment for obesity and type 2 diabetes mellitus (T2DM) is suboptimal. Thus, identifying novel molecular target(s) exerting protective effects against these metabolic imbalances is of enormous medical significance. Sirt6 loss- and gain-of-function studies have generated confounding data regarding the role of this sirtuin on energy and glucose homeostasis, leaving unclear whether activation or inhibition of SIRT6 may be beneficial for the treatment of obesity and/or T2DM. Methods To address these issues, we developed and studied a novel mouse model designed to produce eutopic and physiological overexpression of SIRT6 (Sirt6BAC mice). These mutants and their controls underwent several metabolic analyses. These include whole-blood reverse phase high-performance liquid chromatography assay, glucose and pyruvate tolerance tests, hyperinsulinemic-euglycemic clamp assays, and assessment of basal and insulin-induced level of phosphorylated AKT (p-AKT)/AKT in gastrocnemius muscle. Results Sirt6BAC mice physiologically overexpress functionally competent SIRT6 protein. While Sirt6BAC mice have normal body weight and adiposity, they are protected from developing high-caloric-diet (HCD)-induced hyperglycemia and glucose intolerance. Also, Sirt6BAC mice display increased circulating level of the polyamine spermidine. The ability of insulin to suppress endogenous glucose production was significantly enhanced in Sirt6BAC mice compared to wild-type controls. Insulin-stimulated glucose uptake was increased in Sirt6BAC mice in both gastrocnemius and soleus muscle, but not in brain, interscapular brown adipose, or epididymal adipose tissue. Insulin-induced p-AKT/AKT ratio was increased in gastrocnemius muscle of Sirt6BAC mice compared to wild-type controls. Conclusions Our data indicate that moderate, physiological overexpression of SIRT6 enhances insulin sensitivity in skeletal muscle and liver, engendering protective actions against diet-induced T2DM. Hence

  17. Insulin Sensitivity and Mitochondrial Function Are Improved in Children With Burn Injury During a Randomized Controlled Trial of Fenofibrate

    PubMed Central

    Cree, Melanie G.; Zwetsloot, Jennifer J.; Herndon, David N.; Qian, Ting; Morio, Beatrice; Fram, Ricki; Sanford, Arthur P.; Aarsland, Asle; Wolfe, Robert R.

    2007-01-01

    Objective: To determine some of the mechanisms involved in insulin resistance immediately following burn trauma, and to determine the efficacy of PPAR-α agonism for alleviating insulin resistance in this population. Summary Background Data: Hyperglycemia following trauma, especially burns, is well documented. However, the underlying insulin resistance is not well understood, and there are limited treatment options. Methods: Twenty-one children 4 to 16 years of age with >40% total body surface area burns were enrolled in a double-blind, prospective, placebo-controlled randomized trial. Whole body and liver insulin sensitivity were assessed with a hyperinsulinemic-euglycemic clamp, and insulin signaling and mitochondrial function were measured in muscle biopsies taken before and after ∼2 weeks of either placebo (PLA) or 5 mg/kg of PPAR-α agonist fenofibrate (FEN) treatment, within 3 weeks of injury. Results: The change in average daily glucose concentrations was significant between groups after treatment (146 ± 9 vs. 161 ± 9 mg/dL PLA and 158 ± 7 vs. 145 ± 4 FEN; pretreatment vs. posttreatment; P = 0.004). Insulin-stimulated glucose uptake increased significantly in FEN (4.3 ± 0.6 vs. 4.5 ± 0.7 PLA and 5.2 ± 0.5 vs. 7.6 ± 0.6 mg/kg per minute FEN; pretreatment vs. posttreatment; P = 0.003). Insulin trended to suppress hepatic glucose release following fenofibrate treatment (P = 0.06). Maximal mitochondrial ATP production from pyruvate increased significantly after fenofibrate (P = 0.001) and was accompanied by maintained levels of cytochrome C oxidase and citrate synthase activity levels. Tyrosine phosphorylation of the insulin receptor and insulin receptor substrate-1 in response to insulin increased significantly following fenofibrate treatment (P = 0.04 for both). Conclusions: Fenofibrate treatment started within 1 week postburn and continued for 2 weeks significantly decreased plasma glucose concentrations by improving insulin sensitivity, insulin

  18. Exercise-induced increase in IL-6 level enhances GLUT4 expression and insulin sensitivity in mouse skeletal muscle.

    PubMed

    Ikeda, Shin-Ichi; Tamura, Yoshifumi; Kakehi, Saori; Sanada, Hiromi; Kawamori, Ryuzo; Watada, Hirotaka

    2016-05-13

    A single bout of exercise is known to increase the insulin sensitivity of skeletal muscle; however, the underlying mechanism of this phenomenon is not fully understood. Because a single bout of exercise induces a transient increase in blood interleukin-6 (IL-6) level, we hypothesized that the enhancement of insulin sensitivity after a single bout of exercise in skeletal muscle is mediated at least in part through IL-6-dependent mechanisms. To test this hypothesis, C57BL6J mice were intravenously injected with normal IgG or an IL-6 neutralizing antibody before exercise. Twenty-four hours after a single bout of exercise, the plantaris muscle was harvested to measure insulin sensitivity and glucose transporter (GLUT)-4 expression levels by ex-vivo insulin-stimulated 2-deoxyglucose (2-DG) uptake and Western blotting, respectively. Compared with sedentary mice, mice that performed exercise showed enhanced IL-6 concentration, insulin-stimulated 2-DG uptake, and GLUT-4 expression in the plantaris muscle. The enhanced insulin sensitivity and GLUT4 expression were canceled by injection of the IL-6 neutralizing antibody before exercise. In addition, IL-6 injection increased GLUT4 expression, both in the plantaris muscle and the soleus muscle in C57BL6J mice. Furthermore, a short period of incubation with IL-6 increased GLUT4 expression in differentiated C2C12 myotubes. In summary, these results suggested that IL-6 increased GLUT4 expression in muscle and that this phenomenon may play a role in the post-exercise enhancement of insulin sensitivity in skeletal muscle. PMID:27040770

  19. Expression and Regulation of Facilitative Glucose Transporters in Equine Insulin-Sensitive Tissue: From Physiology to Pathology

    PubMed Central

    Lacombe, Véronique A.

    2014-01-01

    Glucose uptake is the rate-limiting step in glucose utilization in mammalians and is tightly regulated by a family of specialized proteins, called the facilitated glucose transporters (GLUTs/SLC2). GLUT4, the major isoform in insulin-responsive tissue, translocates from an intracellular pool to the cell surface and as such determines insulin-stimulated glucose uptake. However, despite intensive research over 50 years, the insulin-dependent and -independent pathways that mediate GLUT4 translocation are not fully elucidated in any species. Insulin resistance (IR) is one of the hallmarks of equine metabolic syndrome and is the most common metabolic predisposition for laminitis in horses. IR is characterized by the impaired ability of insulin to stimulate glucose disposal into insulin-sensitive tissues. Similar to other species, the functional capability of the insulin-responsive GLUTs is impaired in muscle and adipose tissue during IR in horses. However, the molecular mechanisms of altered glucose transport remain elusive in all species, and there is still much to learn about the physiological and pathophysiological functions of the GLUT family members, especially in regard to class III. Since GLUTs are key regulators of whole-body glucose homeostasis, they have received considerable attention as potential therapeutic targets to treat metabolic disorders in human and equine patients. PMID:24977043

  20. Microneedle-array patches loaded with hypoxia-sensitive vesicles provide fast glucose-responsive insulin delivery

    PubMed Central

    Yu, Jicheng; Zhang, Yuqi; Ye, Yanqi; DiSanto, Rocco; Sun, Wujin; Ranson, Davis; Ligler, Frances S.; Buse, John B.; Gu, Zhen

    2015-01-01

    A glucose-responsive “closed-loop” insulin delivery system mimicking the function of pancreatic cells has tremendous potential to improve quality of life and health in diabetics. Here, we report a novel glucose-responsive insulin delivery device using a painless microneedle-array patch (“smart insulin patch”) containing glucose-responsive vesicles (GRVs; with an average diameter of 118 nm), which are loaded with insulin and glucose oxidase (GOx) enzyme. The GRVs are self-assembled from hypoxia-sensitive hyaluronic acid (HS-HA) conjugated with 2-nitroimidazole (NI), a hydrophobic component that can be converted to hydrophilic 2-aminoimidazoles through bioreduction under hypoxic conditions. The local hypoxic microenvironment caused by the enzymatic oxidation of glucose in the hyperglycemic state promotes the reduction of HS-HA, which rapidly triggers the dissociation of vesicles and subsequent release of insulin. The smart insulin patch effectively regulated the blood glucose in a mouse model of chemically induced type 1 diabetes. The described work is the first demonstration, to our knowledge, of a synthetic glucose-responsive device using a hypoxia trigger for regulation of insulin release. The faster responsiveness of this approach holds promise in avoiding hyperglycemia and hypoglycemia if translated for human therapy. PMID:26100900

  1. Microneedle-array patches loaded with hypoxia-sensitive vesicles provide fast glucose-responsive insulin delivery.

    PubMed

    Yu, Jicheng; Zhang, Yuqi; Ye, Yanqi; DiSanto, Rocco; Sun, Wujin; Ranson, Davis; Ligler, Frances S; Buse, John B; Gu, Zhen

    2015-07-01

    A glucose-responsive "closed-loop" insulin delivery system mimicking the function of pancreatic cells has tremendous potential to improve quality of life and health in diabetics. Here, we report a novel glucose-responsive insulin delivery device using a painless microneedle-array patch ("smart insulin patch") containing glucose-responsive vesicles (GRVs; with an average diameter of 118 nm), which are loaded with insulin and glucose oxidase (GOx) enzyme. The GRVs are self-assembled from hypoxia-sensitive hyaluronic acid (HS-HA) conjugated with 2-nitroimidazole (NI), a hydrophobic component that can be converted to hydrophilic 2-aminoimidazoles through bioreduction under hypoxic conditions. The local hypoxic microenvironment caused by the enzymatic oxidation of glucose in the hyperglycemic state promotes the reduction of HS-HA, which rapidly triggers the dissociation of vesicles and subsequent release of insulin. The smart insulin patch effectively regulated the blood glucose in a mouse model of chemically induced type 1 diabetes. The described work is the first demonstration, to our knowledge, of a synthetic glucose-responsive device using a hypoxia trigger for regulation of insulin release. The faster responsiveness of this approach holds promise in avoiding hyperglycemia and hypoglycemia if translated for human therapy. PMID:26100900

  2. Polysaccharide isolated from Triticum aestivum stimulates insulin release from pancreatic cells via the ATP-sensitive K+ channel.

    PubMed

    Lee, Sun-Hee; Lim, Sung-Won; Lee, Young-Mi; Lee, Hoi-Seon; Kim, Dae-Ki

    2012-05-01

    Traditional natural plants have been used throughout the world for their antidiabetic effects. The aim of the present study was to investigate the stimulating activity of a polysaccharide extract derived from T. aestivum sprout (TASP) on insulin secretion in vitro using the RIN-5F pancreatic β-cell line and rat pancreatic islets. In these experiments, TASP (0.1 to 2 mg/ml) augmented glucose-stimulated insulin secretion in a dose-dependent manner in the presence of a stimulatory glucose concentration (16.7 mM), but not of a basal concentration (1.1 mM). Although TASP failed to enhance the high K+-induced insulin secretion, the insulinotropic effect of TASP was significantly inhibited by diazoxide, an opener of ATP-sensitive K+ channel blocking insulin release. TASP potentiated the insulin secretion induced by other secretagogues, such as IBMX and tolbutamide. Moreover, glucose-derived blood insulin levels were significantly elevated by oral administration of TASP to mice, similarly to antidiabetic drugs. We also demonstrated that TASP significantly increased glucose-induced 45Ca2+ uptake and proinsulin mRNA expression in rat islets. Overall, our results suggest that TASP has a stimulating effect on insulin secretion and production in pancreatic β-cells via K+ channel closure and calcium influx. These results suggest that TASP may be useful as a candidate for the therapy of diabetes mellitus. PMID:22322245

  3. Expression and regulation of facilitative glucose transporters in equine insulin-sensitive tissue: from physiology to pathology.

    PubMed

    Lacombe, Véronique A

    2014-01-01

    Glucose uptake is the rate-limiting step in glucose utilization in mammalians and is tightly regulated by a family of specialized proteins, called the facilitated glucose transporters (GLUTs/SLC2). GLUT4, the major isoform in insulin-responsive tissue, translocates from an intracellular pool to the cell surface and as such determines insulin-stimulated glucose uptake. However, despite intensive research over 50 years, the insulin-dependent and -independent pathways that mediate GLUT4 translocation are not fully elucidated in any species. Insulin resistance (IR) is one of the hallmarks of equine metabolic syndrome and is the most common metabolic predisposition for laminitis in horses. IR is characterized by the impaired ability of insulin to stimulate glucose disposal into insulin-sensitive tissues. Similar to other species, the functional capability of the insulin-responsive GLUTs is impaired in muscle and adipose tissue during IR in horses. However, the molecular mechanisms of altered glucose transport remain elusive in all species, and there is still much to learn about the physiological and pathophysiological functions of the GLUT family members, especially in regard to class III. Since GLUTs are key regulators of whole-body glucose homeostasis, they have received considerable attention as potential therapeutic targets to treat metabolic disorders in human and equine patients. PMID:24977043

  4. Insulin regulates enzyme activity, malonyl-CoA sensitivity and mRNA abundance of hepatic carnitine palmitoyltransferase-I.

    PubMed Central

    Park, E A; Mynatt, R L; Cook, G A; Kashfi, K

    1995-01-01

    The regulation of hepatic mitochondrial carnitine palmitoyltransferase-I (CPT-I) was studied in rats during starvation and insulin-dependent diabetes and in rat H4IIE cells. The Vmax. for CPT-I in hepatic mitochondrial outer membranes isolated from starved and diabetic rats increased 2- and 3-fold respectively over fed control values with no change in Km values for substrates. Regulation of malonyl-CoA sensitivity of CPT-I in isolated mitochondrial outer membranes was indicated by an 8-fold increase in Ki during starvation and by a 50-fold increase in Ki in the diabetic state. Peroxisomal and microsomal CPT also had decreased sensitivity to inhibition by malonyl-CoA during starvation. CPT-I mRNA abundance was 7.5 times greater in livers of 48-h-starved rats and 14.6 times greater in livers of insulin-dependent diabetic rats compared with livers of fed rats. In H4IIE cells, insulin increased CPT-I sensitivity to inhibition by malonyl-CoA in 4 h, and sensitivity continued to increase up to 24 h after insulin addition. CPT-I mRNA levels in H4IIE cells were decreased by insulin after 4 h and continued to decrease so that at 24 h there was a 10-fold difference. The half-life of CPT-I mRNA was 4 h in the presence of actinomycin D or with actinomycin D plus insulin. These results suggest that insulin regulates CPT-I by inhibiting transcription of the CPT-I gene. Images Figure 2 Figure 4 PMID:7575418

  5. Skeletal muscle phosphatidylcholine and phosphatidylethanolamine are related to insulin sensitivity and respond to acute exercise in humans.

    PubMed

    Newsom, Sean A; Brozinick, Joseph T; Kiseljak-Vassiliades, Katja; Strauss, Allison N; Bacon, Samantha D; Kerege, Anna A; Bui, Hai Hoang; Sanders, Phil; Siddall, Parker; Wei, Tao; Thomas, Melissa; Kuo, Ming Shang; Nemkov, Travis; D'Alessandro, Angelo; Hansen, Kirk C; Perreault, Leigh; Bergman, Bryan C

    2016-06-01

    Several recent reports indicate that the balance of skeletal muscle phosphatidylcholine (PC) and phosphatidylethanolamine (PE) is a key determinant of muscle contractile function and metabolism. The purpose of this study was to determine relationships between skeletal muscle PC, PE and insulin sensitivity, and whether PC and PE are dynamically regulated in response to acute exercise in humans. Insulin sensitivity was measured via intravenous glucose tolerance in sedentary obese adults (OB; n = 14), individuals with type 2 diabetes (T2D; n = 15), and endurance-trained athletes (ATH; n = 15). Vastus lateralis muscle biopsies were obtained at rest, immediately after 90 min of cycle ergometry at 50% maximal oxygen consumption (V̇o2 max), and 2-h postexercise (recovery). Skeletal muscle PC and PE were measured via infusion-based mass spectrometry/mass spectrometry analysis. ATH had greater levels of muscle PC and PE compared with OB and T2D (P < 0.05), with total PC and PE positively relating to insulin sensitivity (both P < 0.05). Skeletal muscle PC:PE ratio was elevated in T2D compared with OB and ATH (P < 0.05), tended to be elevated in OB vs. ATH (P = 0.07), and was inversely related to insulin sensitivity among the entire cohort (r = -0.43, P = 0.01). Muscle PC and PE were altered by exercise, particularly after 2 h of recovery, in a highly group-specific manner. However, muscle PC:PE ratio remained unchanged in all groups. In summary, total muscle PC and PE are positively related to insulin sensitivity while PC:PE ratio is inversely related to insulin sensitivity in humans. A single session of exercise significantly alters skeletal muscle PC and PE levels, but not PC:PE ratio. PMID:27032901

  6. Association of cardiorespiratory fitness with insulin sensitivity in overweight and obese postmenopausal women: a Montreal Ottawa New Emerging Team study.

    PubMed

    Messier, Virginie; Malita, Florin M; Rabasa-Lhoret, Rémi; Brochu, Martin; Karelis, Antony D

    2008-09-01

    The purpose of this study was to examine the relation between insulin sensitivity and cardiorespiratory fitness in overweight and obese postmenopausal women. The study population consisted of 127 overweight and obese postmenopausal women (age, 57.7 +/- 4.8 years; body mass index, 32.7 +/- 4.7 kg/m(2)). Subjects were classified by dividing the entire cohort into tertiles (T) based on insulin sensitivity expressed per kilograms of lean body mass (LBM) (T1, <10.9; T2, 10.9-12.9, T3, >12.9 mg/min per kilogram of LBM, respectively). Outcome measures were body composition (dual-energy x-ray absorptiometry), visceral adipose tissue (computed tomography), insulin sensitivity (hyperinsulinemic-euglycemic clamp), cardiorespiratory fitness (indirect calorimetry), lower-body muscle strength (1 maximal repetition), physical activity energy expenditure (doubly labeled water), fasting lipids, and inflammatory profile. We found a significant positive relationship between insulin sensitivity and cardiorespiratory fitness (r = 0.25, P = .005). Moreover, cardiorespiratory fitness was higher in the T3 group compared to the T1 group (36.2 +/- 6.1 vs 33.1 +/- 5.0 mL/kg LBM per minute, respectively; P = .028). However, the difference was no longer significant after controlling for visceral adipose tissue or muscle strength. Finally, cardiorespiratory fitness was an independent predictor of insulin sensitivity. High levels of cardiorespiratory fitness are associated with higher levels of insulin sensitivity in overweight and obese postmenopausal women. Moreover, visceral adipose tissue accumulation or muscle strength may be potential mediators of this relationship. PMID:18702957

  7. UCP1 is an essential mediator of the effects of methionine restriction on energy balance but not insulin sensitivity

    PubMed Central

    Wanders, Desiree; Burk, David H.; Cortez, Cory C.; Van, Nancy T.; Stone, Kirsten P.; Baker, Mollye; Mendoza, Tamra; Mynatt, Randall L.; Gettys, Thomas W.

    2015-01-01

    Dietary methionine restriction (MR) by 80% increases energy expenditure (EE), reduces adiposity, and improves insulin sensitivity. We propose that the MR-induced increase in EE limits fat deposition by increasing sympathetic nervous system–dependent remodeling of white adipose tissue and increasing uncoupling protein 1 (UCP1) expression in both white and brown adipose tissue. In independent assessments of the role of UCP1 as a mediator of MR’s effects on EE and insulin sensitivity, EE did not differ between wild-type (WT) and Ucp1−/− mice on the control diet, but MR increased EE by 31% and reduced adiposity by 25% in WT mice. In contrast, MR failed to increase EE or reduce adiposity in Ucp1−/− mice. However, MR was able to increase overall insulin sensitivity by 2.2-fold in both genotypes. Housing temperatures used to minimize (28°C) or increase (23°C) sympathetic nervous system activity revealed temperature-independent effects of the diet on EE. Metabolomics analysis showed that genotypic and dietary effects on white adipose tissue remodeling resulted in profound increases in fatty acid metabolism within this tissue. These findings establish that UCP1 is required for the MR-induced increase in EE but not insulin sensitivity and suggest that diet-induced improvements in insulin sensitivity are not strictly derived from dietary effects on energy balance.—Wanders, D., Burk, D. H., Cortez, C. C., Van, N. T., Stone, K. P., Baker, M., Mendoza, T., Mynatt, R. L., Gettys, T. W. UCP1 is an essential mediator of the effects of methionine restriction on energy balance but not insulin sensitivity. PMID:25742717

  8. Rosmarinic acid ameliorates hyperglycemia and insulin sensitivity in diabetic rats, potentially by modulating the expression of PEPCK and GLUT4

    PubMed Central

    Runtuwene, Joshua; Cheng, Kai-Chun; Asakawa, Akihiro; Amitani, Haruka; Amitani, Marie; Morinaga, Akinori; Takimoto, Yoshiyuki; Kairupan, Bernabas Harold Ralph; Inui, Akio

    2016-01-01

    Background Rosmarinic acid (RA) is a natural substance that may be useful for treating diabetes mellitus. The present study investigated the effects of RA on glucose homeostasis and insulin regulation in rats with streptozocin (STZ)-induced type 1 diabetes or high-fat diet (HFD)-induced type 2 diabetes. Methods Glucose homeostasis was determined using oral glucose tolerance tests and postprandial glucose tests, and insulin activity was evaluated using insulin tolerance tests and the homeostatic model assessment for insulin resistance. Additionally, the protein expression levels of PEPCK and GLUT4 were determined using Western blot analysis. Results RA administration exerted a marked hypoglycemic effect on STZ-induced diabetic rats and enhanced glucose utilization and insulin sensitivity in HFD-fed diabetic rats. These effects of RA were dose-dependent. Meanwhile, RA administration reversed the STZ- and HFD-induced increase in PEPCK expression in the liver and the STZ- and HFD-induced decrease in GLUT4 expression in skeletal muscle. Conclusion RA reduces hyperglycemia and ameliorates insulin sensitivity by decreasing PEPCK expression and increasing GLUT4 expression. PMID:27462144

  9. Inactivation of the Class II PI3K-C2β Potentiates Insulin Signaling and Sensitivity

    PubMed Central

    Alliouachene, Samira; Bilanges, Benoit; Chicanne, Gaëtan; Anderson, Karen E.; Pearce, Wayne; Ali, Khaled; Valet, Colin; Posor, York; Low, Pei Ching; Chaussade, Claire; Scudamore, Cheryl L.; Salamon, Rachel S.; Backer, Jonathan M.; Stephens, Len; Hawkins, Phill T.; Payrastre, Bernard; Vanhaesebroeck, Bart

    2015-01-01

    Summary In contrast to the class I phosphoinositide 3-kinases (PI3Ks), the organismal roles of the kinase activity of the class II PI3Ks are less clear. Here, we report that class II PI3K-C2β kinase-dead mice are viable and healthy but display an unanticipated enhanced insulin sensitivity and glucose tolerance, as well as protection against high-fat-diet-induced liver steatosis. Despite having a broad tissue distribution, systemic PI3K-C2β inhibition selectively enhances insulin signaling only in metabolic tissues. In a primary hepatocyte model, basal PI3P lipid levels are reduced by 60% upon PI3K-C2β inhibition. This results in an expansion of the very early APPL1-positive endosomal compartment and altered insulin receptor trafficking, correlating with an amplification of insulin-induced, class I PI3K-dependent Akt signaling, without impacting MAPK activity. These data reveal PI3K-C2β as a critical regulator of endosomal trafficking, specifically in insulin signaling, and identify PI3K-C2β as a potential drug target for insulin sensitization. PMID:26655903

  10. Isolation of insulin-sensitive phosphatidylinositol-glycan from rat adipocytes. Its impaired breakdown in the streptozotocin-diabetic rat.

    PubMed Central

    Macaulay, S L; Larkins, R G

    1990-01-01

    In this study an insulin-sensitive glycophospholipid from rat adipocytes was isolated and partially characterized. A material that activated pyruvate dehydrogenase was extracted from rat adipocyte membrane supernatants. Its release was stimulated by insulin and phosphatidylinositol-specific-phospholipase C and its activity was destroyed by nitrous acid deamination. These findings suggested that insulin might stimulate breakdown of a glycophospholipid containing inositol and glucosamine, as previously reported for some other cell types [Low & Saltiel (1988) Science 239, 268-275]. A lipid that incorporated [3H]glucosamine, [3H]galactose, [3H]inositol, and [3H]myristate and whose turnover was stimulated by insulin was subsequently isolated from intact adipocytes by sequential t.l.c. using an acidic solvent system followed by a basic solvent system. The effects of insulin on turnover of the lipid in these cells were transient, with maximal effects at 1 min, and there was a typical concentration-response curve to insulin (0.07 nM-7 nM), with effects being detected over the physiological range of insulin concentrations. In contrast with studies in other cells, there was appreciable turnover of the sugar labels. The majority of the [3H]glucosamine and [3H]galactose labels were cycled through to triacylglycerol in the adipocyte. However, of that recovered in the glycophospholipid band, a major proportion (less than 40%) was recovered as the native label. Digestion of the purified molecule with phosphatidylinositol-specific phospholipase C generated a material that activated both pyruvate dehydrogenase and low-Km cyclic AMP phosphodiesterase. Impairment in insulin-stimulated breakdown of the molecule in adipocytes of streptozotocin-diabetic rats was found, consistent with the impaired insulin activation of pyruvate dehydrogenase and glucose utilization seen in this model. These findings suggest that insulin stimulates breakdown of this glycophospholipid by stimulating an

  11. Dairy fat intake is associated with glucose tolerance, hepatic and systemic insulin sensitivity, and liver fat but not β-cell function in humans123

    PubMed Central

    Marcovina, Santica; Nelson, James E; Yeh, Matthew M; Kowdley, Kris V; Callahan, Holly S; Song, Xiaoling; Di, Chongzhi; Utzschneider, Kristina M

    2014-01-01

    Background: Plasma phospholipid concentrations of trans-palmitoleic acid (trans-16:1n−7), a biomarker of dairy fat intake, are inversely associated with incident type 2 diabetes in 2 US cohorts. Objective: The objective was to investigate whether the intake of trans-16:1n−7 in particular, or dairy fat in general, is associated with glucose tolerance and key factors determining glucose tolerance. Design: A cross-sectional investigation was undertaken in 17 men and women with nonalcoholic fatty liver disease and 15 body mass index (BMI)- and age-matched controls. The concentrations of trans-16:1n−7 and 2 other biomarkers of dairy fat intake, 15:0 and 17:0, were measured in plasma phospholipids and free fatty acids (FFAs). Liver fat was estimated by computed tomography–derived liver-spleen ratio. Intravenous-glucose-tolerance tests and oral-glucose-tolerance test (OGTT) and hyperinsulinemic-euglycemic clamps were performed to assess β-cell function and hepatic and systemic insulin sensitivity. Results: In multivariate analyses adjusted for age, sex, and BMI, phospholipid 17:0, phospholipid trans-16:1n−7, FFA 15:0, and FFA 17:0 were inversely associated with fasting plasma glucose, the area under the curve for glucose during an OGTT, and liver fat. Phospholipid trans-16:1n−7 was also positively associated with hepatic and systemic insulin sensitivity. None of the biomarkers were associated with β-cell function. The associations between dairy fat intake and glucose tolerance were attenuated by adjusting for insulin sensitivity or liver fat, but strengthened by adjusting for β-cell function. Conclusion: Although we cannot rule out reverse causation, these data support the hypothesis that dairy fat improves glucose tolerance, possibly through a mechanism involving improved hepatic and systemic insulin sensitivity and reduced liver fat. This trial was registered at clinicaltrials.gov as NCT01289639. PMID:24740208

  12. Routine OGTT: A Robust Model Including Incretin Effect for Precise Identification of Insulin Sensitivity and Secretion in a Single Individual

    PubMed Central

    De Gaetano, Andrea; Panunzi, Simona; Matone, Alice; Samson, Adeline; Vrbikova, Jana; Bendlova, Bela; Pacini, Giovanni

    2013-01-01

    In order to provide a method for precise identification of insulin sensitivity from clinical Oral Glucose Tolerance Test (OGTT) observations, a relatively simple mathematical model (Simple Interdependent glucose/insulin MOdel SIMO) for the OGTT, which coherently incorporates commonly accepted physiological assumptions (incretin effect and saturating glucose-driven insulin secretion) has been developed. OGTT data from 78 patients in five different glucose tolerance groups were analyzed: normal glucose tolerance (NGT), impaired glucose tolerance (IGT), impaired fasting glucose (IFG), IFG+IGT, and Type 2 Diabetes Mellitus (T2DM). A comparison with the 2011 Salinari (COntinuos GI tract MOdel, COMO) and the 2002 Dalla Man (Dalla Man MOdel, DMMO) models was made with particular attention to insulin sensitivity indices ISCOMO, ISDMMO and kxgi (the insulin sensitivity index for SIMO). ANOVA on kxgi values across groups resulted significant overall (P<0.001), and post-hoc comparisons highlighted the presence of three different groups: NGT (8.62×10−5±9.36×10−5 min−1pM−1), IFG (5.30×10−5±5.18×10−5) and combined IGT, IFG+IGT and T2DM (2.09×10−5±1.95×10−5, 2.38×10−5±2.28×10−5 and 2.38×10−5±2.09×10−5 respectively). No significance was obtained when comparing ISCOMO or ISDMMO across groups. Moreover, kxgi presented the lowest sample average coefficient of variation over the five groups (25.43%), with average CVs for ISCOMO and ISDMMO of 70.32% and 57.75% respectively; kxgi also presented the strongest correlations with all considered empirical measures of insulin sensitivity. While COMO and DMMO appear over-parameterized for fitting single-subject clinical OGTT data, SIMO provides a robust, precise, physiologically plausible estimate of insulin sensitivity, with which habitual empirical insulin sensitivity indices correlate well. The kxgi index, reflecting insulin secretion dependency on glycemia, also significantly differentiates clinically

  13. Routine OGTT: a robust model including incretin effect for precise identification of insulin sensitivity and secretion in a single individual.

    PubMed

    De Gaetano, Andrea; Panunzi, Simona; Matone, Alice; Samson, Adeline; Vrbikova, Jana; Bendlova, Bela; Pacini, Giovanni

    2013-01-01

    In order to provide a method for precise identification of insulin sensitivity from clinical Oral Glucose Tolerance Test (OGTT) observations, a relatively simple mathematical model (Simple Interdependent glucose/insulin MOdel SIMO) for the OGTT, which coherently incorporates commonly accepted physiological assumptions (incretin effect and saturating glucose-driven insulin secretion) has been developed. OGTT data from 78 patients in five different glucose tolerance groups were analyzed: normal glucose tolerance (NGT), impaired glucose tolerance (IGT), impaired fasting glucose (IFG), IFG+IGT, and Type 2 Diabetes Mellitus (T2DM). A comparison with the 2011 Salinari (COntinuos GI tract MOdel, COMO) and the 2002 Dalla Man (Dalla Man MOdel, DMMO) models was made with particular attention to insulin sensitivity indices ISCOMO, ISDMMO and kxgi (the insulin sensitivity index for SIMO). ANOVA on kxgi values across groups resulted significant overall (P<0.001), and post-hoc comparisons highlighted the presence of three different groups: NGT (8.62×10(-5)±9.36×10(-5) min(-1)pM(-1)), IFG (5.30×10(-5)±5.18×10(-5)) and combined IGT, IFG+IGT and T2DM (2.09×10(-5)±1.95×10(-5), 2.38×10(-5)±2.28×10(-5) and 2.38×10(-5)±2.09×10(-5) respectively). No significance was obtained when comparing ISCOMO or ISDMMO across groups. Moreover, kxgi presented the lowest sample average coefficient of variation over the five groups (25.43%), with average CVs for ISCOMO and ISDMMO of 70.32% and 57.75% respectively; kxgi also presented the strongest correlations with all considered empirical measures of insulin sensitivity. While COMO and DMMO appear over-parameterized for fitting single-subject clinical OGTT data, SIMO provides a robust, precise, physiologically plausible estimate of insulin sensitivity, with which habitual empirical insulin sensitivity indices correlate well. The kxgi index, reflecting insulin secretion dependency on glycemia, also significantly differentiates clinically

  14. Postprandial glucose fluxes and insulin sensitivity during exercise: a study in healthy individuals.

    PubMed

    Schiavon, Michele; Hinshaw, Ling; Mallad, Ashwini; Dalla Man, Chiara; Sparacino, Giovanni; Johnson, Matthew; Carter, Rickey; Basu, Rita; Kudva, Yogish; Cobelli, Claudio; Basu, Ananda

    2013-08-15

    Quantifying the effect size of acute exercise on insulin sensitivity (SI(exercise)) and simultaneous measurement of glucose disappearance (R(d)), endogenous glucose production (EGP), and meal glucose appearance in the postprandial state has not been developed in humans. To do so, we studied 12 healthy subjects [5 men, age 37.1 ± 3.1 yr, body mass index 24.1 ± 1.1 kg/m², fat-free mass (FFM) 50.9 ± 3.9 kg] during moderate exercise at 50% V(O₂max) for 75 min, 120-195 min after a triple-tracer mixed meal consumed at time 0. Tracer infusion rates were adjusted to achieve constant tracer-to-tracee ratio and minimize non-steady-state errors. Glucose turnover was estimated by accounting for the nonstationary kinetics introduced by exercise. Insulin sensitivity index was calculated in each subject both in the absence [time (t) = 0-120 min, SI(rest)] and presence (t = 0-360 min, SI(exercise)) of physical activity. EGP at t = 0 min (13.4 ± 1.1 μM·kg FFM⁻¹·min⁻¹) fell at t = 120 min (2.4 ± 0.4 μM·kg FFM⁻¹·min⁻¹) and then rapidly rose almost eightfold at t = 180 min (18.2 ± 2.6 μM·kg FFM⁻¹·min⁻¹) before gradually falling at t = 360 min (10.6 ± 0.9 μM·kg FFM⁻¹·min⁻¹). R(d) rapidly peaked at t = 120 min at the start of exercise (89.5 ± 11.6 μM·kg FFM⁻¹·min⁻¹) and then gradually declined at t = 195 min (26.4 ± 3.3 μM·kg FFM⁻¹·min⁻¹) before returning to baseline at t = 360 min. SI(exercise) was significantly higher than SI(rest) (21.6 ± 3.7 vs. 12.5 ± 2.0 10⁻⁴ dl·kg⁻¹·min⁻¹ per μU/ml, P < 0.0005). Glucose turnover was estimated for the first time during exercise with the triple-tracer technique. Our results, applying state-of-the-art techniques, show that moderate exercise almost doubles postprandial insulin sensitivity index in healthy subjects. PMID:23820621

  15. PRAS40 prevents development of diabetic cardiomyopathy and improves hepatic insulin sensitivity in obesity

    PubMed Central

    Völkers, Mirko; Doroudgar, Shirin; Nguyen, Nathalie; Konstandin, Mathias H; Quijada, Pearl; Din, Shabana; Ornelas, Luis; Thuerauf, Donna J; Gude, Natalie; Friedrich, Kilian; Herzig, Stephan; Glembotski, Christopher C; Sussman, Mark A

    2014-01-01

    Diabetes is a multi-organ disease and diabetic cardiomyopathy can result in heart failure, which is a leading cause of morbidity and mortality in diabetic patients. In the liver, insulin resistance contributes to hyperglycaemia and hyperlipidaemia, which further worsens the metabolic profile. Defects in mTOR signalling are believed to contribute to metabolic dysfunctions in diabetic liver and hearts, but evidence is missing that mTOR activation is causal to the development of diabetic cardiomyopathy. This study shows that specific mTORC1 inhibition by PRAS40 prevents the development of diabetic cardiomyopathy. This phenotype was associated with improved metabolic function, blunted hypertrophic growth and preserved cardiac function. In addition PRAS40 treatment improves hepatic insulin sensitivity and reduces systemic hyperglycaemia in obese mice. Thus, unlike rapamycin, mTORC1 inhibition with PRAS40 improves metabolic profile in diabetic mice. These findings may open novel avenues for therapeutic strategies using PRAS40 directed against diabetic-related diseases. PMID:24408966

  16. Preventing High Fat Diet-induced Obesity and Improving Insulin Sensitivity through Neuregulin 4 Gene Transfer

    PubMed Central

    Ma, Yongjie; Gao, Mingming; Liu, Dexi

    2016-01-01

    Neuregulin 4 (NRG4), an epidermal growth factor-like signaling molecule, plays an important role in cell-to-cell communication during tissue development. Its function to regulate energy metabolism has recently been reported. This current study was designed to assess the preventive and therapeutic effects of NRG4 overexpression on high fat diet (HFD)-induced obesity. Using the hydrodynamic gene transfer method, we demonstrate that Nrg4 gene transfer in mice suppressed the development of diet-induced obesity, but did not affect pre-existing adiposity and body weight in obese mice. Nrg4 gene transfer curbed HFD-induced hepatic steatosis by inhibiting lipogenesis and PPARγ-mediated lipid storage. Concurrently, overexpression of NRG4 reduced chronic inflammation in both preventive and treatment studies, evidenced by lower mRNA levels of macrophage marker genes including F4/80, Cd68, Cd11b, Cd11c, and macrophage chemokine Mcp1, resulting in improved insulin sensitivity. Collectively, these results demonstrate that overexpression of the Nrg4 gene by hydrodynamic gene delivery prevents HFD-induced weight gain and fatty liver, alleviates obesity-induced chronic inflammation and insulin resistance, and supports the health benefits of NRG4 in managing obesity and obesity-associated metabolic disorders. PMID:27184920

  17. Characterization of lipid metabolism in insulin-sensitive adipocytes differentiated from immortalized human mesenchymal stem cells

    SciTech Connect

    Prawitt, Janne; Niemeier, Andreas; Kassem, Moustapha; Beisiegel, Ulrike; Heeren, Joerg

    2008-02-15

    There is a great demand for cell models to study human adipocyte function. Here we describe the adipogenic differentiation of a telomerase-immortalized human mesenchymal stem cell line (hMSC-Tert) that maintains numerous features of terminally differentiated adipocytes even after prolonged withdrawal of the peroxisome proliferator activated receptor {gamma} (PPAR{gamma}) agonist rosiglitazone. Differentiated hMSC-Tert developed the characteristic monolocular phenotype of mature adipocytes. The expression of adipocyte specific markers was highly increased during differentiation. Most importantly, the presence of the PPAR{gamma} agonist rosiglitazone was not required for the stable expression of lipoprotein lipase, adipocyte fatty acid binding protein and perilipin on mRNA and protein levels. Adiponectin expression was post-transcriptionally down-regulated in the absence of rosiglitazone. Insulin sensitivity as measured by insulin-induced phosphorylation of Akt and S6 ribosomal protein was also independent of rosiglitazone. In addition to commonly used adipogenic markers, we investigated further PPAR{gamma}-stimulated proteins with a role in lipid metabolism. We observed an increase of lipoprotein receptor (VLDLR, LRP1) and apolipoprotein E expression during differentiation. Despite this increased expression, the receptor-mediated endocytosis of lipoproteins was decreased in differentiated adipocytes, suggesting that these proteins may have an additional function in adipose tissue beyond lipoprotein uptake.

  18. Preventing High Fat Diet-induced Obesity and Improving Insulin Sensitivity through Neuregulin 4 Gene Transfer.

    PubMed

    Ma, Yongjie; Gao, Mingming; Liu, Dexi

    2016-01-01

    Neuregulin 4 (NRG4), an epidermal growth factor-like signaling molecule, plays an important role in cell-to-cell communication during tissue development. Its function to regulate energy metabolism has recently been reported. This current study was designed to assess the preventive and therapeutic effects of NRG4 overexpression on high fat diet (HFD)-induced obesity. Using the hydrodynamic gene transfer method, we demonstrate that Nrg4 gene transfer in mice suppressed the development of diet-induced obesity, but did not affect pre-existing adiposity and body weight in obese mice. Nrg4 gene transfer curbed HFD-induced hepatic steatosis by inhibiting lipogenesis and PPARγ-mediated lipid storage. Concurrently, overexpression of NRG4 reduced chronic inflammation in both preventive and treatment studies, evidenced by lower mRNA levels of macrophage marker genes including F4/80, Cd68, Cd11b, Cd11c, and macrophage chemokine Mcp1, resulting in improved insulin sensitivity. Collectively, these results demonstrate that overexpression of the Nrg4 gene by hydrodynamic gene delivery prevents HFD-induced weight gain and fatty liver, alleviates obesity-induced chronic inflammation and insulin resistance, and supports the health benefits of NRG4 in managing obesity and obesity-associated metabolic disorders. PMID:27184920

  19. Different phosphorylated forms of an insulin-sensitive glycosylphosphatidylinositol from rat hepatocytes.

    PubMed

    Merida, I; Corrales, F J; Clemente, R; Ruiz-Albusac, J M; Villalba, M; Mato, J M

    1988-08-15

    Labeling with [3H]galactose was employed to isolate a glycosylphosphatidylinositol from rat hepatocytes which might be involved in the action of insulin. The polar head group of this glycosylphosphatidylinositol was generated by phosphodiesterase hydrolysis with a phosphatidylinositol-specific phospholipase C from Bacillus cereus. By Dowex AG1 x 8 chromatography the polar head group could be separated into three radioactive peaks eluting at 100 mM (peak I), 200 mM (peak II) and 500 mM (peak III) ammonium formate, respectively. Peak III was the most active as an inhibitor of the cAMP-dependent protein kinase. Treatment of peak III with alkaline phosphatase markedly reduced its activity on cAMP-dependent protein kinase. When peaks I, II or III were treated with alkaline phosphatase and analyzed again by Dowex AG1 x 8 chromatography, the radioactivity eluted with the aqueous fraction. The above results indicate that the polar head group of the insulin-sensitive glycosylphosphatidylinositol from rat hepatocytes exists in three different phosphorylated forms and that the biological activity of this molecule depends on its phosphorylation state. PMID:3042467

  20. A PPARγ-Bnip3 Axis Couples Adipose Mitochondrial Fusion-Fission Balance to Systemic Insulin Sensitivity.

    PubMed

    Tol, Marc J; Ottenhoff, Roelof; van Eijk, Marco; Zelcer, Noam; Aten, Jan; Houten, Sander M; Geerts, Dirk; van Roomen, Cindy; Bierlaagh, Marlou C; Scheij, Saskia; Hoeksema, Marten A; Aerts, Johannes M; Bogan, Jonathan S; Dorn, Gerald W; Argmann, Carmen A; Verhoeven, Arthur J

    2016-09-01

    Aberrant mitochondrial fission plays a pivotal role in the pathogenesis of skeletal muscle insulin resistance. However, fusion-fission dynamics are physiologically regulated by inherent tissue-specific and nutrient-sensitive processes that may have distinct or even opposing effects with respect to insulin sensitivity. Based on a combination of mouse population genetics and functional in vitro assays, we describe here a regulatory circuit in which peroxisome proliferator-activated receptor γ (PPARγ), the adipocyte master regulator and receptor for the thiazolidinedione class of antidiabetic drugs, controls mitochondrial network fragmentation through transcriptional induction of Bnip3. Short hairpin RNA-mediated knockdown of Bnip3 in cultured adipocytes shifts the balance toward mitochondrial elongation, leading to compromised respiratory capacity, heightened fatty acid β-oxidation-associated mitochondrial reactive oxygen species generation, insulin resistance, and reduced triacylglycerol storage. Notably, the selective fission/Drp1 inhibitor Mdivi-1 mimics the effects of Bnip3 knockdown on adipose mitochondrial bioenergetics and glucose disposal. We further show that Bnip3 is reciprocally regulated in white and brown fat depots of diet-induced obesity and leptin-deficient ob/ob mouse models. Finally, Bnip3(-/-) mice trade reduced adiposity for increased liver steatosis and develop aggravated systemic insulin resistance in response to high-fat feeding. Together, our data outline Bnip3 as a key effector of PPARγ-mediated adipose mitochondrial network fragmentation, improving insulin sensitivity and limiting oxidative stress. PMID:27325287

  1. Jicama (Pachyrhizus erosus) extract increases insulin sensitivity and regulates hepatic glucose in C57BL/Ksj-db/db mice

    PubMed Central

    Park, Chan Joo; Lee, Hyun-Ah; Han, Ji-Sook

    2016-01-01

    This study investigated the effect of jicama extract on hyperglycemia and insulin sensitivity in an animal model of type 2 diabetes. Male C57BL/Ksj-db/db mice were divided into groups subsequently fed a regular diet (controls), or diet supplemented with jicama extract, and rosiglitazone. After 6 weeks, blood levels of glucose and glycosylated hemoglobin were significantly lower in animals administered the jicama extract than the control group. Additionally, glucose and insulin tolerance tests showed that jicama extract increased insulin sensitivity. The homeostatic index of insulin resistance was lower in the jicama extract-treated group than in the diabetic control group. Administration of jicama extract significantly enhanced the expressions of the phosphorylated AMP-activated protein kinase and Akt substrate of 160 kDa, and plasma membrane glucose transporter type 4 in skeletal muscle. Jicama extract administration also decreased the expressions of glucose 6-phosphatase and phosphoenol pyruvate carboxykinase in the liver. Jicama extract may increases insulin sensitivity and inhibites the gluconeogenesis in the liver. PMID:26798198

  2. Jicama (Pachyrhizus erosus) extract increases insulin sensitivity and regulates hepatic glucose in C57BL/Ksj-db/db mice.

    PubMed

    Park, Chan Joo; Lee, Hyun-Ah; Han, Ji-Sook

    2016-01-01

    This study investigated the effect of jicama extract on hyperglycemia and insulin sensitivity in an animal model of type 2 diabetes. Male C57BL/Ksj-db/db mice were divided into groups subsequently fed a regular diet (controls), or diet supplemented with jicama extract, and rosiglitazone. After 6 weeks, blood levels of glucose and glycosylated hemoglobin were significantly lower in animals administered the jicama extract than the control group. Additionally, glucose and insulin tolerance tests showed that jicama extract increased insulin sensitivity. The homeostatic index of insulin resistance was lower in the jicama extract-treated group than in the diabetic control group. Administration of jicama extract significantly enhanced the expressions of the phosphorylated AMP-activated protein kinase and Akt substrate of 160 kDa, and plasma membrane glucose transporter type 4 in skeletal muscle. Jicama extract administration also decreased the expressions of glucose 6-phosphatase and phosphoenol pyruvate carboxykinase in the liver. Jicama extract may increases insulin sensitivity and inhibites the gluconeogenesis in the liver. PMID:26798198

  3. Leptin enhances insulin sensitivity by direct and sympathetic nervous system regulation of muscle IGFBP-2 expression: evidence from nonrodent models.

    PubMed

    Yau, Steven W; Henry, Belinda A; Russo, Vincenzo C; McConell, Glenn K; Clarke, Iain J; Werther, George A; Sabin, Matthew A

    2014-06-01

    Leptin is produced from white adipose tissue and acts primarily to regulate energy balance. Obesity is associated with leptin resistance and increased circulating levels of leptin. Leptin has recently been shown to influence levels of IGF binding protein-2 (IGFBP-2), a protein that is reduced in obesity and type 2 diabetes. Overexpression of IGFBP-2 protects against obesity and type 2 diabetes. As such, IGFBP-2 signaling may represent a novel pathway by which leptin regulates insulin sensitivity. We sought to investigate how leptin regulates skeletal muscle IGFBP-2 levels and to assess the impact of this on insulin signaling and glucose uptake. In vitro experiments were undertaken in cultured human skeletal myotubes, whereas in vivo experiments assessed the effect of intracerebroventricular leptin on peripheral skeletal muscle IGFBP-2 expression and insulin sensitivity in sheep. Leptin directly increased IGFBP-2 mRNA and protein in human skeletal muscle through both signal transducer and activator of transcription-3 and phosphatidylinositol 3-kinase signaling, in parallel with enhanced insulin signaling. Silencing IGFBP-2 lowered leptin- and insulin-stimulated protein kinase B phosphorylation and glucose uptake. In in vivo experiments, intracerebroventricular leptin significantly increased hind-limb skeletal muscle IGFBP-2, an effect completely blocked by concurrent peripheral infusion of a β-adrenergic blocking agent. Sheep receiving central leptin showed improvements in glucose tolerance and circulating insulin levels after an iv glucose load. In summary, leptin regulates skeletal muscle IGFBP-2 by both direct peripheral and central (via the sympathetic nervous system) mechanisms, and these likely impact on peripheral insulin sensitivity and glucose metabolism. PMID:24654786

  4. CB1 antagonism restores hepatic insulin sensitivity without normalization of adiposity in diet-induced obese dogs

    PubMed Central

    Woolcott, Orison O.; Hsu, Isabel R.; Stefanoski, Darko; Harrison, L. Nicole; Zheng, Dan; Lottati, Maya; Kolka, Cathryn; Catalano, Karyn J.; Chiu, Jenny D.; Kabir, Morvarid; Ionut, Viorica; Bergman, Richard N.; Richey, Joyce M.

    2012-01-01

    The endocannabinoid system is highly implicated in the development of insulin resistance associated with obesity. It has been shown that antagonism of the CB1 receptor improves insulin sensitivity (SI). However, it is unknown whether this improvement is due to the direct effect of CB1 blockade on peripheral tissues or secondary to decreased fat mass. Here, we examine in the canine dog model the longitudinal changes in SI and fat deposition when obesity was induced with a high-fat diet (HFD) and animals were treated with the CB1 antagonist rimonabant. SI was assessed (n = 20) in animals fed a HFD for 6 wk to establish obesity. Thereafter, while HFD was continued for 16 additional weeks, animals were divided into two groups: rimonabant (1.25 mg·kg−1·day−1 RIM; n = 11) and placebo (n = 9). Euglycemic hyperinsulinemic clamps were performed to evaluate changes in insulin resistance and glucose turnover before HFD (week −6) after HFD but before treatment (week 0) and at weeks 2, 6, 12, and 16 of treatment (or placebo) + HFD. Magnetic resonance imaging was performed to determine adiposity- related changes in SI. Animals developed significant insulin resistance and increased visceral and subcutaneous adiposity after 6 wk of HFD. Treatment with RIM resulted in a modest decrease in total trunk fat with relatively little change in peripheral glucose uptake. However, there was significant improvement in hepatic insulin resistance after only 2 wk of RIM treatment with a concomitant increase in plasma adiponectin levels; both were maintained for the duration of the RIM treatment. CB1 receptor antagonism appears to have a direct effect on hepatic insulin sensitivity that may be mediated by adiponectin and independent of pronounced reductions in body fat. However, the relatively modest effect on peripheral insulin sensitivity suggests that significant improvements may be secondary to reduced fat mass. PMID:22374758

  5. Lower body adipose tissue removal decreases glucose tolerance and insulin sensitivity in mice with exposure to high fat diet.

    PubMed

    Cox-York, K; Wei, Y; Wang, D; Pagliassotti, M J; Foster, M T

    2015-01-01

    It has been postulated that the protective effects of lower body subcutaneous adipose tissue (LBSAT) occur via its ability to sequester surplus lipid and thus serve as a "metabolic sink." However, the mechanisms that mediate this protective function are unknown thus this study addresses this postulate. Ad libitum, chow-fed mice underwent Sham-surgery or LBSAT removal (IngX, inguinal depot removal) and were subsequently provided chow (Chow; typical adipocyte expansion) or high fat diet (HFD; enhanced adipocyte expansion) for 5 weeks. Primary outcome measures included glucose tolerance and subsequent insulin response, muscle insulin sensitivity, liver and muscle triglycerides, adipose tissue gene expression, and circulating lipids and adipokines. In a follow up study the consequences of extended experiment length post-surgery (13 wks) or pre-existing glucose intolerance were examined. At 5 wks post-surgery IngX in HFD-fed mice reduced glucose tolerance and muscle insulin sensitivity and increased circulating insulin compared with HFD Sham. In Chow-fed mice, muscle insulin sensitivity was the only measurement reduced following IngX. At 13 wks circulating insulin concentration of HFD IngX mice continued to be higher than HFD Sham. Surgery did not induce changes in mice with pre-existing glucose intolerance. IngX also increased muscle, but not liver, triglyceride concentration in Chow- and HFD-fed mice 5 wks post-surgery, but chow group only at 13 wks. These data suggest that the presence of LBSAT protects against triglyceride accumulation in the muscle and HFD-induced glucose intolerance and muscle insulin resistance. These data suggest that lower body subcutaneous adipose tissue can function as a "metabolic sink." PMID:26167400

  6. Partial Inhibition of Adipose Tissue Lipolysis Improves Glucose Metabolism and Insulin Sensitivity Without Alteration of Fat Mass

    PubMed Central

    Girousse, Amandine; Tavernier, Geneviève; Valle, Carine; Moro, Cedric; Mejhert, Niklas; Dinel, Anne-Laure; Houssier, Marianne; Roussel, Balbine; Besse-Patin, Aurèle; Combes, Marion; Mir, Lucile; Monbrun, Laurent; Bézaire, Véronic; Prunet-Marcassus, Bénédicte; Waget, Aurélie; Vila, Isabelle; Caspar-Bauguil, Sylvie; Louche, Katie; Marques, Marie-Adeline; Mairal, Aline; Renoud, Marie-Laure; Galitzky, Jean; Holm, Cecilia; Mouisel, Etienne; Thalamas, Claire; Viguerie, Nathalie; Sulpice, Thierry; Burcelin, Rémy; Arner, Peter; Langin, Dominique

    2013-01-01

    When energy is needed, white adipose tissue (WAT) provides fatty acids (FAs) for use in peripheral tissues via stimulation of fat cell lipolysis. FAs have been postulated to play a critical role in the development of obesity-induced insulin resistance, a major risk factor for diabetes and cardiovascular disease. However, whether and how chronic inhibition of fat mobilization from WAT modulates insulin sensitivity remains elusive. Hormone-sensitive lipase (HSL) participates in the breakdown of WAT triacylglycerol into FAs. HSL haploinsufficiency and treatment with a HSL inhibitor resulted in improvement of insulin tolerance without impact on body weight, fat mass, and WAT inflammation in high-fat-diet–fed mice. In vivo palmitate turnover analysis revealed that blunted lipolytic capacity is associated with diminution in FA uptake and storage in peripheral tissues of obese HSL haploinsufficient mice. The reduction in FA turnover was accompanied by an improvement of glucose metabolism with a shift in respiratory quotient, increase of glucose uptake in WAT and skeletal muscle, and enhancement of de novo lipogenesis and insulin signalling in liver. In human adipocytes, HSL gene silencing led to improved insulin-stimulated glucose uptake, resulting in increased de novo lipogenesis and activation of cognate gene expression. In clinical studies, WAT lipolytic rate was positively and negatively correlated with indexes of insulin resistance and WAT de novo lipogenesis gene expression, respectively. In obese individuals, chronic inhibition of lipolysis resulted in induction of WAT de novo lipogenesis gene expression. Thus, reduction in WAT lipolysis reshapes FA fluxes without increase of fat mass and improves glucose metabolism through cell-autonomous induction of fat cell de novo lipogenesis, which contributes to improved insulin sensitivity. PMID:23431266

  7. Partial inhibition of adipose tissue lipolysis improves glucose metabolism and insulin sensitivity without alteration of fat mass.

    PubMed

    Girousse, Amandine; Tavernier, Geneviève; Valle, Carine; Moro, Cedric; Mejhert, Niklas; Dinel, Anne-Laure; Houssier, Marianne; Roussel, Balbine; Besse-Patin, Aurèle; Combes, Marion; Mir, Lucile; Monbrun, Laurent; Bézaire, Véronic; Prunet-Marcassus, Bénédicte; Waget, Aurélie; Vila, Isabelle; Caspar-Bauguil, Sylvie; Louche, Katie; Marques, Marie-Adeline; Mairal, Aline; Renoud, Marie-Laure; Galitzky, Jean; Holm, Cecilia; Mouisel, Etienne; Thalamas, Claire; Viguerie, Nathalie; Sulpice, Thierry; Burcelin, Rémy; Arner, Peter; Langin, Dominique

    2013-01-01

    When energy is needed, white adipose tissue (WAT) provides fatty acids (FAs) for use in peripheral tissues via stimulation of fat cell lipolysis. FAs have been postulated to play a critical role in the development of obesity-induced insulin resistance, a major risk factor for diabetes and cardiovascular disease. However, whether and how chronic inhibition of fat mobilization from WAT modulates insulin sensitivity remains elusive. Hormone-sensitive lipase (HSL) participates in the breakdown of WAT triacylglycerol into FAs. HSL haploinsufficiency and treatment with a HSL inhibitor resulted in improvement of insulin tolerance without impact on body weight, fat mass, and WAT inflammation in high-fat-diet-fed mice. In vivo palmitate turnover analysis revealed that blunted lipolytic capacity is associated with diminution in FA uptake and storage in peripheral tissues of obese HSL haploinsufficient mice. The reduction in FA turnover was accompanied by an improvement of glucose metabolism with a shift in respiratory quotient, increase of glucose uptake in WAT and skeletal muscle, and enhancement of de novo lipogenesis and insulin signalling in liver. In human adipocytes, HSL gene silencing led to improved insulin-stimulated glucose uptake, resulting in increased de novo lipogenesis and activation of cognate gene expression. In clinical studies, WAT lipolytic rate was positively and negatively correlated with indexes of insulin resistance and WAT de novo lipogenesis gene expression, respectively. In obese individuals, chronic inhibition of lipolysis resulted in induction of WAT de novo lipogenesis gene expression. Thus, reduction in WAT lipolysis reshapes FA fluxes without increase of fat mass and improves glucose metabolism through cell-autonomous induction of fat cell de novo lipogenesis, which contributes to improved insulin sensitivity. PMID:23431266

  8. Lower body adipose tissue removal decreases glucose tolerance and insulin sensitivity in mice with exposure to high fat diet

    PubMed Central

    Cox-York, K; Wei, Y; Wang, D; Pagliassotti, MJ; Foster, MT

    2014-01-01

    It has been postulated that the protective effects of lower body subcutaneous adipose tissue (LBSAT) occur via its ability to sequester surplus lipid and thus serve as a “metabolic sink.” However, the mechanisms that mediate this protective function are unknown thus this study addresses this postulate. Ad libitum, chow-fed mice underwent Sham-surgery or LBSAT removal (IngX, inguinal depot removal) and were subsequently provided chow (Chow; typical adipocyte expansion) or high fat diet (HFD; enhanced adipocyte expansion) for 5 weeks. Primary outcome measures included glucose tolerance and subsequent insulin response, muscle insulin sensitivity, liver and muscle triglycerides, adipose tissue gene expression, and circulating lipids and adipokines. In a follow up study the consequences of extended experiment length post-surgery (13 wks) or pre-existing glucose intolerance were examined. At 5 wks post-surgery IngX in HFD-fed mice reduced glucose tolerance and muscle insulin sensitivity and increased circulating insulin compared with HFD Sham. In Chow-fed mice, muscle insulin sensitivity was the only measurement reduced following IngX. At 13 wks circulating insulin concentration of HFD IngX mice continued to be higher than HFD Sham. Surgery did not induce changes in mice with pre-existing glucose intolerance. IngX also increased muscle, but not liver, triglyceride concentration in Chow- and HFD-fed mice 5 wks post-surgery, but chow group only at 13 wks. These data suggest that the presence of LBSAT protects against triglyceride accumulation in the muscle and HFD-induced glucose intolerance and muscle insulin resistance. These data suggest that lower body subcutaneous adipose tissue can function as a “metabolic sink.” PMID:26167400

  9. Improvements in body composition, cardiometabolic risk factors and insulin sensitivity with trenbolone in normogonadic rats.

    PubMed

    Donner, Daniel G; Beck, Belinda R; Bulmer, Andrew C; Lam, Alfred K; Du Toit, Eugene F

    2015-02-01

    Trenbolone (TREN) is used for anabolic growth-promotion in over 20 million cattle annually and continues to be misused for aesthetic purposes in humans. The current study investigated TREN's effects on body composition and cardiometabolic risk factors; and its tissue-selective effects on the cardiovascular system, liver and prostate. Male rats (n=12) were implanted with osmotic infusion pumps delivering either cyclodextrin vehicle (CTRL) or 2mg/kg/day TREN for 6 weeks. Dual-energy X-ray Absorptiometry assessment of body composition; organ wet weights and serum lipid profiles; and insulin sensitivity were assessed. Cardiac ultrasound examinations were performed before in vivo studies assessed myocardial susceptibility to ischemia-reperfusion (I/R) injury. Circulating sex hormones and liver enzyme activities; and prostate and liver histology were examined. In 6 weeks, fat mass increased by 34±7% in CTRLs (p<0.01). Fat mass decreased by 37±6% and lean mass increased by 11±4% with TREN (p<0.05). Serum triglycerides, HDL and LDL were reduced by 62%, 57% and 78% (p<0.05) respectively in TREN rats. Histological examination of the prostates from TREN-treated rats indicated benign hyperplasia associated with an increased prostate mass (149% compared to CTRLs, p<0.01). No evidence of adverse cardiac or hepatic effects was observed. In conclusion, improvements in body composition, lipid profile and insulin sensitivity (key risk factors for cardiometabolic disease) were achieved with six-week TREN treatment without evidence of adverse cardiovascular or hepatic effects that are commonly associated with traditional anabolic steroid misuse. Sex hormone suppression and benign prostate hyperplasia were confirmed as adverse effects of the treatment. PMID:25554582

  10. Effect of a 1-week, eucaloric, moderately high-fat diet on peripheral insulin sensitivity in healthy premenopausal women

    PubMed Central

    Branis, Natalia M; Etesami, Marjan; Walker, Ryan W; Berk, Evan S; Albu, Jeanine B

    2015-01-01

    Objectives To determine whether a weight-maintaining, moderate (50%) high-fat diet is deleterious to insulin sensitivity in healthy premenopausal women. Design/setting/participants 23 African-American and non-Hispanic white, healthy, overweight, and obese premenopausal women recruited in New York City, USA, fed either a eucaloric, 1-week long high-fat (50% of total Kcal from fat) diet or a eucaloric, 1-week long low-fat (30% of total Kcal from fat) diet, assigned in a randomized crossover design. Main outcome measures Peripheral insulin sensitivity and metabolic flexibility during a euglycemic hyperinsulinemic (80 mU/m2/min) clamp measured during the follicular phase of the menstrual cycle, at the end of each diet period. Results Peripheral insulin sensitivity (mg kg/fat-free mass/min (µU/mL)×10−1) was not decreased after the high-fat diet vs the low-fat diet (0.09±0.01 vs 0.08±0.01, p=0.09, respectively) in the combined group of African-American and white women, with no significant diet by race interaction (p=0.6). Metabolic flexibility (change in substrate utilization, ΔNPRQ, in response to insulin during the clamp) was similarly unaltered by the diet (0.12±0.01 vs 0.11, p=0.48, for the high-fat diet vs the low-fat diet, respectively) in the combined group of women, with no significant diet by race interaction (p=0.9). African–American women had a lower insulin clearance compared with the white women, regardless of the diet (p<0.05). Conclusions We conclude that a short term (1 week), moderate (50%), eucaloric high-fat diet does not lower peripheral insulin sensitivity in healthy, overweight and obese premenopausal women. PMID:26203360

  11. Lifestyle and Metformin Ameliorate Insulin Sensitivity Independently of the Genetic Burden of Established Insulin Resistance Variants in Diabetes Prevention Program Participants.

    PubMed

    Hivert, Marie-France; Christophi, Costas A; Franks, Paul W; Jablonski, Kathleen A; Ehrmann, David A; Kahn, Steven E; Horton, Edward S; Pollin, Toni I; Mather, Kieren J; Perreault, Leigh; Barrett-Connor, Elizabeth; Knowler, William C; Florez, Jose C

    2016-02-01

    Large genome-wide association studies of glycemic traits have identified genetics variants that are associated with insulin resistance (IR) in the general population. It is unknown whether people with genetic enrichment for these IR variants respond differently to interventions that aim to improve insulin sensitivity. We built a genetic risk score (GRS) based on 17 established IR variants and effect sizes (weighted IR-GRS) in 2,713 participants of the Diabetes Prevention Program (DPP) with genetic consent. We tested associations between the weighted IR-GRS and insulin sensitivity index (ISI) at baseline in all participants, and with change in ISI over 1 year of follow-up in the DPP intervention (metformin and lifestyle) and control (placebo) arms. All models were adjusted for age, sex, ethnicity, and waist circumference at baseline (plus baseline ISI for 1-year ISI change models). A higher IR-GRS was associated with lower baseline ISI (β = -0.754 [SE = 0.229] log-ISI per unit, P = 0.001 in fully adjusted models). There was no differential effect of treatment for the association between the IR-GRS on the change in ISI; higher IR-GRS was associated with an attenuation in ISI improvement over 1 year (β = -0.520 [SE = 0.233], P = 0.03 in fully adjusted models; all treatment arms). Lifestyle intervention and metformin treatment improved the ISI, regardless of the genetic burden of IR variants. PMID:26525880

  12. n-3 Fatty acids preserve insulin sensitivity in vivo in a peroxisome proliferator-activated receptor-alpha-dependent manner.

    PubMed

    Neschen, Susanne; Morino, Katsutaro; Dong, Jianying; Wang-Fischer, Yanlin; Cline, Gary W; Romanelli, Anthony J; Rossbacher, Jörg C; Moore, Irene K; Regittnig, Werner; Munoz, David S; Kim, Jung H; Shulman, Gerald I

    2007-04-01

    Recent studies have suggested that n-3 fatty acids, abundant in fish oil, protect against high-fat diet-induced insulin resistance through peroxisome proliferator-activated receptor (PPAR)-alpha activation and a subsequent decrease in intracellular lipid abundance. To directly test this hypothesis, we fed PPAR-alpha null and wild-type mice for 2 weeks with isocaloric high-fat diets containing 27% fat from either safflower oil or safflower oil with an 8% fish oil replacement (fish oil diet). In both genotypes the safflower oil diet blunted insulin-mediated suppression of hepatic glucose production (P < 0.02 vs. genotype control) and PEPCK gene expression. Feeding wild-type mice a fish oil diet restored hepatic insulin sensitivity (hepatic glucose production [HGP], P < 0.002 vs. wild-type mice fed safflower oil), whereas in contrast, in PPAR-alpha null mice failed to counteract hepatic insulin resistance (HGP, P = NS vs. PPAR-alpha null safflower oil-fed mice). In PPAR-alpha null mice fed the fish oil diet, safflower oil plus fish oil, hepatic insulin resistance was dissociated from increases in hepatic triacylglycerol and acyl-CoA but accompanied by a more than threefold increase in hepatic diacylglycerol concentration (P < 0.0001 vs. genotype control). These data support the hypothesis that n-3 fatty acids protect from high-fat diet-induced hepatic insulin resistance in a PPAR-alpha-and diacylglycerol-dependent manner. PMID:17251275

  13. Patterns of use of insulin-sensitizing agents among diabetic, borderline diabetic and non-diabetic women in the National Health and Nutrition Examination Surveys

    PubMed Central

    Beydoun, Hind; Kancherla, Vijaya; Stadtmauer, Laurel; Beydoun, May

    2013-01-01

    The purpose of this cross-sectional study based on the 2001–2006 National Health and Nutrition Examination Survey is to examine demographic, socioeconomic, lifestyle and reproductive characteristics that may distinguish users and non-users of insulin sensitizing agents among U.S. diabetic, borderline diabetic and non-diabetic women. Use of insulin-sensitizing agents was evaluated among 19579 (3882 diabetic, 387 borderline diabetic and 15310 non-diabetic) women. Overall, 2% of women in the study sample were users of insulin-sensitizers, including metformin, rosiglitazone and pioglitazone. Multivariate logistic regression models were constructed for predictors of insulin-sensitizer use according to diabetic status. In the overall sample, being younger or diabetic were the only factors associated with an increased odds of using insulin-sensitizing agents, after adjustment of confounders. Among diabetics, use of insulin-sensitizing agents was inversely related to age, but not other factors in the multivariable model. Among borderline and non-diabetics, body mass index (BMI) was the only predictor that remained significantly associated with use of insulin-sensitizing agents after controlling for confounders. In conclusion, the main predictors of insulin-sensitizer use are young age and diabetic status in all women, young age in diabetic women and high BMI in borderline and non-diabetic women. PMID:23323803

  14. A 12 week aerobic exercise program improves fitness, hepatic insulin sensitivity and glucose metabolism in obese Hispanic adolescents

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The rise in obesity related morbidity in children and adolescents requires urgent prevention and treatment strategies. Strictly controlled exercise programs might be useful tools to improve insulin sensitivity and glucose kinetics. Our objective was to test the hypothesis that a 12-wk aerobic exerci...

  15. Diabetes Alters the Expression and Translocation of the Insulin-Sensitive Glucose Transporters 4 and 8 in the Atria

    PubMed Central

    Maria, Zahra; Campolo, Allison R.; Lacombe, Veronique A.

    2015-01-01

    Although diabetes has been identified as a major risk factor for atrial fibrillation, little is known about glucose metabolism in the healthy and diabetic atria. Glucose transport into the cell, the rate-limiting step of glucose utilization, is regulated by the Glucose Transporters (GLUTs). Although GLUT4 is the major isoform in the heart, GLUT8 has recently emerged as a novel cardiac isoform. We hypothesized that GLUT-4 and -8 translocation to the atrial cell surface will be regulated by insulin and impaired during insulin-dependent diabetes. GLUT protein content was measured by Western blotting in healthy cardiac myocytes and type 1 (streptozotocin-induced, T1Dx) diabetic rodents. Active cell surface GLUT content was measured using a biotinylated photolabeled assay in the perfused heart. In the healthy atria, insulin stimulation increased both GLUT-4 and -8 translocation to the cell surface (by 100% and 240%, respectively, P<0.05). Upon insulin stimulation, we reported an increase in Akt (Th308 and s473 sites) and AS160 phosphorylation, which was positively (P<0.05) correlated with GLUT4 protein content in the healthy atria. During diabetes, active cell surface GLUT-4 and -8 content was downregulated in the atria (by 70% and 90%, respectively, P<0.05). Akt and AS160 phosphorylation was not impaired in the diabetic atria, suggesting the presence of an intact insulin signaling pathway. This was confirmed by the rescued translocation of GLUT-4 and -8 to the atrial cell surface upon insulin stimulation in the atria of type 1 diabetic subjects. In conclusion, our data suggest that: 1) both GLUT-4 and -8 are insulin-sensitive in the healthy atria through an Akt/AS160 dependent pathway; 2) GLUT-4 and -8 trafficking is impaired in the diabetic atria and rescued by insulin treatment. Alterations in atrial glucose transport may induce perturbations in energy production, which may provide a metabolic substrate for atrial fibrillation during diabetes. PMID:26720696

  16. Enhanced insulin sensitivity mediated by adipose tissue browning perturbs islet morphology and hormone secretion in response to autonomic nervous activation in female mice.

    PubMed

    Omar, Bilal A; Kvist-Reimer, Martina; Enerbäck, Sven; Ahrén, Bo

    2016-01-01

    Insulin resistance results in a compensatory increase in insulin secretion to maintain normoglycemia. Conversely, high insulin sensitivity results in reduced insulin secretion to prevent hypoglycemia. The mechanisms for this inverse adaptation are not well understood. We utilized highly insulin-sensitive mice, due to adipocyte-specific overexpression of the FOXC2 transcription factor, to study mechanisms of the reversed islet adaptation to increased insulin sensitivity. We found that Foxc2TG mice responded to mild hyperglycemia with insulin secretion significantly lower than that of wild-type mice; however, when severe hyperglycemia was induced, Foxc2TG mice demonstrated insulin secretion equal to or greater than that of wild-type mice. In response to autonomic nervous activation by 2-deoxyglucose, the acute suppression of insulin seen in wild-type mice was absent in Foxc2TG mice, suggesting impaired sympathetic signaling to the islet. Basal glucagon was increased in Foxc2TG mice, but they displayed severely impaired glucagon responses to cholinergic and autonomic nervous stimuli. These data suggest that the autonomic nerves contribute to the islet adaptation to high insulin sensitivity, which is compatible with a neuro-adipo regulation of islet function being instrumental for maintaining glucose regulation. PMID:26530152

  17. Adipose Tissue Promotes a Serum Cytokine Profile Related to Lower Insulin Sensitivity after Chronic Central Leptin Infusion

    PubMed Central

    Burgos-Ramos, Emma; Canelles, Sandra; Perianes-Cachero, Arancha; Arilla-Ferreiro, Eduardo; Argente, Jesús; Barrios, Vicente

    2012-01-01

    Obesity is an inflammatory state characterized by an augment in circulating inflammatory factors. Leptin may modulate the synthesis of these factors by white adipose tissue decreasing insulin sensitivity. We have examined the effect of chronic central administration of leptin on circulating levels of cytokines and the possible relationship with cytokine expression and protein content as well as with leptin and insulin signaling in subcutaneous and visceral adipose tissues. In addition, we analyzed the possible correlation between circulating levels of cytokines and peripheral insulin resistance. We studied 18 male Wistar rats divided into controls (C), those treated icv for 14 days with a daily dose of 12 μg of leptin (L) and a pair-fed group (PF) that received the same food amount consumed by the leptin group. Serum leptin and insulin were measured by ELISA, mRNA levels of interferon-γ (IFN-γ), interleukin-2 (IL-2), IL-4, IL-6, IL-10 and tumor necrosis factor-α (TNF-α) by real time PCR and serum and adipose tissue levels of these cytokines by multiplexed bead immunoassay. Serum leptin, IL-2, IL-4, IFN-γ and HOMA-IR were increased in L and TNF-α was decreased in PF and L. Serum leptin and IL-2 levels correlate positively with HOMA-IR index and negatively with serum glucose levels during an ip insulin tolerance test. In L, an increase in mRNA levels of IL-2 was found in both adipose depots and IFN-γ only in visceral tissue. Activation of leptin signaling was increased and insulin signaling decreased in subcutaneous fat of L. In conclusion, leptin mediates the production of inflammatory cytokines by adipose tissue independent of its effects on food intake, decreasing insulin sensitivity. PMID:23056516

  18. Adiponectin stimulates autophagy and reduces oxidative stress to enhance insulin sensitivity during high-fat diet feeding in mice.

    PubMed

    Liu, Ying; Palanivel, Rengasamy; Rai, Esther; Park, Min; Gabor, Tim V; Scheid, Michael P; Xu, Aimin; Sweeney, Gary

    2015-01-01

    Numerous studies have characterized the antidiabetic effects of adiponectin, yet the precise cellular mechanisms in skeletal muscle, in particular, changes in autophagy, require further clarification. In the current study, we used a high-fat diet (HFD) to induce obesity and insulin resistance in wild-type (WT) or adiponectin knockout (Ad-KO) mice with and without adiponectin replenishment. Temporal analysis of glucose tolerance and insulin sensitivity using hyperinsulinemic-euglycemic clamp and muscle insulin receptor substrate and Akt phosphorylation demonstrated exaggerated and more rapid HFD-induced insulin resistance in skeletal muscle of Ad-KO mice. Superoxide dismutase activity, the reduced glutathione-to-glutathione disulfide ratio, and lipid peroxidation indicated that HFD-induced oxidative stress was corrected by adiponectin. Gene array analysis implicated several antioxidant enzymes, including Gpxs, Prdx, Sod, and Nox4, in mediating this effect. Adiponectin also attenuated palmitate-induced reactive oxygen species production in cultured myotubes and improved insulin-stimulated glucose uptake in primary muscle cells. Increased LC3-II and decreased p62 expression suggested that HFD induced autophagy in muscle of WT mice; however, these changes were not observed in Ad-KO mice. Replenishing adiponectin in Ad-KO mice increased LC3-II and Beclin1 and decreased p62 protein levels, induced fibroblast growth factor-21 expression, and corrected HFD-induced decreases in LC3, Beclin1, and ULK1 gene expression. In vitro studies examining changes in phospho-ULK1 (Ser555), LC3-II, and lysosomal enzyme activity confirmed that adiponectin directly induced autophagic flux in cultured muscle cells in an AMPK-dependent manner. We overexpressed an inactive mutant of Atg5 to create an autophagy-deficient cell model, and together with pharmacological inhibition of autophagy, demonstrated reduced insulin sensitivity under these conditions. In summary, adiponectin stimulated

  19. Prep1 deficiency induces protection from diabetes and increased insulin sensitivity through a p160-mediated mechanism.

    PubMed

    Oriente, Francesco; Fernandez Diaz, Luis Cesar; Miele, Claudia; Iovino, Salvatore; Mori, Silvia; Diaz, Victor Manuel; Troncone, Giancarlo; Cassese, Angela; Formisano, Pietro; Blasi, Francesco; Beguinot, Francesco

    2008-09-01

    We have examined glucose homeostasis in mice hypomorphic for the homeotic transcription factor gene Prep1. Prep1-hypomorphic (Prep1(i/i)) mice exhibit an absolute reduction in circulating insulin levels but normal glucose tolerance. In addition, these mice exhibit protection from streptozotocin-induced diabetes and enhanced insulin sensitivity with improved glucose uptake and insulin-dependent glucose disposal by skeletal muscle. This muscle phenotype does not depend on reduced expression of the known Prep1 transcription partner, Pbx1. Instead, in Prep1(i/i) muscle, we find normal Pbx1 but reduced levels of the recently identified novel Prep1 interactor p160. Consistent with this reduction, we find a muscle-selective increase in mRNA and protein levels of PGC-1alpha, accompanied by enhanced expression of the GLUT4 transporter, responsible for insulin-stimulated glucose uptake in muscle. Indeed, using L6 skeletal muscle cells, we induced the opposite effects by overexpressing Prep1 or p160, but not Pbx1. In vivo skeletal muscle delivery of p160 cDNA in Prep1(i/i) mice also reverses the molecular phenotype. Finally, we show that Prep1 controls the stability of the p160 protein. We conclude that Prep1 controls insulin sensitivity through the p160-GLUT4 pathway. PMID:18644868

  20. Prep1 Deficiency Induces Protection from Diabetes and Increased Insulin Sensitivity through a p160-Mediated Mechanism▿

    PubMed Central

    Oriente, Francesco; Fernandez Diaz, Luis Cesar; Miele, Claudia; Iovino, Salvatore; Mori, Silvia; Diaz, Victor Manuel; Troncone, Giancarlo; Cassese, Angela; Formisano, Pietro; Blasi, Francesco; Beguinot, Francesco

    2008-01-01

    We have examined glucose homeostasis in mice hypomorphic for the homeotic transcription factor gene Prep1. Prep1-hypomorphic (Prep1i/i) mice exhibit an absolute reduction in circulating insulin levels but normal glucose tolerance. In addition, these mice exhibit protection from streptozotocin-induced diabetes and enhanced insulin sensitivity with improved glucose uptake and insulin-dependent glucose disposal by skeletal muscle. This muscle phenotype does not depend on reduced expression of the known Prep1 transcription partner, Pbx1. Instead, in Prep1i/i muscle, we find normal Pbx1 but reduced levels of the recently identified novel Prep1 interactor p160. Consistent with this reduction, we find a muscle-selective increase in mRNA and protein levels of PGC-1α, accompanied by enhanced expression of the GLUT4 transporter, responsible for insulin-stimulated glucose uptake in muscle. Indeed, using L6 skeletal muscle cells, we induced the opposite effects by overexpressing Prep1 or p160, but not Pbx1. In vivo skeletal muscle delivery of p160 cDNA in Prep1i/i mice also reverses the molecular phenotype. Finally, we show that Prep1 controls the stability of the p160 protein. We conclude that Prep1 controls insulin sensitivity through the p160-GLUT4 pathway. PMID:18644868

  1. Young and old genetically heterogeneous HET3 mice on a rapamycin diet are glucose intolerant but insulin sensitive.

    PubMed

    Lamming, Dudley W; Ye, Lan; Astle, Clinton M; Baur, Joseph A; Sabatini, David M; Harrison, David E

    2013-08-01

    Rapamycin, an inhibitor of the mechanistic target of rapamycin (mTOR) signaling pathway, extends the life span of yeast, worms, flies, and mice. Interventions that promote longevity are often correlated with increased insulin sensitivity, and it therefore is surprising that chronic rapamycin treatment of mice, rats, and humans is associated with insulin resistance (J Am Soc Nephrol., 19, 2008, 1411; Diabetes, 00, 2010, 00; Science, 335, 2012, 1638). We examined the effect of dietary rapamycin treatment on glucose homeostasis and insulin resistance in the genetically heterogeneous HET3 mouse strain, a strain in which dietary rapamycin robustly extends mean and maximum life span. We find that rapamycin treatment leads to glucose intolerance in both young and old HET3 mice, but in contrast to the previously reported effect of injected rapamycin in C57BL/6 mice, HET3 mice treated with dietary rapamycin responded normally in an insulin tolerance test. To gauge the overall consequences of rapamycin treatment on average blood glucose levels, we measured HBA1c. Dietary rapamycin increased HBA1c over the first 3 weeks of treatment in young animals, but the effect was lost by 3 months, and no effect was detected in older animals. Our results demonstrate that the extended life span of HET3 mice on a rapamycin diet occurs in the absence of major changes in insulin sensitivity and highlight the importance of strain background and delivery method in testing effects of longevity interventions. PMID:23648089

  2. Effects of Chronic Consumption of Sugar-Enriched Diets on Brain Metabolism and Insulin Sensitivity in Adult Yucatan Minipigs.

    PubMed

    Ochoa, Melissa; Malbert, Charles-Henri; Meurice, Paul; Val-Laillet, David

    2016-01-01

    Excessive sugar intake might increase the risk to develop eating disorders via an altered reward circuitry, but it remains unknown whether different sugar sources induce different neural effects and whether these effects are dependent from body weight. Therefore, we compared the effects of three high-fat and isocaloric diets varying only in their carbohydrate sources on brain activity of reward-related regions, and assessed whether brain activity is dependent on insulin sensitivity. Twenty-four minipigs underwent 18FDG PET brain imaging following 7-month intake of high-fat diets of which 20% in dry matter weight (36.3% of metabolisable energy) was provided by starch, glucose or fructose (n = 8 per diet). Animals were then subjected to a euglycemic hyperinsulinemic clamp to determine peripheral insulin sensitivity. After a 7-month diet treatment, all groups had substantial increases in body weight (from 36.02±0.85 to 63.33±0.81 kg; P<0.0001), regardless of the diet. All groups presented similar insulin sensitivity index (ISI = 1.39±0.10 mL·min-1·μUI·kg). Compared to starch, chronic exposure to fructose and glucose induced bilateral brain activations, i.e. increased basal cerebral glucose metabolism, in several reward-related brain regions including the anterior and dorsolateral prefrontal cortex, the orbitofrontal cortex, the anterior cingulate cortex, the caudate and putamen. The lack of differences in insulin sensitivity index and body weight suggests that the observed differences in basal brain glucose metabolism are not related to differences in peripheral insulin sensitivity and weight gain. The differences in basal brain metabolism in reward-related brain areas suggest the onset of cerebral functional alterations induced by chronic consumption of dietary sugars. Further studies should explore the underlying mechanisms, such as the availability of intestinal and brain sugar transporter, or the appearance of addictive-like behavioral correlates of these

  3. The effect of rosuvastatin on insulin sensitivity and pancreatic beta-cell function in nondiabetic renal transplant recipients.

    PubMed

    Sharif, A; Ravindran, V; Moore, R; Dunseath, G; Luzio, S; Owens, D; Baboolal, K

    2009-06-01

    Interventions to attenuate abnormal glycemia posttransplantation are required. In addition, surrogate markers of declining glycemic control are valuable. Statins may have pleiotropic properties that attenuate abnormal glucose metabolism. We hypothesized statins would improve glucose metabolism and HbA1c would be advantageous as a surrogate for worsening glycemia. We conducted a prospective, randomized, placebo controlled, crossover study in 20 nondiabetic renal transplant recipients at low risk for NODAT and compared effects of rosuvastatin on insulin secretion/sensitivity. Mathematical model analysis of an intravenous glucose tolerance test determined first-phase insulin secretion, insulin sensitivity and disposition index. Second-phase insulin secretion was determined with a meal tolerance test. Biochemical/clinical parameters were also assessed. Rosuvastatin significantly improved total cholesterol (-30%, p < 0.001), LDL cholesterol (-44%, p < 0.001) and triglycerides (-19%, p = 0.013). C-reactive protein decreased but failed to achieve statistical significance (-31%, p = 0.097). Rosuvastatin failed to influence any glycemic physiological parameter, although an inadequate timeframe to allow pleiotropic mechanisms to clinically manifest raises the possibility of a type II statistical error. On multivariate analysis, glycated hemoglobin (HbA1c) correlated with disposition index (R(2)= 0.201, p = 0.006), first-phase insulin secretion (R(2)= 0.106, p = 0.049) and insulin sensitivity (R(2)= 0.136, p = 0.029). Rosuvastatin fails to modify glucose metabolism in low-risk patients posttransplantation but HbA1c is a useful surrogate for declining glycemic control. PMID:19459810

  4. THE INFLUENCE OF THYROID FUNCTION AND BONE TURNOVER ON LIPOPROTEIN PROFILE IN YOUNG PHYSICALLY ACTIVE MEN WITH DIFFERENT INSULIN SENSITIVITY

    PubMed Central

    Lutosławska, G.; Czajkowska, A.; Tkaczyk, J.; Mazurek, K.; Tomaszewski, P.

    2014-01-01

    Physical activity induces changes in the endocrine system. Previous data indicated that changes in insulin secretion and the tissue response to this hormone are very important for energy metabolism. It is believed that they are accompanied by changes in lipid metabolism, but factors contributing to this process are still disputed. The aim of this study was to assess interactions among insulin sensitivity, thyroid function, a bone turnover marker and serum lipid profile in young physically active men. Eighty-seven physical education students, aged 18-23 years, participated in the study. We measured serum levels of glucose, lipids, insulin, thyroid-stimulating hormone (TSH), osteocalcin and anthropometric parameters. Insulin sensitivity was determined using homeostatic model assessment for insulin resistance (HOMA-IR). The median value of HOMA-IR (1.344) was used to divide the study population into Group A (above the median) and Group B (below the median). Men from both groups did not differ in anthropometric parameters or in daily physical activity. Triglycerides (TG), total cholesterol (TC) and high-density lipoprotein cholesterol (HDL-C) levels were higher in Group A (P < 0.05). TSH and osteocalcin levels were similar in males with different HOMA-IR. Multiple regression analysis for TSH and osteocalcin showed that in Group A these hormones had no effect on plasma lipoproteins. However, in Group B they significantly determined the variation of plasma TC and low-density lipoprotein cholesterol (LDL-C) levels (in about 28% and 29%, respectively). We concluded that TSH and osteocalcin are involved in determination of a more healthy lipid profile at a certain level of insulin sensitivity. PMID:24899778

  5. The influence of thyroid function and bone turnover on lipoprotein profile in young physically active men with different insulin sensitivity.

    PubMed

    Kęska, A; Lutosławska, G; Czajkowska, A; Tkaczyk, J; Mazurek, K; Tomaszewski, P

    2014-06-01

    Physical activity induces changes in the endocrine system. Previous data indicated that changes in insulin secretion and the tissue response to this hormone are very important for energy metabolism. It is believed that they are accompanied by changes in lipid metabolism, but factors contributing to this process are still disputed. The aim of this study was to assess interactions among insulin sensitivity, thyroid function, a bone turnover marker and serum lipid profile in young physically active men. Eighty-seven physical education students, aged 18-23 years, participated in the study. We measured serum levels of glucose, lipids, insulin, thyroid-stimulating hormone (TSH), osteocalcin and anthropometric parameters. Insulin sensitivity was determined using homeostatic model assessment for insulin resistance (HOMA-IR). The median value of HOMA-IR (1.344) was used to divide the study population into Group A (above the median) and Group B (below the median). Men from both groups did not differ in anthropometric parameters or in daily physical activity. Triglycerides (TG), total cholesterol (TC) and high-density lipoprotein cholesterol (HDL-C) levels were higher in Group A (P < 0.05). TSH and osteocalcin levels were similar in males with different HOMA-IR. Multiple regression analysis for TSH and osteocalcin showed that in Group A these hormones had no effect on plasma lipoproteins. However, in Group B they significantly determined the variation of plasma TC and low-density lipoprotein cholesterol (LDL-C) levels (in about 28% and 29%, respectively). We concluded that TSH and osteocalcin are involved in determination of a more healthy lipid profile at a certain level of insulin sensitivity. PMID:24899778

  6. Gender dimorphism in aspartame-induced impairment of spatial cognition and insulin sensitivity.

    PubMed

    Collison, Kate S; Makhoul, Nadine J; Zaidi, Marya Z; Saleh, Soad M; Andres, Bernard; Inglis, Angela; Al-Rabiah, Rana; Al-Mohanna, Futwan A

    2012-01-01

    Previous studies have linked aspartame consumption to impaired retention of learned behavior in rodents. Prenatal exposure to aspartame has also been shown to impair odor-associative learning in guinea pigs; and recently, aspartame-fed hyperlipidemic zebrafish exhibited weight gain, hyperglycemia and acute swimming defects. We therefore investigated the effects of chronic lifetime exposure to aspartame, commencing in utero, on changes in blood glucose parameters, spatial learning and memory in C57BL/6J mice. Morris Water Maze (MWM) testing was used to assess learning and memory, and a random-fed insulin tolerance test was performed to assess glucose homeostasis. Pearson correlation analysis was used to investigate the associations between body characteristics and MWM performance outcome variables. At 17 weeks of age, male aspartame-fed mice exhibited weight gain, elevated fasting glucose levels and decreased insulin sensitivity compared to controls (P<0.05). Females were less affected, but had significantly raised fasting glucose levels. During spatial learning trials in the MWM (acquisition training), the escape latencies of male aspartame-fed mice were consistently higher than controls, indicative of learning impairment. Thigmotactic behavior and time spent floating directionless was increased in aspartame mice, who also spent less time searching in the target quadrant of the maze (P<0.05). Spatial learning of female aspartame-fed mice was not significantly different from controls. Reference memory during a probe test was affected in both genders, with the aspartame-fed mice spending significantly less time searching for the former location of the platform. Interestingly, the extent of visceral fat deposition correlated positively with non-spatial search strategies such as floating and thigmotaxis, and negatively with time spent in the target quadrant and swimming across the location of the escape platform. These data suggest that lifetime exposure to aspartame

  7. Gender Dimorphism in Aspartame-Induced Impairment of Spatial Cognition and Insulin Sensitivity

    PubMed Central

    Collison, Kate S.; Makhoul, Nadine J.; Zaidi, Marya Z.; Saleh, Soad M.; Andres, Bernard; Inglis, Angela; Al-Rabiah, Rana; Al-Mohanna, Futwan A.

    2012-01-01

    Previous studies have linked aspartame consumption to impaired retention of learned behavior in rodents. Prenatal exposure to aspartame has also been shown to impair odor-associative learning in guinea pigs; and recently, aspartame-fed hyperlipidemic zebrafish exhibited weight gain, hyperglycemia and acute swimming defects. We therefore investigated the effects of chronic lifetime exposure to aspartame, commencing in utero, on changes in blood glucose parameters, spatial learning and memory in C57BL/6J mice. Morris Water Maze (MWM) testing was used to assess learning and memory, and a random-fed insulin tolerance test was performed to assess glucose homeostasis. Pearson correlation analysis was used to investigate the associations between body characteristics and MWM performance outcome variables. At 17 weeks of age, male aspartame-fed mice exhibited weight gain, elevated fasting glucose levels and decreased insulin sensitivity compared to controls (P<0.05). Females were less affected, but had significantly raised fasting glucose levels. During spatial learning trials in the MWM (acquisition training), the escape latencies of male aspartame-fed mice were consistently higher than controls, indicative of learning impairment. Thigmotactic behavior and time spent floating directionless was increased in aspartame mice, who also spent less time searching in the target quadrant of the maze (P<0.05). Spatial learning of female aspartame-fed mice was not significantly different from controls. Reference memory during a probe test was affected in both genders, with the aspartame-fed mice spending significantly less time searching for the former location of the platform. Interestingly, the extent of visceral fat deposition correlated positively with non-spatial search strategies such as floating and thigmotaxis, and negatively with time spent in the target quadrant and swimming across the location of the escape platform. These data suggest that lifetime exposure to aspartame

  8. Insulin sensitizers improve learning and attenuate tau hyperphosphorylation and neuroinflammation in 3xTg-AD mice.

    PubMed

    Yu, Yang; Li, Xiaojing; Blanchard, Julie; Li, Yi; Iqbal, Khalid; Liu, Fei; Gong, Cheng-Xin

    2015-04-01

    Sporadic Alzheimer's disease (AD) is a multifactorial metabolic brain disorder characterized by progressive neurodegeneration. Decreased brain energy and glucose metabolism occurs before the appearance of AD symptoms and worsens while the disease progresses. Deregulated brain insulin signaling has also been found in AD recently. To restore brain insulin sensitivity and glucose metabolism, pioglitazone and rosiglitazone, two insulin sensitizers commonly used for treating type 2 diabetes, have been studied and shown to have some beneficial effects in AD mouse models. However, the molecular mechanisms of the beneficial effects remain elusive. In the present study, we treated the 3xTg-AD mice, a widely used mouse model of AD, with pioglitazone and rosiglitazone for 4 months and studied the effects of the treatments on cognitive performance and AD-related brain alterations. We found that the chronic treatment improved spatial learning, enhanced AKT signaling, and attenuated tau hyperphosphorylation and neuroinflammation. These findings shed new light on the possible mechanisms by which these two insulin sensitizers might be useful for treating AD and support further clinical trials evaluating the efficacy of these drugs. PMID:25113171

  9. Effects of eicosapentaenoic acid (EPA) treatment on insulin sensitivity in an animal model of diabetes: improvement of the inflammatory status.

    PubMed

    Figueras, Maite; Olivan, Mireia; Busquets, Sílvia; López-Soriano, Francisco J; Argilés, Josep M

    2011-02-01

    In addition to decreased insulin sensitivity, diabetes is a pathological condition associated with increased inflammation. The ω-3 fatty acids have been proposed as anti-inflammatory agents. Thus, the major goal of this study was to analyze the effects of fatty acid supplementation on both insulin sensitivity and inflammatory status in an animal model of type 2 diabetes. Diabetic rats (Goto-Kakizaki model) were treated with eicosapentaenoic acid (EPA) or linoleic acid at 0.5 g/kg body weigh (bw) dose. In vivo incorporation of (14)C-triolein into adipose tissue was improved by the ω-3 administration. In vitro incubations of adipose tissue slices from EPA-treated rats showed an increase in (14)C-palmitate incorporation into the lipid fraction. These observations were linked with a decreased rate of fatty acid oxidation. EPA treatment resulted in a decreased fatty acid oxidation in incubated strips from extensor digitorum longus (EDL) muscles. The changes in lipid utilization were associated with a decrease in insulin plasma concentration, suggesting an improvement in insulin sensitivity. These changes in lipid metabolism were associated with an activation of AMP-activated protein kinase (AMPK) in white adipose tissue. In addition, EPA treatment resulted in a decreased content of peroxisome proliferator-activated receptor-α (PPARα) and PPARδ and in increased GLUT4 expression in skeletal muscle. Moreover, EPA increased 2-deoxy-D-[(14)C]glucose (2-DOG) uptake in C2C12 myotubes, suggesting an improvement in glucose metabolism. Concerning the inflammatory status, EPA treatment resulted in a decreased gene expression for both tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) both in skeletal muscle and adipose tissue. The data suggest that EPA treatment to diabetic rats clearly improves lipid metabolism although the evidences on insulin sensitization are less clear. PMID:20885391

  10. Adipose Depots, not Disease Related Factors, Account for Skeletal Muscle Insulin Sensitivity in Established and Treated Rheumatoid Arthritis

    PubMed Central

    AbouAssi, Hiba; Tune, K. Noelle; Gilmore, Brian; Bateman, Lori A.; McDaniel, Gary; Muehlbauer, Michael; Huebner, Janet L.; Hoenig, Helen M.; Kraus, Virginia B.; Clair, E. William St.; Kraus, William E.; Huffman, Kim M.

    2014-01-01

    Objectives In prior reports, individuals with rheumatoid arthritis (RA) exhibited increased insulin resistance. However, these studies were limited by either suboptimal assessment methods for insulin sensitivity or a failure to account for important determinants, adiposity and physical activity. Our objectives were to carefully assess, compare and determine predictors of skeletal muscle insulin sensitivity (SI) in RA, accounting for adiposity and physical activity. Methods Thirty-nine individuals with established (seropositive or erosions) and treated RA and 39 age, gender, race, BMI, and physical activity-matched controls underwent a frequently-sampled intravenous glucose tolerance test to determine SI. Inflammation, body composition, and physical activity were assessed with systemic cytokine measurements, CT scans, and accelerometry, respectively. Exclusions were diabetes, cardiovascular disease, medication changes within three months, and prednisone use over 5 mg/d. This investigation was powered to detect a clinically significant, moderate effect size for SI difference. Results Despite elevated systemic inflammation (interleukin (IL)-6, IL-18, tumor necrosis factor-alpha; P<0.05 for all), persons with RA were not less insulin sensitive (SI geometric mean (SD): RA 4.0 (2.4) versus Control 4.9 (2.1)*10−5 min−1/[pmol/l]; P=0.39). Except for visceral adiposity being slightly greater in controls (P=0.03), there were no differences in body composition or physical activity. Lower SI was independently associated with increased abdominal and thigh adiposity, but not with cytokines, disease activity, duration, disability, or disease modifying medication use. Conclusions In established and treated RA, traditional risk factors, specifically excess adiposity, play more of a role in predicting skeletal muscle insulin sensitivity than systemic inflammation or other disease-related factors. PMID:24986846

  11. Lactose in milk replacer can partly be replaced by glucose, fructose, or glycerol without affecting insulin sensitivity in veal calves.

    PubMed

    Pantophlet, A J; Gilbert, M S; van den Borne, J J G C; Gerrits, W J J; Roelofsen, H; Priebe, M G; Vonk, R J

    2016-04-01

    Calf milk replacer (MR) contains 40 to 50% lactose. Lactose strongly fluctuates in price and alternatives are desired. Also, problems with glucose homeostasis and insulin sensitivity (i.e., high incidence of hyperglycemia and hyperinsulinemia) have been described for heavy veal calves (body weight >100kg). Replacement of lactose by other dietary substrates can be economically attractive, and may also positively (or negatively) affect the risk of developing problems with glucose metabolism. An experiment was designed to study the effects of replacing one third of the dietary lactose by glucose, fructose, or glycerol on glucose homeostasis and insulin sensitivity in veal calves. Forty male Holstein-Friesian (body weight=114±2.4kg; age=97±1.4 d) calves were fed an MR containing 462g of lactose/kg (CON), or an MR in which 150g of lactose/kg of MR was replaced by glucose (GLU), fructose (FRU), or glycerol (GLY). During the first 10d of the trial, all calves received CON. The CON group remained on this diet and the other groups received their experimental diets for a period of 8 wk. Measurements were conducted during the first (baseline) and last week of the trial. A frequently sampled intravenous glucose tolerance test was performed to assess insulin sensitivity and 24 h of urine was collected to measure glucose excretion. During the last week of the trial, a bolus of 1.5g of [U-(13)C] substrates was added to their respective meals and plasma glucose, insulin, and (13)C-glucose responses were measured. Insulin sensitivity was low at the start of the trial and remained low [1.2±0.1 and 1.0±0.1 (mU/L)(-1) × min(-1)], and no treatment effect was noted. Glucose excretion was low at the start of the trial (3.4±1.0g/d), but increased in CON and GLU calves (26.9±3.9 and 43.0±10.6g/d) but not in FRU and GLY calves. Postprandial glucose was higher in GLU, lower in FRU, and similar in GLY compared with CON calves. Postprandial insulin was lower in FRU and GLY and similar

  12. Krüppel-like factor 14 increases insulin sensitivity through activation of PI3K/Akt signal pathway.

    PubMed

    Yang, Min; Ren, Yan; Lin, Zhimin; Tang, Chenchen; Jia, Yanjun; Lai, Yerui; Zhou, Tingting; Wu, Shaobo; Liu, Hua; Yang, Gangyi; Li, Ling

    2015-11-01

    Genome-wide association studies (GWAS) have shown that Krüppel-like factor 14 (KLF14) is associated with type 2 diabetes mellitus (T2DM). However, no report has demonstrated a relationship between KLF14 and glucose metabolism. The aim of this study was to determine whether KLF14 is associated with glucose metabolism and insulin signaling in vitro. The mRNA and protein expressions of KLF14 were determined by Real-time PCR and Western blotting. Glucose uptake was assessed by 2-[(3)H]-deoxyglucose (2-DG) uptake. Western blotting was used to identify the activation of insulin signaling proteins. KLF14 mRNA and protein in fat and muscle were significantly decreased in HFD-fed mice, db/db mice and T2DM patients. Overexpression of KLF14 enhanced insulin-stimulated glucose uptake and the activation of Akt kinase in Hepa1-6 cells. The phosphorylation of insulin receptor (InsR), insulin receptor substrate-1(IRS-1), glycogen synthase kinase-3β (GSK-3β) and Akt also elevated significantly by up-regulation of KLF14. KLF14 overexpression in Hepa1-6 cells prevented the inhibition of glucose uptake and Akt phosphorylation induced by high glucose and/or high insulin, or T2DM serum. However, KLF14's ability to increase glucose uptake and Akt activation was significantly attenuated by LY294002, a PI3-kinase inhibitor. These data suggested that KLF14 could increase insulin sensitivity probably through the PI3K/Akt pathway. PMID:26226221

  13. Oxamate Improves Glycemic Control and Insulin Sensitivity via Inhibition of Tissue Lactate Production in db/db Mice

    PubMed Central

    Ye, Weiran; Zheng, Yijia; Zhang, Shanshan; Yan, Li; Cheng, Hua; Wu, Muchao

    2016-01-01

    Oxamate (OXA) is a pyruvate analogue that directly inhibits the lactate dehydrogenase (LDH)-catalyzed conversion process of pyruvate into lactate. Earlier and recent studies have shown elevated blood lactate levels among insulin-resistant and type 2 diabetes subjects and that blood lactate levels independently predicted the development of incident diabetes. To explore the potential of OXA in the treatment of diabetes, db/db mice were treated with OXA in vivo. Treatment of OXA (350–750 mg/kg of body weight) for 12 weeks was shown to decrease body weight gain and blood glucose and HbA1c levels and improve insulin secretion, the morphology of pancreatic islets, and insulin sensitivity in db/db mice. Meanwhile, OXA reduced the lactate production of adipose tissue and skeletal muscle and serum lactate levels and decreased serum levels of TG, FFA, CRP, IL-6, and TNF-α in db/db mice. The PCR array showed that OXA downregulated the expression of Tnf, Il6, leptin, Cxcr3, Map2k1, and Ikbkb, and upregulated the expression of Irs2, Nfkbia, and Pde3b in the skeletal muscle of db/db mice. Interestingly, LDH-A expression increased in the islet cells of db/db mice, and both treatment of OXA and pioglitazone decreased LDH-A expression, which might be related to the improvement of insulin secretion. Taken together, increased lactate production of adipose tissue and skeletal muscle may be at least partially responsible for insulin resistance and diabetes in db/db mice. OXA improved glycemic control and insulin sensitivity in db/db mice primarily via inhibition of tissue lactate production. Oxamic acid derivatives may be a potential drug for the treatment of type 2 diabetes. PMID:26938239

  14. A Fasting Insulin–Raising Allele at IGF1 Locus Is Associated with Circulating Levels of IGF-1 and Insulin Sensitivity

    PubMed Central

    Mannino, Gaia Chiara; Greco, Annalisa; De Lorenzo, Carlo; Andreozzi, Francesco; Marini, Maria A.; Perticone, Francesco; Sesti, Giorgio

    2013-01-01

    Background A meta-analysis of genome-wide data reported the discovery of the rs35767 polymorphism near IGF1 with genome-wide significant association with fasting insulin levels. However, it is unclear whether the effects of this polymorphism on fasting insulin are mediated by a reduced insulin sensitivity or impaired insulin clearance. We investigated the effects of the rs35767 polymorphism on circulating IGF-1 levels, insulin sensitivity, and insulin clearance. Methodology/Principal Findings Two samples of adult nondiabetic white Europeans were studied. In sample 1 (n=569), IGF-1 levels were lower in GG genotype carriers compared with A allele carriers (190±77 vs. 218±97 ng/ml, respectively; P=0.007 after adjusting for age, gender, and BMI). Insulin sensitivity assessed by euglycaemic-hyperinsulinemic clamp was lower in GG genotype carriers compared with A allele carriers (8.9±4.1 vs. 10.1±5.1 mg x Kg-1 free fat mass x min-1, respectively; P=0.03 after adjusting for age, gender, and BMI). The rs35767 polymorphism did not show significant association with insulin clearance. In sample 2 (n=859), IGF-1 levels were lower in GG genotype carriers compared with A allele carriers (155±60 vs. 164±63 ng/ml, respectively; P=0.02 after adjusting for age, gender, and BMI). Insulin sensitivity, as estimated by the HOMA index, was lower in GG genotype carriers compared with A allele carriers (2.8±2.2 vs. 2.5±1.3, respectively; P=0.03 after adjusting for age, gender, and BMI). Conclusion/Significance The rs35767 polymorphism near IGF1 was associated with circulating IGF-1 levels, and insulin sensitivity with carriers of the GG genotype exhibiting lower IGF-1 concentrations and insulin sensitivity as compared with subjects carrying the A allele. PMID:24392014

  15. Topography of subnuclei of the hypothalamic paraventricular nucleus in rats and sensitivity of their neurons to insulin defficiency

    SciTech Connect

    Goufman, E.I.

    1985-07-01

    This investigation was undertaken to study the reaction of paraventricular nuclei (PVN) subnuclei to insulin deficiency and to elevation of the blood glucose level under conditions of experimental alloxan diabetes. Experiments were carried out on 15 control and 15 experimental mature male Wistar rats. The state of the carbohydrate metabolism of the diabetic and control animals was judged by the blood glucose and radioimmune insulin levels. The results of these investigations show that both magnocellular and parvocellular neurons of PVN react to alloxan diabetes, which supports the hypothesis that PVN of the hypothalamus participates in the control of carbohydrate metabolism.

  16. Long-term exposure to abnormal glucose levels alters drug metabolism pathways and insulin sensitivity in primary human hepatocytes

    PubMed Central

    Davidson, Matthew D.; Ballinger, Kimberly R.; Khetani, Salman R.

    2016-01-01

    Hyperglycemia in type 2 diabetes mellitus has been linked to non-alcoholic fatty liver disease, which can progress to inflammation, fibrosis/cirrhosis, and hepatocellular carcinoma. Understanding how chronic hyperglycemia affects primary human hepatocytes (PHHs) can facilitate the development of therapeutics for these diseases. Conversely, elucidating the effects of hypoglycemia on PHHs may provide insights into how the liver adapts to fasting, adverse diabetes drug reactions, and cancer. In contrast to declining PHH monocultures, micropatterned co-cultures (MPCCs) of PHHs and 3T3-J2 murine embryonic fibroblasts maintain insulin-sensitive glucose metabolism for several weeks. Here, we exposed MPCCs to hypo-, normo- and hyperglycemic culture media for ~3 weeks. While albumin and urea secretion were not affected by glucose level, hypoglycemic MPCCs upregulated CYP3A4 enzyme activity as compared to other glycemic states. In contrast, hyperglycemic MPCCs displayed significant hepatic lipid accumulation in the presence of insulin, while also showing decreased sensitivity to insulin-mediated inhibition of glucose output relative to a normoglycemic control. In conclusion, we show for the first time that PHHs exposed to hypo- and hyperglycemia can remain highly functional, but display increased CYP3A4 activity and selective insulin resistance, respectively. In the future, MPCCs under glycemic states can aid in novel drug discovery and mechanistic investigations. PMID:27312339

  17. Sestrin 3 Protein Enhances Hepatic Insulin Sensitivity by Direct Activation of the mTORC2-Akt Signaling

    PubMed Central

    Tao, Rongya; Xiong, Xiwen; Liangpunsakul, Suthat

    2015-01-01

    Sestrin proteins have been implicated in multiple biological processes including resistance to oxidative and genotoxic stresses, protection against aging-related pathologies, and promotion of metabolic homeostasis; however, the underlying mechanisms are incompletely understood. Some evidence suggests that sestrins may inhibit mTORC1 (mechanistic target of rapamycin complex 1) through inhibition of RagA/B GTPases or activation of AMPK; however, whether sestrins are also involved in mTORC2 regulation and function is unclear. To investigate the functions and mechanisms of Sestrin 3 (Sesn3), we generated Sesn3 liver-specific transgenic and knockout mice. Our data show that Sesn3 liver-specific knockout mice exhibit insulin resistance and glucose intolerance, and Sesn3 transgenic mice were protected against insulin resistance induced by a high-fat diet. Using AMPK liver-specific knockout mice, we demonstrate that the Sesn3 insulin-sensitizing effect is largely independent of AMPK. Biochemical analysis reveals that Sesn3 interacts with and activates mTORC2 and subsequently stimulates Akt phosphorylation at Ser473. These findings suggest that Sesn3 can activate Akt via mTORC2 to regulate hepatic insulin sensitivity and glucose metabolism. PMID:25377878

  18. Small Molecule Kaempferol Promotes Insulin Sensitivity and Preserved Pancreatic β-Cell Mass in Middle-Aged Obese Diabetic Mice

    PubMed Central

    Alkhalidy, Hana; Moore, William; Zhang, Yanling; Wang, Aihua; Ali, Mostafa; Suh, Kyung-Shin; Zhen, Wei; Cheng, Zhiyong; Jia, Zhenquan; Hulver, Matthew

    2015-01-01

    Insulin resistance and a progressive decline in functional β-cell mass are hallmarks of developing type 2 diabetes (T2D). Thus, searching for natural, low-cost compounds to target these two defects could be a promising strategy to prevent the pathogenesis of T2D. Here, we show that dietary intake of flavonol kaempferol (0.05% in the diet) significantly ameliorated hyperglycemia, hyperinsulinemia, and circulating lipid profile, which were associated with the improved peripheral insulin sensitivity in middle-aged obese mice fed a high-fat (HF) diet. Kaempferol treatment reversed HF diet impaired glucose transport-4 (Glut4) and AMP-dependent protein kinase (AMPK) expression in both muscle and adipose tissues from obese mice. In vitro, kaempferol increased lipolysis and prevented high fatty acid-impaired glucose uptake, glycogen synthesis, AMPK activity, and Glut4 expression in skeletal muscle cells. Using another mouse model of T2D generated by HF diet feeding and low doses of streptozotocin injection, we found that kaempferol treatment significantly improved hyperglycemia, glucose tolerance, and blood insulin levels in obese diabetic mice, which are associated with the improved islet β-cell mass. These results demonstrate that kaempferol may be a naturally occurring anti-diabetic agent by improving peripheral insulin sensitivity and protecting against pancreatic β-cell dysfunction. PMID:26064984

  19. Spirulina versicolor improves insulin sensitivity and attenuates hyperglycemia-mediated oxidative stress in fructose-fed rats

    PubMed Central

    Hozayen, Walaa G.; Mahmoud, Ayman M.; Soliman, Hanan A.; Mostafa, Sanura R.

    2016-01-01

    Aim: The current study aimed to investigate the anti-hyperglycemic, anti-hyperlipidemic and insulin sensitizing effects of the cyanobacterium Spirulina versicolor extract in fructose-fed rats. Materials and Methods: Rats were fed 30% fructose solution in drinking water for 4 weeks. Animals exhibited hyperglycemia and hyperinsulinemia were selected for further investigations. Diabetic and control rats were orally supplemented with 50 mg/kg body weight S. versicolor extract for 4 weeks. Results: At the end of 8 weeks, fructose-fed rats showed a significant increase in serum glucose, insulin, cholesterol, triglycerides, cardiovascular risk indices and insulin resistance. Treatment of the fructose-fed rats with S. versicolor extract improved this metabolic profile. Fructose feeding produced a significant increase in serum tumor necrosis factor alpha and a decrease in adiponectin levels. In addition, fructose-fed rats exhibited a significant increase in liver, kidney and heart lipid peroxidation levels, and declined antioxidant defenses. Supplementation of the fructose-fed rats with S. versicolor extract reversed these alterations. Conclusion: S. versicolor attenuates hyperglycemia-mediated oxidative stress and inflammation, and is thus effective in improving insulin sensitivity in fructose-fed rats. PMID:27069726

  20. Long-term exposure to abnormal glucose levels alters drug metabolism pathways and insulin sensitivity in primary human hepatocytes.

    PubMed

    Davidson, Matthew D; Ballinger, Kimberly R; Khetani, Salman R

    2016-01-01

    Hyperglycemia in type 2 diabetes mellitus has been linked to non-alcoholic fatty liver disease, which can progress to inflammation, fibrosis/cirrhosis, and hepatocellular carcinoma. Understanding how chronic hyperglycemia affects primary human hepatocytes (PHHs) can facilitate the development of therapeutics for these diseases. Conversely, elucidating the effects of hypoglycemia on PHHs may provide insights into how the liver adapts to fasting, adverse diabetes drug reactions, and cancer. In contrast to declining PHH monocultures, micropatterned co-cultures (MPCCs) of PHHs and 3T3-J2 murine embryonic fibroblasts maintain insulin-sensitive glucose metabolism for several weeks. Here, we exposed MPCCs to hypo-, normo- and hyperglycemic culture media for ~3 weeks. While albumin and urea secretion were not affected by glucose level, hypoglycemic MPCCs upregulated CYP3A4 enzyme activity as compared to other glycemic states. In contrast, hyperglycemic MPCCs displayed significant hepatic lipid accumulation in the presence of insulin, while also showing decreased sensitivity to insulin-mediated inhibition of glucose output relative to a normoglycemic control. In conclusion, we show for the first time that PHHs exposed to hypo- and hyperglycemia can remain highly functional, but display increased CYP3A4 activity and selective insulin resistance, respectively. In the future, MPCCs under glycemic states can aid in novel drug discovery and mechanistic investigations. PMID:27312339

  1. Hydrogen Sulfide Treatment Promotes Glucose Uptake by Increasing Insulin Receptor Sensitivity and Ameliorates Kidney Lesions in Type 2 Diabetes

    PubMed Central

    Xue, Rong; Hao, Dan-Dan; Sun, Ji-Ping; Li, Wen-Wen; Zhao, Man-Man; Li, Xing-Hui; Chen, Ying; Zhu, Jian-Hua; Ding, Ying-Jiong; Liu, Jun

    2013-01-01

    Abstract Aims: To examine if hydrogen sulfide (H2S) can promote glucose uptake and provide amelioration in type 2 diabetes. Results: Treatment with sodium hydrosulfide (NaHS, an H2S donor) increased glucose uptake in both myotubes and adipocytes. The H2S gas solution showed similar effects. The NaHS effects were blocked by an siRNA-mediated knockdown of the insulin receptor (IR). NaHS also increased phosphorylation of the IR, PI3K, and Akt. In Goto-Kakizaki (GK) diabetic rats, chronic NaHS treatment (30 μmol·kg−1·day−1) decreased fasting blood glucose, increased insulin sensitivity, and increased glucose tolerance with increased phosphorylation of PI3K and Akt in muscles. Similar insulin-sensitizing effects of NaHS treatment were also observed in Wistar rats. Moreover, glucose uptake was reduced in the cells with siRNA-mediated knockdown of the H2S-generating enzyme cystathionine γ-lyase in the presence or absence of exogenous H2S. Moreover, chronic NaHS treatment reduced oxygen species and the number of crescentic glomeruli in the kidney of GK rats. Innovation and Conclusion: This study provides the first piece of evidence for the insulin-sensitizing effect of NaHS/H2S in the both in vitro and in vivo models of insulin resistance. Rebound Track: This work was rejected during a standard peer review and rescued by the Rebound Peer Review (Antoxid Redox Signal 16: 293–296, 2012) with the following serving as open reviewers: Jin-Song Bian, Samuel Dudley, Hideo Kimura, and Xian Wang. Antioxid. Redox Signal. 19, 5–23. PMID:23293908

  2. Monoclonal antibodies as surrogate receptors in a high throughput screen for compounds that enhance insulin sensitivity.

    PubMed

    Bright, S W; Gold, G; Sage, S W; Sportsman, J R; Tinsley, F C; Dominianni, S J; Schmiegel, K K; Kellam, M L; Fitch, L L; Yen, T T

    1997-01-01

    Monoclonal antibodies (MoAbs) were made to a known insulin sensitivity enhancer (ISE) compound, CS-045. The MoAbs were characterized with respect to binding other known thiazolidinedione ISE compounds using a CS-045 labeled with b-phycoerythrin in a competitive particle concentration fluorescence immunoassay (PCFIA). By comparing the rank order of IC50 values for each compound to its respective potency as an ISE, one MoAb (13E3) was selected for further characterization. This MoAb was also used as a surrogate receptor in a high throughput screen to identify novel compounds that compete for binding to CS-045. Some of the hits were found to have efficacy in reducing blood glucose. Subsequently, another group reported that several compounds with the core thiazolidinedione structure of the ISE compounds bound with high affinity to peroxisome proliferator-activating receptors (PPAR). Therefore, we used the MoAb assay to test these and other compounds that are known to bind to PPARgamma and noted crossreactivity with some of the compounds. PMID:9408053

  3. Reduced Insulin Sensitivity Is Related to Less Endogenous Dopamine at D2/3 Receptors in the Ventral Striatum of Healthy Nonobese Humans

    PubMed Central

    Caravaggio, Fernando; Borlido, Carol; Hahn, Margaret; Feng, Zhe; Fervaha, Gagan; Gerretsen, Philip; Nakajima, Shinichiro; Plitman, Eric; Chung, Jun Ku; Iwata, Yusuke; Wilson, Alan; Remington, Gary

    2015-01-01

    Background: Food addiction is a debated topic in neuroscience. Evidence suggests diabetes is related to reduced basal dopamine levels in the nucleus accumbens, similar to persons with drug addiction. It is unknown whether insulin sensitivity is related to endogenous dopamine levels in the ventral striatum of humans. We examined this using the agonist dopamine D2/3 receptor radiotracer [11C]-(+)-PHNO and an acute dopamine depletion challenge. In a separate sample of healthy persons, we examined whether dopamine depletion could alter insulin sensitivity. Methods: Insulin sensitivity was estimated for each subject from fasting plasma glucose and insulin using the Homeostasis Model Assessment II. Eleven healthy nonobese and nondiabetic persons (3 female) provided a baseline [11C]-(+)-PHNO scan, 9 of which provided a scan under dopamine depletion, allowing estimates of endogenous dopamine at dopamine D2/3 receptor. Dopamine depletion was achieved via alpha-methyl-para-tyrosine (64mg/kg, P.O.). In 25 healthy persons (9 female), fasting plasma and glucose was acquired before and after dopamine depletion. Results: Endogenous dopamine at ventral striatum dopamine D2/3 receptor was positively correlated with insulin sensitivity (r(7)=.84, P=.005) and negatively correlated with insulin levels (r(7)=-.85, P=.004). Glucose levels were not correlated with endogenous dopamine at ventral striatum dopamine D2/3 receptor (r(7)=-.49, P=.18). Consistently, acute dopamine depletion in healthy persons significantly decreased insulin sensitivity (t(24)=2.82, P=.01), increased insulin levels (t(24)=-2.62, P=.01), and did not change glucose levels (t(24)=-0.93, P=.36). Conclusion: In healthy individuals, diminished insulin sensitivity is related to less endogenous dopamine at dopamine D2/3 receptor in the ventral striatum. Moreover, acute dopamine depletion reduces insulin sensitivity. These findings may have important implications for neuropsychiatric populations with metabolic

  4. MicroRNA-16 modulates macrophage polarization leading to improved insulin sensitivity in myoblasts.

    PubMed

    Talari, Malathi; Kapadia, Bandish; Kain, Vasundhara; Seshadri, Sriram; Prajapati, Bhumika; Rajput, Parth; Misra, Parimal; Parsa, Kishore V L

    2015-12-01

    Uncontrolled inflammation leads to several diseases such as insulin resistance, T2D and several types of cancers. The functional role of microRNAs in inflammation induced insulin resistance is poorly studied. MicroRNAs are post-transcriptional regulatory molecules which mediate diverse biological processes. We here show that miR-16 expression levels are down-regulated in different inflammatory conditions such as LPS/IFNγ or palmitate treated macrophages, palmitate exposed myoblasts and insulin responsive tissues of high sucrose diet induced insulin resistant rats. Importantly, forced expression of miR-16 in macrophages impaired the production of TNF-α, IL-6 and IFN-β leading to enhanced insulin stimulated glucose uptake in co-cultured skeletal myoblasts. Further, ectopic expression of miR-16 enhanced insulin stimulated glucose uptake in skeletal myoblasts via the up-regulation of GLUT4 and MEF2A, two key players involved in insulin stimulated glucose uptake. Collectively, our data highlight the important role of miR-16 in ameliorating inflammation induced insulin resistance. PMID:26453808

  5. beta-Cell function and insulin sensitivity in adolescents from an OGTT

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Given the increase in the incidence of insulin resistance, obesity, and type 2 diabetes in children and adolescents, it would be of paramount importance to assess quantitative indices of insulin secretion and action during a physiological perturbation, such as a meal or an oral glucose-tolerance tes...

  6. Breed differences in insulin sensitivity and insulinemic responses to oral glucose in horses and ponies of moderate body condition score.

    PubMed

    Bamford, N J; Potter, S J; Harris, P A; Bailey, S R

    2014-04-01

    Breed-related differences may occur in the innate insulin sensitivity (SI) of horses and ponies, an important factor believed to be associated with the risk of laminitis. The aim of this study was to measure the glucose and insulin responses of different breeds of horses and ponies in moderate body condition to a glucose-containing meal and to compare these responses with the indices of SI as determined by a frequently sampled intravenous glucose tolerance test (FSIGT). Eight Standardbred horses, 8 mixed-breed ponies, and 7 Andalusian-cross horses with a mean ± SEM BCS 5.0 ± 0.3 of 9 were used in this study. Each animal underwent an oral glucose tolerance test (OGTT) in which they were fed a fiber-based ration (2.0 g/kg BW) containing 1.5 g/kg BW added glucose, as well as a standard FSIGT with minimal model analysis. The glucose response variables from the OGTT were similar between groups; however, the peak insulin concentration was higher in ponies (94.1 ± 29.1 μIU/mL; P = 0.003) and Andalusians (85.3 ± 18.6; P = 0.004) than in Standardbreds (21.2 ± 3.5). The insulin area under the curve was also higher in ponies (13.5 ± 3.6 IU · min · L(-1); P = 0.009) and Andalusians (15.0 ± 2.7; P = 0.004) than in Standardbreds (3.1 ± 0.6). Insulin sensitivity, as determined by the FSIGT, was lower in Andalusians (0.99 ± 0.18 × 10(-4)/[mIU · min]) than in Standardbreds (5.43 ± 0.94; P < 0.001) and in ponies (2.12 ± 0.44; P = 0.003) than in Standardbreds. Peak insulin concentrations from the OGTT were negatively correlated with SI (P < 0.001; rs = -0.75). These results indicate that there are clear breed-related differences in the insulin responses of horses and ponies to oral and intravenous glucose. All animals were in moderate body condition, indicating that breed-related differences in insulin dynamics occurred independent of obesity. PMID:24308928

  7. Resistant Starch from High-Amylose Maize Increases Insulin Sensitivity in Overweight and Obese Men123

    PubMed Central

    Maki, Kevin C.; Pelkman, Christine L.; Finocchiaro, E. Terry; Kelley, Kathleen M.; Lawless, Andrea L.; Schild, Arianne L.; Rains, Tia M.

    2012-01-01

    This study evaluated the effects of 2 levels of intake of high-amylose maize type 2 resistant starch (HAM-RS2) on insulin sensitivity (SI) in participants with waist circumference ≥89 (women) or ≥102 cm (men). Participants received 0 (control starch), 15, or 30 g/d (double-blind) of HAM-RS2 in random order for 4-wk periods separated by 3-wk washouts. Minimal model SI was assessed at the end of each period using the insulin-modified i.v. glucose tolerance test. The efficacy evaluable sample included 11 men and 22 women (mean ± SEM) age 49.5 ± 1.6 y, with a BMI of 30.6 ± 0.5 kg/m2 and waist circumference 105.3 ± 1.3 cm. A treatment main effect (P = 0.018) and a treatment × sex interaction (P = 0.033) were present. In men, least squares geometric mean analysis for SI did not differ after intake of 15 g/d HAM-RS2 (6.90 × 10−5 pmol−1 · L−1 × min−1) and 30 g/d HAM-RS2 (7.13 × 10−5 pmol−1 · L−1 × min−1), but both were higher than after the control treatment (4.66 × 10−5 pmol−1 · L−1 × min−1) (P < 0.05). In women, there was no difference among the treatments (overall least squares ln-transformed mean ± pooled SEM = 1.80 ± 0.08; geometric mean = 6.05 × 10−5 pmol−1 · L−1 × min−1). These results suggest that consumption of 15–30 g/d of HAM-RS2 improves SI in men. Additional research is needed to understand the mechanisms that might account for the treatment × sex interaction observed. PMID:22357745

  8. The Mechanism by Which Safflower Yellow Decreases Body Fat Mass and Improves Insulin Sensitivity in HFD-Induced Obese Mice

    PubMed Central

    Zhu, Huijuan; Wang, Xiangqing; Pan, Hui; Dai, Yufei; Li, Naishi; Wang, Linjie; Yang, Hongbo; Gong, Fengying

    2016-01-01

    Objectives: Safflower yellow (SY) is the main effective ingredient of Carthamus tinctorius L. It has been reported that SY plays an important role in anti-inflammation, anti-platelet aggregation, and inhibiting thrombus formation. In present study, we try to investigate the effects of SY on body weight, body fat mass, insulin sensitivity in high fat diet (HFD)-induced obese mice. Methods: HFD-induced obese male ICR mice were intraperitoneally injected with SY (120 mg kg−1) daily. Eight weeks later, intraperitoneal insulin tolerance test (IPITT), and intraperitoneal glucose tolerance test (IPGTT) were performed, and body weight, body fat mass, serum insulin levels were measured. The expression of glucose and lipid metabolic related genes in white adipose tissue (WAT) were determined by RT-qPCR and western blot technologies. Results: The administration obese mice with SY significantly reduced the body fat mass of HFD-induced obese mice (P < 0.05). IPITT test showed that the insulin sensitivity of SY treated obese mice were evidently improved. The mRNA levels of insulin signaling pathway related genes including insulin receptor substrate 1(IRS1), PKB protein kinase (AKT), glycogen synthase kinase 3β (GSK3β) and forkhead box protein O1(FOXO1) in mesenteric WAT of SY treated mice were significantly increased to 1.9- , 2.8- , 3.3- , and 5.9-folds of that in HFD-induced control obese mice, respectively (P < 0.05). The protein levels of AKT and GSK3β were also significantly increased to 3.0 and 5.2-folds of that in HFD-induced control obese mice, respectively (P < 0.05). Meanwhile, both the mRNA and protein levels of peroxisome proliferator-activated receptorgamma coactivator 1α (PGC1α) in inguinal subcutaneous WAT of SY group were notably increased to 2.5 and 3.0-folds of that in HFD-induced control obese mice (P < 0.05). Conclusions: SY significantly reduce the body fat mass, fasting blood glucose and increase insulin sensitivity of HFD-induced obese mice. The

  9. Effect of Metformin Glycinate on Glycated Hemoglobin A1c Concentration and Insulin Sensitivity in Drug-Naive Adult Patients with Type 2 Diabetes Mellitus

    PubMed Central

    Martínez-Abundis, Esperanza; Robles-Cervantes, José A.; Ramos-Zavala, Maria G.; Barrera-Durán, Carmelita; González-Canudas, Jorge

    2012-01-01

    Abstract Aim This study evaluated the effect of metformin glycinate on glycated hemoglobin A1c (A1C) concentration and insulin sensitivity in drug-naive adult patients with type 2 diabetes mellitus (T2DM). Subjects and Methods A randomized, double-blind, placebo-controlled clinical trial was carried out in 20 patients with drug-naive T2DM. Ten subjects received metformin glycinate (1,050.6 mg) once daily during the first month and force-titrated twice daily during the second month. Ten additional patients received placebo as the control group. Before and after the intervention, metabolic profile including A1C and insulin sensitivity (euglycemic-hyperinsulinemic clamp technique) was estimated. Results A1C concentrations decreased significantly with metformin glycinate administration (8.0±0.7% vs. 7.1±0.9%, P=0.008) before and after the intervention, respectively. There were significant differences in changes from baseline of A1C between groups (0.0±0.7% vs. −1.0±0.5% for placebo and metformin glycinate groups, respectively; P=0.004). A reduction of ≥1% in A1C levels was reached in 60.0% of patients with metformin glycinate administration (P=0.02). Insulin sensitivity was not modified by the intervention. Conclusions Administration of metformin glycinate during a 2-month period showed a greater decrease in A1C concentrations than placebo in a selected group of drug-naive adult patients with T2DM. PMID:22974412

  10. Transcriptional Regulation by Nuclear Corepressors and PGC-1α: Implications for Mitochondrial Quality Control and Insulin Sensitivity

    PubMed Central

    Qi, Zhengtang; Ding, Shuzhe

    2012-01-01

    The peroxisome proliferator-activated receptors (PPARs) and estrogen-related receptor (ERRα) are ligand-activated nuclear receptors that coordinately regulate gene expression. Recent evidence suggests that nuclear corepressors, NCoR, RIP140, and SMRT, repress nuclear receptors-mediated transcriptional activity on specific promoters, and thus regulate insulin sensitivity, adipogenesis, mitochondrial number, and activity in vivo. Moreover, the coactivator PGC-1α that increases mitochondrial biogenesis during exercise and calorie restriction directly regulates autophagy in skeletal muscle and mitophagy in the pathogenesis of Parkinson's disease. In this paper, we discuss the PGC-1α's novel role in mitochondrial quality control and the role of nuclear corepressors in regulating insulin sensitivity and interacting with PGC-1α. PMID:23304112

  11. Internalized insulin-receptor complexes are unidirectionally translocated to chloroquine-sensitive degradative sites. Dependence on metabolic energy

    SciTech Connect

    Berhanu, P.

    1988-04-25

    Insulin receptors on the surface of isolated rat adipocytes were photoaffinity labeled at 12 degrees C with the iodinated photoreactive insulin analogue, 125I-B2 (2-nitro-4-azidophenylacetyl)-des-PheB1-insulin, and the pathways in the intracellular processing of the labeled receptors were studied at 37 degrees C. During 37 degrees C incubations, the labeled 440-kDa insulin receptors were continuously internalized (as assessed by trypsin inaccessibility) and degraded such that up to 50% of the initially labeled receptors were lost by 120 min. Metabolic poisons (0.125-0.75 mM 2,4-dinitrophenol (DNP) and 1-10 mM NaF), which led to dose-dependent depletion of adipocyte ATP pools, inhibited receptor loss, and caused up to 3-fold increase in intracellular receptor accumulation. This effect was due to inhibition of intracellular receptor degradation, and there was no apparent effect of the metabolic poisons on initial internalization of the receptors. Following maximal intracellular accumulation of labeled insulin receptors in the presence of NaF or DNP, removal of these agents resulted in a subsequent, time-dependent degradation of the accumulated receptors. However, when the lysosomotropic agent, chloroquine (0.2 mM), was added immediately following removal of the metabolic poisons, further degradation of the intracellularly accumulated receptors was prevented, suggesting that the chloroquine-sensitive degradation of insulin receptors occurs distal to the site of inhibition by NaF or DNP. To confirm this, maximal intracellular accumulation of labeled receptors was first allowed to occur in the presence of chloroquine and the cells were then washed and reincubated in chloroquine-free media in the absence or presence of NaF or DNP. Under these conditions, degradation of the intracellularly accumulated receptors continued to occur, and NaF or DNP failed to block the degradation.

  12. Non-steroidal anti-inflammatory drugs increase insulin release from beta cells by inhibiting ATP-sensitive potassium channels

    PubMed Central

    Li, J; Zhang, N; Ye, B; Ju, W; Orser, B; Fox, J E M; Wheeler, M B; Wang, Q; Lu, W-Y

    2007-01-01

    Background and purpose: Some non-steroidal anti-inflammatory drugs (NSAIDs) incidentally induce hypoglycemia, which is often seen in diabetic patients receiving sulphonylureas. NSAIDs influence various ion channel activities, thus they may cause hypoglycemia by affecting ion channel functions in insulin secreting beta cells. This study investigated the effects of the NSAID meclofenamic acid (MFA) on the electrical excitability and the secretion of insulin from pancreatic beta cells. Experimental approach: Using patch clamp techniques and insulin secretion assays, the effects of MFA on the membrane potential and transmembrane current of INS-1 cells, and insulin secretion were studied. Key results: Under perforated patch recordings, MFA induced a rapid depolarization in INS-1 cells bathed in low (2.8mM), but not high (28mM) glucose solutions. MFA, as well as acetylsalicylic acid (ASA) and flufenamic acid (FFA), excited the cells by inhibiting ATP-sensitive potassium channels (KATP). In whole cell recordings, KATP conductance consistently appeared when intracellular ATP was diluted. Intracellular glibenclamide prevented the development of KATP activity, whereas intracellular MFA had no effect. At low glibenclamide concentrations, MFA induced additional inhibition of the KATP current. Live cell Ca2+ imaging displayed that MFA elevated intracellular Ca2+ at low glucose concentrations. Furthermore, MFA dose-dependently increased insulin release under low, but not high, glucose conditions. Conclusions and Implications: MFA blocked KATP through an extracellular mechanism and thus increased insulin secretion. As some NSAIDs synergistically inhibit KATP activity together with sulphonylureas, the risk of NSAID-induced hypoglycemia should be considered when glucose-lowering compounds are administered. PMID:17435793

  13. Acute effects of 17 β-estradiol and genistein on insulin sensitivity and spatial memory in aged ovariectomized female rats.

    PubMed

    Alonso, Ana; González-Pardo, Héctor; Garrido, Pablo; Conejo, Nélida M; Llaneza, Plácido; Díaz, Fernando; Del Rey, Carmen González; González, Celestino

    2010-12-01

    Aging is characterized by decline in metabolic function and insulin resistance, and both seem to be in the basis of neurodegenerative diseases and cognitive dysfunction. Estrogens prevent age-related changes, and phytoestrogens influence learning and memory. Our hypothesis was that estradiol and genistein, using rapid-action mechanisms, are able to modify insulin sensitivity, process of learning, and spatial memory. Young and aged ovariectomized rats received acute treatment with estradiol or genistein. Aged animals were more insulin-resistant than young. In each age, estradiol and genistein-treated animals were less insulin-resistant than the others, except in the case of young animals treated with high doses of genistein. In aged rats, no differences between groups were found in spatial memory test, showing a poor performance in the water maze task. However, young females treated with estradiol or high doses of genistein performed well in spatial memory task like the control group. Only rats treated with high doses of genistein showed an optimal spatial memory similar to the control group. Conversely, acute treatment with high doses of phytoestrogens improved spatial memory consolidation only in young rats, supporting the critical period hypothesis for the beneficial effects of estrogens on memory. Therefore, genistein treatment seems to be suitable treatment in aged rats in order to prevent insulin resistance but not memory decline associated with aging. Acute genistein treatment is not effective to restore insulin resistance associated to the early loss of ovarian function, although it can be useful to improve memory deficits in this condition. PMID:20467821

  14. Insulin sensitizer in prediabetes: a clinical study with DLBS3233, a combined bioactive fraction of Cinnamomum burmanii and Lagerstroemia speciosa

    PubMed Central

    Manaf, Asman; Tjandrawinata, Raymond R; Malinda, Desi

    2016-01-01

    Background The aim of this paper is to evaluate the efficacy and safety of DLBS3233, a novel bioactive fraction derived from Cinnamomum burmanii and Lagerstroemia speciosa, in improving insulin resistance and preserving β-cell performance in patients with impaired glucose tolerance (IGT). Patients and methods Eighty adult subjects with IGT, defined as 2-hour postprandial glucose level of 140–199 mg/dL, were enrolled in this two-arm, 12-week, double-blind, randomized, placebo-controlled preliminary study. Eligible subjects were randomly allocated to receive either DLBS3233 at a dose of 50–100 mg daily or placebo for 12 weeks. The study mainly assessed the improvement of homeostatic model-assessed insulin resistance (HOMA-IR), the 15-minute and 2-hour plasma insulin levels, and the oral disposition index. Results After 12 weeks, DLBS3233 improved insulin resistance better than placebo as reflected by a reduced HOMA-IR (−27.04%±29.41% vs −4.90%±41.27%, P=0.013). The improvement of the first- and second-phase insulin secretion was consistently greater in DLBS3233 group than placebo group (−144.78±194.06 vs −71.21±157.19, P=0.022, and −455.03±487.56 vs −269.49±467.77, P=0.033, respectively). Further, DLBS3233 also significantly better improved oral disposition index than placebo. No serious hypoglycemia, edema, or cardiovascular-related adverse events were found in either groups. Conclusion This study has shown that DLBS3233 at the dose of 50–100 mg once daily was well tolerated, and promisingly efficacious in improving insulin sensitivity as well as preserving β-cell performance in subjects with IGT. PMID:27099473

  15. mTOR Inhibition: Reduced Insulin Secretion and Sensitivity in a Rat Model of Metabolic Syndrome

    PubMed Central

    Rovira, Jordi; Ramírez-Bajo, María Jose; Banon-Maneus, Elisenda; Moya-Rull, Daniel; Ventura-Aguiar, Pedro; Hierro-Garcia, Natalia; Lazo-Rodriguez, Marta; Revuelta, Ignacio; Torres, Armando; Oppenheimer, Federico; Campistol, Josep M.; Diekmann, Fritz

    2016-01-01

    Background Sirolimus (SRL) has been associated with new-onset diabetes mellitus after transplantation. The aim was to determine the effect of SRL on development of insulin resistance and β-cell toxicity. Methods Lean Zucker rat (LZR) and obese Zucker rat (OZR) were distributed into groups: vehicle and SRL (0.25, 0.5, or 1.0 mg/kg) during 12 or 28 days. Intraperitoneal glucose tolerance test (IPGTT) was evaluated at days 0, 12, 28, and 45. Islet morphometry, β-cell proliferation, and apoptosis were analyzed at 12 days. Islets were isolated to analyze insulin content, insulin secretion, and gene expression. Results After 12 days, SRL treatment only impaired IPGTT in a dose-dependent manner in OZR. Treatment prolongation induced increase of area under the curve of IPGTT in LZR and OZR; however, in contrast to OZR, LZR normalized glucose levels after 2 hours. The SRL reduced pancreas weight and islet proliferation in LZR and OZR as well as insulin content. Insulin secretion was only affected in OZR. Islets from OZR + SRL rats presented a downregulation of Neurod1, Pax4, and Ins2 gene. Genes related with insulin secretion remained unchanged or upregulated. Conclusions In conditions that require adaptive β-cell proliferation, SRL might reveal harmful effects by blocking β-cell proliferation, insulin production and secretion. These effects disappeared when removing the therapy.

  16. Myeloid SIRT1 regulates macrophage infiltration and insulin sensitivity in mice fed a high-fat diet.

    PubMed

    Ka, Sun-O; Song, Mi-Young; Bae, Eun Ju; Park, Byung-Hyun

    2015-02-01

    Inflammation is an important factor in the development of insulin resistance. SIRT1, a class 3 histone/protein deacetylase, has anti-inflammatory functions. Myeloid-specific deletion of Sirt1 promotes macrophage infiltration into insulin-sensitive organs and aggravates tissue inflammation. In this study, we investigated how SIRT1 in macrophages alters tissue inflammation in the pancreas as well as liver and adipose tissue, and further explored the role of SIRT1 in locomotion of macrophages. Myeloid-specific Sirt1-deleted mice (mS1KO) and WT littermates were fed a 60% calorie high-fat diet (HFD) for 16 weeks. Tissue inflammation and metabolic phenotypes were compared. Bone marrow macrophages (BMMs) from WT or mS1KO mice were used in in vitro chemotaxis assays and macrophage polarization studies. mS1KO mice fed a HFD exhibited glucose intolerance, reduced insulin secretion, and insulin sensitivity with a slight decrease in body weight. Consistent with these results, pancreatic islets of mS1KO mice fed a HFD displayed decreased mass with profound apoptotic cell damage and increased macrophage infiltration and inflammation. Liver and adipose tissues from mS1KO HFD mice also showed greater accumulation of macrophages and tissue inflammation. Results from in vitro experiments indicated that deletion of myeloid Sirt1 stimulated proinflammatory M1-like polarization of BMMs and augmented the adipocyte-mediated macrophage chemotaxis. The latter effect was accompanied by increased expression and acetylation of focal adhesion kinase, as well as nuclear factor kappa B. Our results indicate that myeloid SIRT1 plays a crucial role in macrophage polarization and chemotaxis, and thus regulates the development of HFD-induced pancreatic inflammation and insulin secretion, and metabolic derangements in liver and adipose tissue. PMID:25349250

  17. Association of PPARG Pro12Ala polymorphism with insulin sensitivity and body mass index in patients with polycystic ovary syndrome

    PubMed Central

    BALDANI, DINKA PAVICIC; SKRGATIC, LANA; CERNE, JASMINA Z.; FERK, POLONCA; SIMUNIC, VELIMIR; GERSAK, KSENIJA

    2014-01-01

    Insulin resistance is one of the key factors in the pathogenesis of polycystic ovary syndrome (PCOS). The peroxisome proliferator-activated receptor gamma (PPARG) plays a role in the regulation of insulin sensitivity. The aim of the present study was to establish a possible association of the PPARG Pro12Ala polymorphism with PCOS and its effect on family and personal history, as well as on the metabolic and endocrine parameters in PCOS patients. A total of 151 PCOS patients and 179 healthy women of reproductive age were enrolled. History, body mass index (BMI), waist-to-hip ratio and the presence of phenotypic hyperandrogenism were recorded. Hormonal, metabolic and biochemical profiles were assessed. A molecular analysis for the genetic polymorphism was performed. One third (29.8%) of the PCOS patients were found to be carriers of at least one variant of the Ala allele (X/Ala), while 70.2% carried two wild-type Pro alleles (Pro/Pro), with an equal distribution observed in the control group. The PCOS patients carrying the X/Ala alleles exhibited lower serum fasting insulin levels, homeostatic model assessment of insulin resistance (HOMA-IR) and BMI compared to Pro/Pro carriers. This finding was significant only in the lean PCOS group. The polymorphic genotype exerted no effect on history, hormonal and clinical hyperandrogenism, lipid status or C-reactive protein, leptin, adiponectin, resistin and ghrelin serum levels in women with PCOS. In conclusion, although the PPARG Pro12Ala polymorphism is not a major determinant of PCOS in the Croatian population, it may exert a positive effect on insulin sensitivity and BMI. As these associations were recorded exclusively in the lean group of patients with PCOS, this polymorphism potentially contributes to a protective role against hyperinsulinemia and obesity. PMID:24649096

  18. Effects of colesevelam on glucose absorption and hepatic/peripheral insulin sensitivity in patients with type 2 diabetes mellitus

    PubMed Central

    Henry, R. R.; Aroda, V. R.; Mudaliar, S.; Garvey, W. T.; Chou, H. S.; Jones, M. R.

    2016-01-01

    Aim Colesevelam lowers glucose and low-density lipoprotein cholesterol levels in patients with type 2 diabetes mellitus. This study examined the mechanisms by which colesevelam might affect glucose control. Methods In this 12-week, randomized, double-blind, placebo-controlled study, subjects with type 2 diabetes and haemoglobin A1c(HbA1c) ≥7.5% on either stable diet and exercise or sulphonylurea therapy were randomized to colesevelam 3.75 g/day (n = 16) or placebo (n = 14). Hepatic/peripheral insulin sensitivity was evaluated at baseline and at week 12 by infusion of 3H-labelled glucose followed by a 2-step hyperinsulinemic–euglycemic clamp. Two 75-g oral glucose tolerance tests (OGTTs) were conducted at baseline, one with and one without co-administration of colesevelam. A final OGTT was conducted at week 12. HbA1c and fasting plasma glucose (FPG) levels were evaluated pre-and post-treatment. Results Treatment with colesevelam, compared to placebo, had no significant effects on basal endogenous glucose output, response to insulin or on maximal steady-state glucose disposal rate. At baseline, co-administration of colesevelam with oral glucose reduced total area under the glucose curve (AUCg) but not incremental AUCg. At week 12, neither total AUCg nor incremental AUCg were changed from pre-treatment values in either group. Post-load insulin levels increased with colesevelam at 30 and 120 min, but these changes in total area under the insulin curve (AUCi) and incremental AUCi did not differ between groups. Both HbA1c and FPG improved with colesevelam, but treatment differences were not significant. Conclusions Colesevelam does not affect hepatic or peripheral insulin sensitivity and does not directly affect glucose absorption. PMID:21831167

  19. Chronic Angiotensin-(1-7) Improves Insulin Sensitivity in High-Fat Fed Mice Independent of Blood Pressure.

    PubMed

    Williams, Ian M; Otero, Yolanda F; Bracy, Deanna P; Wasserman, David H; Biaggioni, Italo; Arnold, Amy C

    2016-05-01

    Angiotensin-(1-7) improves glycemic control in animal models of cardiometabolic syndrome. The tissue-specific sites of action and blood pressure dependence of these metabolic effects, however, remain unclear. We hypothesized that Ang-(1-7) improves insulin sensitivity by enhancing peripheral glucose delivery. Adult male C57BL/6J mice were placed on standard chow or 60% high-fat diet for 11 weeks. Ang-(1-7) (400 ng/kg per minute) or saline was infused subcutaneously during the last 3 weeks of diet, and hyperinsulinemic-euglycemic clamps were performed at the end of treatment. High-fat fed mice exhibited modest hypertension (systolic blood pressure: 137 ± 3 high fat versus 123 ± 5 mm Hg chow;P=0.001), which was not altered by Ang-(1-7) (141 ± 4 mm Hg;P=0.574). Ang-(1-7) did not alter body weight or fasting glucose and insulin in chow or high-fat fed mice. Ang-(1-7) increased the steady-state glucose infusion rate needed to maintain euglycemia in high-fat fed mice (31 ± 5 Ang-(1-7) versus 16 ± 1 mg/kg per minute vehicle;P=0.017) reflecting increased whole-body insulin sensitivity, with no effect in chow-fed mice. The improved insulin sensitivity in high-fat fed mice was because of an enhanced rate of glucose disappearance (34 ± 5 Ang-(1-7) versus 20 ± 2 mg/kg per minute vehicle;P=0.049). Ang-(1-7) enhanced glucose uptake specifically into skeletal muscle by increasing translocation of glucose transporter 4 to the sarcolemma. Our data suggest that Ang-(1-7) has direct insulin-sensitizing effects on skeletal muscle, independent of changes in blood pressure. These findings provide new insight into mechanisms by which Ang-(1-7) improves insulin action, and provide further support for targeting this peptide in cardiometabolic disease. PMID:26975707

  20. Na+-sensitive elevation in blood pressure is ENaC independent in diet-induced obesity and insulin resistance.

    PubMed

    Nizar, Jonathan M; Dong, Wuxing; McClellan, Robert B; Labarca, Mariana; Zhou, Yuehan; Wong, Jared; Goens, Donald G; Zhao, Mingming; Velarde, Nona; Bernstein, Daniel; Pellizzon, Michael; Satlin, Lisa M; Bhalla, Vivek

    2016-05-01

    The majority of patients with obesity, insulin resistance, and metabolic syndrome have hypertension, but the mechanisms of hypertension are poorly understood. In these patients, impaired sodium excretion is critical for the genesis of Na(+)-sensitive hypertension, and prior studies have proposed a role for the epithelial Na(+) channel (ENaC) in this syndrome. We characterized high fat-fed mice as a model in which to study the contribution of ENaC-mediated Na(+) reabsorption in obesity and insulin resistance. High fat-fed mice demonstrated impaired Na(+) excretion and elevated blood pressure, which was significantly higher on a high-Na(+) diet compared with low fat-fed control mice. However, high fat-fed mice had no increase in ENaC activity as measured by Na(+) transport across microperfused cortical collecting ducts, electrolyte excretion, or blood pressure. In addition, we found no difference in endogenous urinary aldosterone excretion between groups on a normal or high-Na(+) diet. High fat-fed mice provide a model of metabolic syndrome, recapitulating obesity, insulin resistance, impaired natriuresis, and a Na(+)-sensitive elevation in blood pressure. Surprisingly, in contrast to previous studies, our data demonstrate that high fat feeding of mice impairs natriuresis and produces elevated blood pressure that is independent of ENaC activity and likely caused by increased Na(+) reabsorption upstream of the aldosterone-sensitive distal nephron. PMID:26841823

  1. Exercise and Weight Loss Improve Muscle Mitochondrial Respiration, Lipid Partitioning, and Insulin Sensitivity After Gastric Bypass Surgery.

    PubMed

    Coen, Paul M; Menshikova, Elizabeth V; Distefano, Giovanna; Zheng, Donghai; Tanner, Charles J; Standley, Robert A; Helbling, Nicole L; Dubis, Gabriel S; Ritov, Vladimir B; Xie, Hui; Desimone, Marisa E; Smith, Steven R; Stefanovic-Racic, Maja; Toledo, Frederico G S; Houmard, Joseph A; Goodpaster, Bret H

    2015-11-01

    Both Roux-en-Y gastric bypass (RYGB) surgery and exercise can improve insulin sensitivity in individuals with severe obesity. However, the impact of RYGB with or without exercise on skeletal muscle mitochondria, intramyocellular lipids, and insulin sensitivity index (SI) is unknown. We conducted a randomized exercise trial in patients (n = 101) who underwent RYGB surgery and completed either a 6-month moderate exercise (EX) or a health education control (CON) intervention. SI was determined by intravenous glucose tolerance test. Mitochondrial respiration and intramyocellular triglyceride, sphingolipid, and diacylglycerol content were measured in vastus lateralis biopsy specimens. We found that EX provided additional improvements in SI and that only EX improved cardiorespiratory fitness, mitochondrial respiration and enzyme activities, and cardiolipin profile with no change in mitochondrial content. Muscle triglycerides were reduced in type I fibers in CON, and sphingolipids decreased in both groups, with EX showing a further reduction in a number of ceramide species. In conclusion, exercise superimposed on bariatric surgery-induced weight loss enhances mitochondrial respiration, induces cardiolipin remodeling, reduces specific sphingolipids, and provides additional improvements in insulin sensitivity. PMID:26293505

  2. Inadequate Sensitivity of Laboratory Risk Indicator to Rule Out Necrotizing Fasciitis in the Emergency Department

    PubMed Central

    Burner, Elizabeth; Henderson, Sean O.; Burke, Guenevere; Nakashioya, Jeffrey; Hoffman, Jerome R.

    2016-01-01

    Introduction Necrotizing fasciitis (NF) is a life-threatening illness, particularly when surgical debridement is delayed. The Laboratory Risk Indicator for Necrotizing Fasciitis (LRINEC) score was developed to identify patients at higher risk for NF. Despite limited information in this regard, the LRINEC score is often used to “rule out” NF if negative. We describe the sensitivity of the LRINEC score in emergency department (ED) patients for the diagnosis of NF. Methods We conducted a chart review of ED patients in whom coding of hospital discharge diagnoses included NF. We employed standard methods to minimize bias. We used laboratory data to calculate the LRINEC score, and confirmed the diagnosis of NF via explicit chart review. We then calculated the sensitivity of a positive LRINEC score (standardly defined as six or greater) in our cohort. We examined the role of patient characteristics in the performance of the LRINEC score. Finally, we performed sensitivity analyses to estimate whether missing data for c-reactive protein (CRP) results were likely to impact our results. Results Of 266 ED patients coded as having a discharge diagnosis of NF, we were able to confirm the diagnosis, by chart review, in 167. We were able to calculate a LRINEC score in only 80 patients (due to absence of an initial CRP value); an LRINEC score of 6 or greater had a sensitivity of 77%. Sensitivity analyses of missing data supported our finding of inadequate sensitivity to rule out NF. In sub-analysis, NF patients with concurrent diabetes were more likely to be accurately categorized by the LRINEC score. Conclusion Used in isolation, the LRINEC score is not sufficiently sensitive to rule out NF in a general ED population. PMID:27330667

  3. A Single Dose of Prednisolone as a Modulator of Undercarboxylated Osteocalcin and Insulin Sensitivity Post-Exercise in Healthy Young Men: A Study Protocol

    PubMed Central

    Brennan-Speranza, Tara C; Stepto, Nigel K; Jerums, George; Parker, Lewan; McConell, Glenn K; Anderson, Mitchell; Garnham, Andrew; Hare, David L; Ebeling, Peter R; Seeman, Ego

    2016-01-01

    Background Undercarboxylated osteocalcin (ucOC) increases insulin sensitivity in mice. In humans, data are supportive, but the studies are mostly cross-sectional. Exercise increases whole-body insulin sensitivity, in part via ucOC, while acute glucocorticoid treatment suppresses ucOC in humans and mice. Objectives A single dose of prednisolone reduces the rise in ucOC produced by exercise, which partly accounts for the failed increase in insulin sensitivity following exercise. Methods Healthy young men (n=12) aged 18 to 40 years will be recruited. Initial assessments will include analysis of fasting blood, body composition, aerobic power (VO2peak), and peak heart rate. Participants will then be randomly allocated, double-blind, to a single dose of 20 mg of prednisolone or placebo. The two experimental trials will involve 30 minutes of interval exercise (90%-95% peak heart rate), followed by 3 hours of recovery and 2 hours of euglycaemic- hyperinsulinaemic clamp (insulin clamp). Seven muscle biopsies and blood samples will be obtained at rest, following exercise and post-insulin clamps. Results The study is funded by the National Heart Foundation of Australia and Victoria University. Enrollment has already commenced and data collection will be completed in 2016. Conclusion If the hypothesis is confirmed, the study will provide novel insights into the potential role of ucOC in insulin sensitivity in human subjects and will elucidate pathways involved in exercise-induced insulin sensitivity. PMID:27259402

  4. The CDP-Ethanolamine Pathway Regulates Skeletal Muscle Diacylglycerol Content and Mitochondrial Biogenesis without Altering Insulin Sensitivity.

    PubMed

    Selathurai, Ahrathy; Kowalski, Greg M; Burch, Micah L; Sepulveda, Patricio; Risis, Steve; Lee-Young, Robert S; Lamon, Severine; Meikle, Peter J; Genders, Amanda J; McGee, Sean L; Watt, Matthew J; Russell, Aaron P; Frank, Matthew; Jackowski, Suzanne; Febbraio, Mark A; Bruce, Clinton R

    2015-05-01

    Accumulation of diacylglycerol (DG) in muscle is thought to cause insulin resistance. DG is a precursor for phospholipids, thus phospholipid synthesis could be involved in regulating muscle DG. Little is known about the interaction between phospholipid and DG in muscle; therefore, we examined whether disrupting muscle phospholipid synthesis, specifically phosphatidylethanolamine (PtdEtn), would influence muscle DG content and insulin sensitivity. Muscle PtdEtn synthesis was disrupted by deleting CTP:phosphoethanolamine cytidylyltransferase (ECT), the rate-limiting enzyme in the CDP-ethanolamine pathway, a major route for PtdEtn production. While PtdEtn was reduced in muscle-specific ECT knockout mice, intramyocellular and membrane-associated DG was markedly increased. Importantly, however, this was not associated with insulin resistance. Unexpectedly, mitochondrial biogenesis and muscle oxidative capacity were increased in muscle-specific ECT knockout mice and were accompanied by enhanced exercise performance. These findings highlight the importance of the CDP-ethanolamine pathway in regulating muscle DG content and challenge the DG-induced insulin resistance hypothesis. PMID:25955207

  5. Hormone-sensitive lipase deficiency suppresses insulin secretion from pancreatic islets of Lep{sup ob/ob} mice

    SciTech Connect

    Sekiya, Motohiro; Yahagi, Naoya; Tamura, Yoshiaki; Okazaki, Hiroaki; Igarashi, Masaki; Ohta, Keisuke; Takanashi, Mikio; Kumagai, Masayoshi; Takase, Satoru; Nishi, Makiko; Takeuchi, Yoshinori; Izumida, Yoshihiko; Kubota, Midori; Ohashi, Ken; Iizuka, Yoko; Yagyu, Hiroaki; Gotoda, Takanari; Nagai, Ryozo; Shimano, Hitoshi; Yamada, Nobuhiro; and others

    2009-09-25

    It has long been a matter of debate whether the hormone-sensitive lipase (HSL)-mediated lipolysis in pancreatic {beta}-cells can affect insulin secretion through the alteration of lipotoxicity. We generated mice lacking both leptin and HSL (Lep{sup ob/ob}/HSL{sup -/-}) and explored the role of HSL in pancreatic {beta}-cells in the setting of obesity. Lep{sup ob/ob}/HSL{sup -/-} developed elevated blood glucose levels and reduced plasma insulin levels compared with Lep{sup ob/ob}/HSL{sup +/+} in a fed state, while the deficiency of HSL did not affect glucose homeostasis in Lep{sup +/+} background. The deficiency of HSL exacerbated the accumulation of triglycerides in Lep{sup ob/ob} islets, leading to reduced glucose-stimulated insulin secretion. The deficiency of HSL also diminished the islet mass in Lep{sup ob/ob} mice due to decreased cell proliferation. In conclusion, HSL affects insulin secretary capacity especially in the setting of obesity.

  6. NAMPT-Mediated NAD(+) Biosynthesis in Adipocytes Regulates Adipose Tissue Function and Multi-organ Insulin Sensitivity in Mice.

    PubMed

    Stromsdorfer, Kelly L; Yamaguchi, Shintaro; Yoon, Myeong Jin; Moseley, Anna C; Franczyk, Michael P; Kelly, Shannon C; Qi, Nathan; Imai, Shin-Ichiro; Yoshino, Jun

    2016-08-16

    Obesity is associated with adipose tissue dysfunction and multi-organ insulin resistance. However, the mechanisms of such obesity-associated systemic metabolic complications are not clear. Here, we characterized mice with adipocyte-specific deletion of nicotinamide phosphoribosyltransferase (NAMPT), a rate-limiting NAD(+) biosynthetic enzyme known to decrease in adipose tissue of obese and aged rodents and people. We found that adipocyte-specific Nampt knockout mice had severe insulin resistance in adipose tissue, liver, and skeletal muscle and adipose tissue dysfunction, manifested by increased plasma free fatty acid concentrations and decreased plasma concentrations of a major insulin-sensitizing adipokine, adiponectin. Loss of Nampt increased phosphorylation of CDK5 and PPARγ (serine-273) and decreased gene expression of obesity-linked phosphorylated PPARγ targets in adipose tissue. These deleterious alterations were normalized by administering rosiglitazone or a key NAD(+) intermediate, nicotinamide mononucleotide (NMN). Collectively, our results provide important mechanistic and therapeutic insights into obesity-associated systemic metabolic derangements, particularly multi-organ insulin resistance. PMID:27498863

  7. Cinnamaldehyde Contributes to Insulin Sensitivity by Activating PPARδ, PPARγ, and RXR.

    PubMed

    Li, Juan-E; Futawaka, Kumi; Yamamoto, Hiroyuki; Kasahara, Masato; Tagami, Tetsuya; Liu, Tong-Hua; Moriyama, Kenji

    2015-01-01

    Cinnamon is a traditional folk herb used in Asia and has been reported to have antidiabetic effects. Our previous study showed that cinnamaldehyde (CA), a major effective compound in cinnamon, exhibited hypoglycemic and hypolipidemic effects together in db/db mice. The aim of the present study was to elucidate the molecular mechanisms of the effects of CA on the transcriptional activities of three peroxisome proliferator-activated receptors, (PPAR) α, δ, and γ. We studied the effects of CA through a transient expression assay with TSA201 cells, derivatives of human embryonic kidney cell line (HEK293). Quantitative reverse transcription polymerase chain reaction (qRT-PCR) analysis was also performed to evaluate mRNA expression levels. We show here that CA induced PPARδ, PPARγ and retinoid X receptor (RXR) activation. CA may activate PPARγ in a different manner than pioglitazone, as CA selectively stimulated PPARγ S342A mutant while pioglitazone did not. In addition, CA and L-165041 had a synergistic effect on PPARδ activation. To gather the biological evidence that CA increases PPARs transcription, we further measured the expressions of PPARδ and PPARγ target genes in 3T3-L1 adipocytes. The data showed CA induced the expression of PPARδ and PPARγ target genes, namely aP2 and CD36, in differentiated adipocytes. As a result, PPARδ, PPARγ and their heterodimeric partner RXR appear to play a part in the CA action in the target tissues, thereby enhancing insulin sensitivity and fatty acid β-oxidation and energy uncoupling in skeletal muscle and adipose tissue. PMID:26227398

  8. Serum uric acid and insulin sensitivity in adolescents and adults with and without type 1 diabetes

    PubMed Central

    Bjornstad, Petter; Snell-Bergeon, Janet K.; McFann, Kimberly; Wadwa, R. Paul; Rewers, Marian; Rivard, Christopher J.; Jalal, Diana; Chonchol, Michel B.; Johnson, Richard J.; Maahs, David M.

    2014-01-01

    Hypothesis Decreased insulin sensitivity (IS) exists in type 1 diabetes. Serum uric acid (SUA), whose concentration is related to renal clearance, predicts vascular complications in type 1 diabetes. SUA is also inversely associated with IS in non-diabetics, but has not been examined in type 1 diabetes. We hypothesized SUA would be associated with reduced IS in adolescents and adults with type 1 diabetes. Methods The cross-sectional and longitudinal associations of SUA with IS was investigated in 254 adolescents with type 1 diabetes and 70 without in the Determinants of Macrovascular Disease in Adolescents with Type 1 Diabetes Study, and in 471 adults with type 1 diabetes and 571 without in the Coronary Artery Calcification in Type 1 diabetes (CACTI) study. Results SUA was lower in subjects with type 1 diabetes (p<0.0001), but still remained inversely associated with IS after multivariable adjustments- in adolescents (β±SE: −1.99±0.62, p=0.001, R2=2%) and adults (β±SE:−0.91±0.33, p=0.006, R2=6%) with type 1 diabetes, though less strongly than in non-diabetic controls (adolescents: β±SE: −2.70±1.19, p=0.03, R2=15%, adults: β±SE:−5.99±0.75, p<0.0001, R2=39%). Conclusion We demonstrated a significantly weaker relationship between SUA and reduced IS in subjects with type 1 diabetes than non-diabetic controls. PMID:24461546

  9. Combined effects of endurance training and dietary unsaturated fatty acids on physical performance, fat oxidation and insulin sensitivity.

    PubMed

    Boss, Andreas; Lecoultre, Virgile; Ruffieux, Christiane; Tappy, Luc; Schneiter, Philippe

    2010-04-01

    Endurance training improves exercise performance and insulin sensitivity, and these effects may be in part mediated by an enhanced fat oxidation. Since n-3 and n-9 unsaturated fatty acids may also increase fat oxidation, we hypothesised that a diet enriched in these fatty acids may enhance the effects of endurance training on exercise performance, insulin sensitivity and fat oxidation. To assess this hypothesis, sixteen normal-weight sedentary male subjects were randomly assigned to an isoenergetic diet enriched with fish and olive oils (unsaturated fatty acid group (UFA): 52 % carbohydrates, 34 % fat (12 % SFA, 12 % MUFA, 5 % PUFA), 14 % protein), or a control diet (control group (CON): 62 % carbohydrates, 24 % fat (12 % SFA, 6 % MUFA, 2 % PUFA), 14 % protein) and underwent a 10 d gradual endurance training protocol. Exercise performance was evaluated by measuring VO2max and the time to exhaustion during a cycling exercise at 80 % VO2max; glucose homeostasis was assessed after ingestion of a test meal. Fat oxidation was assessed by indirect calorimetry at rest and during an exercise at 50 % VO2max. Training significantly increased time to exhaustion, but not VO2max, and lowered incremental insulin area under the curve after the test meal, indicating improved insulin sensitivity. Those effects were, however, of similar magnitude in UFA and CON. Fat oxidation tended to increase in UFA, but not in CON. This difference was, however, not significant. It is concluded that a diet enriched with fish- and olive oil does not substantially enhance the effects of a short-term endurance training protocol in healthy young subjects. PMID:19948079

  10. Brain GLP-1 Signaling Regulates Femoral Artery Blood Flow and Insulin Sensitivity Through Hypothalamic PKC-δ

    PubMed Central

    Cabou, Cendrine; Vachoux, Christelle; Campistron, Gérard; Drucker, Daniel J.; Burcelin, Rémy

    2011-01-01

    OBJECTIVE Glucagon-like peptide 1 (GLP-1) is a gut-brain hormone that regulates food intake, energy metabolism, and cardiovascular functions. In the brain, through a currently unknown molecular mechanism, it simultaneously reduces femoral artery blood flow and muscle glucose uptake. By analogy to pancreatic β-cells where GLP-1 activates protein kinase C (PKC) to stimulate insulin secretion, we postulated that PKC enzymes would be molecular targets of brain GLP-1 signaling that regulate metabolic and vascular function. RESEARCH DESIGN AND METHODS We used both genetic and pharmacological approaches to investigate the role of PKC isoforms in brain GLP-1 signaling in the conscious, free-moving mouse simultaneous with metabolic and vascular measurements. RESULTS In normal wild-type (WT) mouse brain, the GLP-1 receptor (GLP-1R) agonist exendin-4 selectively promotes translocation of PKC-δ (but not -βII, -α, or -ε) to the plasma membrane. This translocation is blocked in Glp1r−/− mice and in WT mice infused in the brain with exendin-9, an antagonist of the GLP-1R. This mechanism coordinates both blood flow in the femoral artery and whole-body insulin sensitivity. Consequently, in hyperglycemic, high-fat diet–fed diabetic mice, hypothalamic PKC-δ activity was increased and its pharmacological inhibition improved both insulin-sensitive metabolic and vascular phenotypes. CONCLUSIONS Our studies show that brain GLP-1 signaling activates hypothalamic glucose-dependent PKC-δ to regulate femoral artery blood flow and insulin sensitivity. This mechanism is attenuated during the development of experimental hyperglycemia and may contribute to the pathophysiology of type 2 diabetes. PMID:21810595

  11. Growth-Blocking Peptides As Nutrition-Sensitive Signals for Insulin Secretion and Body Size Regulation.

    PubMed

    Koyama, Takashi; Mirth, Christen K

    2016-02-01

    In Drosophila, the fat body, functionally equivalent to the mammalian liver and adipocytes, plays a central role in regulating systemic growth in response to nutrition. The fat body senses intracellular amino acids through Target of Rapamycin (TOR) signaling, and produces an unidentified humoral factor(s) to regulate insulin-like peptide (ILP) synthesis and/or secretion in the insulin-producing cells. Here, we find that two peptides, Growth-Blocking Peptide (GBP1) and CG11395 (GBP2), are produced in the fat body in response to amino acids and TOR signaling. Reducing the expression of GBP1 and GBP2 (GBPs) specifically in the fat body results in smaller body size due to reduced growth rate. In addition, we found that GBPs stimulate ILP secretion from the insulin-producing cells, either directly or indirectly, thereby increasing insulin and insulin-like growth factor signaling activity throughout the body. Our findings fill an important gap in our understanding of how the fat body transmits nutritional information to the insulin producing cells to control body size. PMID:26928023

  12. Growth-Blocking Peptides As Nutrition-Sensitive Signals for Insulin Secretion and Body Size Regulation

    PubMed Central

    Koyama, Takashi; Mirth, Christen K.

    2016-01-01

    In Drosophila, the fat body, functionally equivalent to the mammalian liver and adipocytes, plays a central role in regulating systemic growth in response to nutrition. The fat body senses intracellular amino acids through Target of Rapamycin (TOR) signaling, and produces an unidentified humoral factor(s) to regulate insulin-like peptide (ILP) synthesis and/or secretion in the insulin-producing cells. Here, we find that two peptides, Growth-Blocking Peptide (GBP1) and CG11395 (GBP2), are produced in the fat body in response to amino acids and TOR signaling. Reducing the expression of GBP1 and GBP2 (GBPs) specifically in the fat body results in smaller body size due to reduced growth rate. In addition, we found that GBPs stimulate ILP secretion from the insulin-producing cells, either directly or indirectly, thereby increasing insulin and insulin-like growth factor signaling activity throughout the body. Our findings fill an important gap in our understanding of how the fat body transmits nutritional information to the insulin producing cells to control body size. PMID:26928023

  13. Fitness, adiposopathy, and adiposity are independent predictors of insulin sensitivity in middle-aged men without diabetes.

    PubMed

    Huth, Claire; Pigeon, Étienne; Riou, Marie-Ève; St-Onge, Josée; Arguin, Hélène; Couillard, Erick; Dubois, Marie-Julie; Marette, André; Tremblay, Angelo; Weisnagel, S John; Lacaille, Michel; Mauriège, Pascale; Joanisse, Denis R

    2016-09-01

    Adiposopathy, or sick fat, refers to adipose tissue dysfunction that can lead to several complications such as dyslipidemia, insulin resistance, and hyperglycemia. The relative contribution of adiposopathy in predicting insulin resistance remains unclear. We investigated the relationship between adiposopathy, as assessed as a low plasma adiponectin/leptin ratio, with anthropometry, body composition (hydrostatic weighing), insulin sensitivity (hyperinsulinemic-euglycemic clamp), inflammation, and fitness level (ergocycle VO2max, mL/kgFFM/min) in 53 men (aged 34-53 years) from four groups: sedentary controls without obesity (body mass index [BMI] <25 kg/m(2)), sedentary with obesity (BMI > 30 kg/m(2)), sedentary with obesity and glucose intolerance, and endurance trained active without obesity. The adiponectin/leptin ratio was the highest in trained men (4.75 ± 0.82) and the lowest in glucose intolerant subjects with obesity (0.27 ± 0.06; ANOVA p < 0.0001) indicating increased adiposopathy in those with obesity. The ratio was negatively associated with adiposity (e.g., waist circumference, r = -0.59, p < 0.01) and positively associated with VO2max (r = 0.67, p < 0.01) and insulin sensitivity (M/I, r = 0.73, p < 0.01). Multiple regression analysis revealed fitness as the strongest independent predictor of insulin sensitivity (partial R (2) = 0.61). While adiposopathy was also an independent and significant contributor (partial R (2) = 0.10), waist circumference added little power to the model (partial R (2) = 0.024). All three variables remained significant independent predictors when trained subjects were excluded from the model. Plasma lipids were not retained in the model. We conclude that low fitness, adiposopathy, as well as adiposity (and in particular abdominal obesity) are independent contributors to insulin resistance in men without diabetes. PMID:27139423

  14. Effects of a 12-month moderate weight loss intervention on insulin sensitivity and inflammation status in nondiabetic overweight and obese subjects.

    PubMed

    Ho, T P; Zhao, X; Courville, A B; Linderman, J D; Smith, S; Sebring, N; Della Valle, D M; Fitzpatrick, B; Simchowitz, L; Celi, F S

    2015-04-01

    Weight loss intervention is the principal non-pharmacological method for prevention and treatment of type 2 diabetes. However, little is known whether it influences insulin sensitivity directly or via its anti-inflammatory effect. The aim of this study was to assess the independent role of changes in inflammation status and weight loss on insulin sensitivity in this population.Overweight and obese nondiabetic participants without co-morbidities underwent a one-year weight loss intervention focused on caloric restriction and behavioral support. Markers of inflammation, body composition, anthropometric para-meters, and insulin sensitivity were recorded at baseline, 6, and 12 months. Insulin sensitivity was assessed with frequently sampled intravenous glucose tolerance test and Minimal Model. Twenty-eight participants (F: 15, M: 13, age 39±5 years, BMI 33.2±4.6 kg/m(2)) completed the study, achieving 9.4±6.9% weight loss, which was predominantly fat mass (7.7±5.6 kg, p<0.0001). Dietary intervention resulted in significant decrease in leptin, leptin-to-adiponectin ratio, hs-CRP, and IL-6 (all p<0.02), and improvement in HOMA-IR and Insulin Sensitivity Index (SI) (both p<0.001). In response to weight loss IL-1β, IL-2, leptin, and resistin were significantly associated with insulin, sensitivity, whereas sICAM-1 had only marginal additive effect. Moderate weight loss in otherwise healthy overweight and obese individuals resulted in an improvement in insulin sensitivity and in the overall inflammation state; the latter played only a minimal independent role in modulating insulin sensitivity. PMID:24977656

  15. Correlation of insulin resistance, beta cell function and insulin sensitivity with serum sFas and sFasL in newly diagnosed type 2 diabetes.

    PubMed

    Kumar, Hemant; Mishra, Manish; Bajpai, Surabhi; Pokhria, Deepa; Arya, Awadhesh Kumar; Singh, Rakesh Kumar; Tripathi, Kamlakar

    2013-08-01

    Pancreatic beta cell dysfunction and reduced insulin sensitivity are fundamental factors associated with glucotoxicity, lipotoxicity and oxidative stress in type 2 diabetic patients (T2DM). Diabetic milieu can induce apoptosis in several types of cells. The aim of present study was to compare circulating soluble apoptotic markers (sFas and sFas-L) with HOMA-IR, HOMA-%S, HOMA-%B in the serum of newly diagnosed T2DM and healthy subjects. For this study, 94 T2DM and 60 healthy subjects were enroled and evaluated for various parameters. Biochemical quantifications were performed with Syncron CX5 auto-analyzer. The levels of serum sFas-L, TNF-α and IL-6 were estimated by flowcytometry. The fasting serum insulin and sFas quantified by ELISA. HOMA-IR, HOMA-%S and HOMA-%B were calculated with HOMA calculator v2.2.2. The levels of TC, TG, LDL-C, VLDL-C were augmented and HDL declined significantly (P < 0.001) in diabetics. The levels of serum insulin, TNF-α, IL-6, sFas, HOMA-IR were raised (P < 0.001) and sFas-L, HOMA-%S and HOMA-%B were decreased significantly (P < 0.001) in T2DM subjects than healthy. In diabetics, serum sFas was positively correlated with HOMA-IR (r = 0.720, P < 0.001) and negatively with HOMA-%B (r = -0.642, P < 0.001) significantly while serum sFasL was negatively correlated with HOMA-IR (r = -0.483, P < 0.001) and positively with HOMA-%B (r = 0.466, P < 0.001) significantly. Further, the multivariate stepwise regression analysis shows that HOMA-IR contributes significantly to the variance of sFas and sFasL. Our findings suggest that the pancreatic beta cell dysfunction along with increased insulin resistance appears to be associated with apoptotic markers. PMID:21695404

  16. Spironolactone in the treatment of polycystic ovary syndrome: effects on clinical features, insulin sensitivity and lipid profile.

    PubMed

    Zulian, E; Sartorato, P; Benedini, S; Baro, G; Armanini, D; Mantero, F; Scaroni, C

    2005-01-01

    This prospective clinical trial was designed to assess the effects of a long-term therapy with spironolactone, with and without dietary-induced weight-loss, on clinical features, lipid profile and insulin levels in women with polycystic ovary syndrome (PCOS). Twenty-five patients (range of age 16-32 yr; 13 lean and 12 overweight) fulfilling formal diagnostic criteria for PCOS (oligomenorrhea and/or amenorrhea, biochemical and/or clinical evidence of hyperadrogenism) were studied at baseline and then received oral spironolactone (100 mg/die) for 12 months; association with lifestyle modifications was recommended to all over-weight patients. Clinical, endocrine and metabolic parameters [oral glucose tolerance test (OGTT), lipid profile] were measured at baseline and at the end of the antiandrogen treatment. The therapy was associated with a significant average decline of triglycerides in overweight subjects and with increased HDL-cholesterol levels in lean patients. The insulin levels at 60 min during OGTT, homeostasis model assessment-insulin resistance and area under curve of insulin were significantly lowered in overweight women after 12 months of spironolactone and weight loss and no negative changes in insulin secretion and sensitivity were observed in PCOS women after pharmacological treatment alone. The efficacy of spironolactone on the androgenic clinical aspects of PCOS has been confirmed in this study. Furthermore, our data show that long-term treatment with spironolactone exerts no negative effects on lipoprotein profile and glucose metabolism; more relevant beneficial effects on glucose and lipid metabolism were observed when the antiandrogen was associated with weight loss in overweight PCOS women. PMID:15816371

  17. Modulation of insulin dose titration using a hypoglycaemia-sensitive algorithm: insulin glargine versus neutral protamine Hagedorn insulin in insulin-naïve people with type 2 diabetes

    PubMed Central

    Home, P D; Bolli, G B; Mathieu, C; Deerochanawong, C; Landgraf, W; Candelas, C; Pilorget, V; Dain, M-P; Riddle, M C

    2015-01-01

    Aims To examine whether insulin glargine can lead to better control of glycated haemoglobin (HbA1c) than that achieved by neutral protamine Hagedorn (NPH) insulin, using a protocol designed to limit nocturnal hypoglycaemia. Methods The present study, the Least One Oral Antidiabetic Drug Treatment (LANCELOT) Study, was a 36-week, randomized, open-label, parallel-arm study conducted in Europe, Asia, the Middle East and South America. Participants were randomized (1 : 1) to begin glargine or NPH, on background of metformin with glimepiride. Weekly insulin titration aimed to achieve median prebreakfast and nocturnal plasma glucose levels ≤5.5 mmol/l, while limiting values ≤4.4 mmol/l. Results The efficacy population (n = 701) had a mean age of 57 years, a mean body mass index of 29.8 kg/m2, a mean duration of diabetes of 9.2 years and a mean HbA1c level of 8.2% (66 mmol/mol). At treatment end, HbA1c values and the proportion of participants with HbA1c <7.0 % (<53 mmol/mol) were not significantly different for glargine [7.1 % (54 mmol/mol) and 50.3%] versus NPH [7.2 % (55 mmol/mol) and 44.3%]. The rate of symptomatic nocturnal hypoglycaemia, confirmed by plasma glucose ≤3.9 or ≤3.1 mmol/l, was 29 and 48% less with glargine than with NPH insulin. Other outcomes were similar between the groups. Conclusion Insulin glargine was not superior to NPH insulin in improving glycaemic control. The insulin dosing algorithm was not sufficient to equalize nocturnal hypoglycaemia between the two insulins. This study confirms, in a globally heterogeneous population, the reduction achieved in nocturnal hypoglycaemia while attaining good glycaemic control with insulin glargine compared with NPH, even when titrating basal insulin to prevent nocturnal hypoglycaemia rather than treating according to normal fasting glucose levels. PMID:24957785

  18. Coordinated balancing of muscle oxidative metabolism through PGC-1{alpha} increases metabolic flexibility and preserves insulin sensitivity

    SciTech Connect

    Summermatter, Serge; Santos, Gesa

    2011-04-29

    Highlights: {yields} PGC-1{alpha} enhances muscle oxidative capacity. {yields} PGC-1{alpha} promotes concomitantly positive and negative regulators of lipid oxidation. {yields} Regulator abundance enhances metabolic flexibility and balances oxidative metabolism. {yields} Balanced oxidation prevents detrimental acylcarnitine and ROS generation. {yields} Absence of detrimental metabolites preserves insulin sensitivity -- Abstract: The peroxisome proliferator-activated receptor {gamma} coactivator 1{alpha} (PGC-1{alpha}) enhances oxidative metabolism in skeletal muscle. Excessive lipid oxidation and electron transport chain activity can, however, lead to the accumulation of harmful metabolites and impair glucose homeostasis. Here, we investigated the effect of over-expression of PGC-1{alpha} on metabolic control and generation of insulin desensitizing agents in extensor digitorum longus (EDL), a muscle that exhibits low levels of PGC-1{alpha} in the untrained state and minimally relies on oxidative metabolism. We demonstrate that PGC-1{alpha} induces a strictly balanced substrate oxidation in EDL by concomitantly promoting the transcription of activators and inhibitors of lipid oxidation. Moreover, we show that PGC-1{alpha} enhances the potential to uncouple oxidative phosphorylation. Thereby, PGC-1{alpha} boosts elevated, yet tightly regulated oxidative metabolism devoid of side products that are detrimental for glucose homeostasis. Accordingly, PI3K activity, an early phase marker for insulin resistance, is preserved in EDL muscle. Our findings suggest that PGC-1{alpha} coordinately coactivates the simultaneous transcription of gene clusters implicated in the positive and negative regulation of oxidative metabolism and thereby increases metabolic flexibility. Thus, in mice fed a normal chow diet, over-expression of PGC-1{alpha} does not alter insulin sensitivity and the metabolic adaptations elicited by PGC-1{alpha} mimic the beneficial effects of endurance training

  19. BLX‐1002 restores glucose sensitivity and enhances insulin secretion stimulated by GLP‐1 and sulfonylurea in type 2 diabetic pancreatic islets

    PubMed Central

    Zhang, Qimin; Zhang, Fan; Sjöholm, Åke

    2014-01-01

    Abstract BLX‐1002 is a novel thiazolidinedione with no peroxisome proliferator‐activated receptor (PPAR) activity that has been shown to improve glycemia in type 2 diabetes without weight gain. We previously found that BLX‐1002 selectively augments glucose‐sensitive (but not basal) insulin secretion in normal mouse β‐cells. We have now extended these observations to other insulin secretagogues and to diabetic rat islets. To this end, dynamics of insulin secretion stimulated by glucose, GLP‐1, and the sulfonylurea tolbutamide were examined in pancreatic islets from nondiabetic Wistar and type 2 diabetic Goto‐Kakizaki rats ex vivo. BLX‐1002 restored normal glucose‐sensitive insulin secretion in otherwise “glucose‐blind” islets from GK rats, but did not affect basal or glucose‐stimulated secretion in normal Wistar rat islets. The stimulatory effect of BLX‐1002 on insulin secretion at high glucose required Ca2+ and involved phosphatidylinositol 3‐kinase (PI3K) activity. Consistent with its effects on insulin secretion, BLX‐1002 also augmented insulin secretion and cytoplasmic‐free Ca2+ concentrations ([Ca2+]i) stimulated by high glucose, GLP‐1, and tolbutamide in islets from GK, but not Wistar, rats. The inactive analog BLX‐1237 had no effects. In conclusion, our findings suggest that BLX‐1002 potentiates insulin secretion by different stimuli in diabetic β‐cells only, in a Ca2+‐dependent manner and involving PI3K. PMID:24872354

  20. Effects of chromium supplementation to feedlot steers on growth performance, insulin sensitivity, and carcass characteristics.

    PubMed

    Kneeskern, S G; Dilger, A C; Loerch, S C; Shike, D W; Felix, T L

    2016-01-01

    Objectives were to determine the effects of chromium propionate supplementation on growth performance, insulin and glucose metabolism, and carcass characteristics of beef cattle. Steers ( = 34) were stratified by BW and assigned to 1 of 2 treatments: 1) no supplemental Cr (Cont) or 2) 3 mg supplemental Cr·steer·d (CrP). Both supplements, Cont and CrP, were delivered via 0.454 kg ground corn top-dressed on the basal diet. There was no effect ( ≥ 0.45) of CrP on ADG, DMI, G:F, or final BW. However, steers fed CrP needed more ( = 0.10) days on feed (DOF) to achieve the same carcass back fat (BF) as steers fed Cont. There were no effects ( ≥ 0.41) of CrP on HCW, BF, or KPH. Steers fed CrP had increased ( = 0.01) dressing percentage (DP) and tended to have a 4.21 cm greater LM area ( = 0.15), decreased marbling scores ( = 0.11), and decreased intramuscular fat ( = 0.11) compared to steers fed Cont. There were no differences ( ≥ 0.25) in quality or yield grade distributions. A glucose tolerance test was conducted early (21 DOF) and late (98 DOF) in the finishing phase. There was a feedlot treatment (FT) × time × DOF interaction ( = 0.08) for glucose concentrations, but no other interactions ( ≥ 0.21) for glucose or insulin concentrations. There were no FT × DOF interactions ( ≥ 0.21) for insulin area under the curve (iAUC), insulin:glucose ratio, insulin or glucose baseline, or peak insulin or glucose concentrations. At 21 DOF, steers fed CrP had decreased glucose area under the curve (gAUC; = 0.01), decreased glucose clearance rate (; = 0.02), and increased glucose half-life (T; = 0.07) compared to steers fed Cont; however, by 98 DOF, no differences were observed between treatments. At 98 DOF, all steers, regardless of treatment, had increased ( < 0.01) peak glucose and insulin, , iAUC, insulin:glucose ratio, and baseline insulin when compared to values at 21 DOF, but gAUC and T decreased ( < 0.01). Although steers fed CrP tended ( = 0.11) to have

  1. Enhancement of out-of-band rejection in optical filters based on phase-sensitive amplification.

    PubMed

    Agarwal, Anjali; Dailey, James M; McKinstrie, Colin J; Toliver, Paul

    2016-06-15

    We present a novel optical filter based on amplification and deamplification in a phase-sensitive amplifier (PSA), whose out-of-band rejection is enhanced by slightly imbalancing the inputs to the PSA. The out-of-band rejection of the PSA-based filter with balanced input signal and idler powers is given by G2 in the optical domain, where G is the maximum phase-sensitive gain. By unbalancing the input to the PSA, the optical out-of-band rejection is significantly enhanced beyond G2, thus enabling filters with high rejection even with moderate-gain PSAs. We demonstrate a filter with optical and electrical extinctions of 29 dB and 60 dB, respectively, using a moderate PSA gain of only 10 dB. Further, this technique allows for ultrawideband frequency tuning, spanning multiterahertz bandwidths along with filter response reconfigurability. These novel concepts will be invaluable for optical signal processing in high-performance analog and digital systems. PMID:27304304

  2. Effects of Combined Calcium and Vitamin D Supplementation on Insulin Secretion, Insulin Sensitivity and β-Cell Function in Multi-Ethnic Vitamin D-Deficient Adults at Risk for Type 2 Diabetes: A Pilot Randomized, Placebo-Controlled Trial

    PubMed Central

    Gagnon, Claudia; Daly, Robin M.; Carpentier, André; Lu, Zhong X.; Shore-Lorenti, Catherine; Sikaris, Ken; Jean, Sonia; Ebeling, Peter R.

    2014-01-01

    Objectives To examine whether combined vitamin D and calcium supplementation improves insulin sensitivity, insulin secretion, β-cell function, inflammation and metabolic markers. Design 6-month randomized, placebo-controlled trial. Participants Ninety-five adults with serum 25-hydroxyvitamin D [25(OH)D] ≤55 nmol/L at risk of type 2 diabetes (with prediabetes or an AUSDRISK score ≥15) were randomized. Analyses included participants who completed the baseline and final visits (treatment n = 35; placebo n = 45). Intervention Daily calcium carbonate (1,200 mg) and cholecalciferol [2,000–6,000 IU to target 25(OH)D >75 nmol/L] or matching placebos for 6 months. Measurements Insulin sensitivity (HOMA2%S, Matsuda index), insulin secretion (insulinogenic index, area under the curve (AUC) for C-peptide) and β-cell function (Matsuda index x AUC for C-peptide) derived from a 75 g 2-h OGTT; anthropometry; blood pressure; lipid profile; hs-CRP; TNF-α; IL-6; adiponectin; total and undercarboxylated osteocalcin. Results Participants were middle-aged adults (mean age 54 years; 69% Europid) at risk of type 2 diabetes (48% with prediabetes). Compliance was >80% for calcium and vitamin D. Mean serum 25(OH)D concentration increased from 48 to 95 nmol/L in the treatment group (91% achieved >75 nmol/L), but remained unchanged in controls. There were no significant changes in insulin sensitivity, insulin secretion and β-cell function, or in inflammatory and metabolic markers between or within the groups, before or after adjustment for potential confounders including waist circumference and season of recruitment. In a post hoc analysis restricted to participants with prediabetes, a significant beneficial effect of vitamin D and calcium supplementation on insulin sensitivity (HOMA%S and Matsuda) was observed. Conclusions Daily vitamin D and calcium supplementation for 6 months may not change OGTT-derived measures of insulin sensitivity, insulin secretion and

  3. Estimated Insulin Sensitivity and Cardiovascular Disease Risk Factors in Adolescents with and without Type 1 Diabetes

    PubMed Central

    Specht, Brian J; Wadwa, R Paul; Snell-Bergeon, Janet K; Nadeau, Kristen J; Bishop, Franziska K; Maahs, David M.

    2012-01-01

    Objective To test the hypothesis that cardiovascular disease (CVD) risk factors are similar in adolescents with and without diabetes (T1D) in the most insulin sensitive (IS) tertile and CVD risk factors are more atherogenic with decreasing IS in adolescents with T1D. Study design Adolescents with IS T1D (n=292; age=15.4±2.1 years; duration=8.8±3.0 years, HbA1c=8.9±1.6%) and non-diabetic (non-DM) controls (n=89; age=15.4±2.1 years) was estimated using the model: logeIS=4.64725 – 0.02032(waist, cm) – 0.09779(HbA1c, %) – 0.00235(triglycerides, mg/dl). CVD risk factors (blood pressure, fasting total, LDL and HDL-cholesterol, hs-CRP, and BMI Z-score) were compared between all non-DM adolescents and those with T1D in the most IS tertile, and then examined for a linear trend by IS tertile in adolescents with T1D, adjusted for sex, race/ethnicity and Tanner Stage. Results Estimated IS was significantly lower in adolescents with T1D compared with those without (T1D=7.8±2.4, non-DM=11.5±2.9; p<0.0001). CVD risk factors were similar for non-DM compared with the adolescents with most IS T1D, except for higher HDL-c and DBP in adolescents with T1D (p<0.05). Among adolescents with T1D, all CVD risk factors except for HDL-c, were more atherogenic across decreasing IS tertiles in linear regression analysis (p<0.05). Conclusion Adolescents with T1D who are the most IS have similar CVD risk factors compared with non-DM adolescents. CVD risk factors are inversely associated with adolescents with IS T1D. IS may be an important therapeutic target for reducing CVD risk factors in adolescents with T1D. PMID:22921593

  4. Increased inflammation and decreased insulin sensitivity indicate metabolic disturbances in zoo-managed compared to free-ranging black rhinoceros (Diceros bicornis).

    PubMed

    Schook, Mandi W; Wildt, David E; Raghanti, Mary Ann; Wolfe, Barbara A; Dennis, Patricia M

    2015-01-01

    Black rhinoceros (rhinos) living in zoos express a host of unusual disease syndromes that are associated with increased morbidity and mortality, including hemolytic anemia, rhabdomyolysis, hepatopathy and ulcerative skin disease, hypophosphatemia and iron overload. We hypothesized that iron overload is a consequence and indicator of disturbances related to inflammation and insulin/glucose metabolism. The objectives of this study were to: (1) generate the first baseline information on biomarkers of inflammation (tumor necrosis factor alpha [TNFα], serum amyloid A [SAA]), insulin sensitivity (insulin, glucose and proxy calculations of insulin sensitivity), phosphate and iron stores (ferritin) using banked serum from free-ranging black rhinos; and (2) then compare serum biomarkers between zoo-managed (n=86 individuals) and free-ranging (n=120) animals. Enzyme immunoassays were validated for serum and then biomarker levels analyzed using mixed models while controlling for sex, age and year of sample collection. Concentrations of TNFα, SAA, insulin and insulin-to glucose ratio were higher (P<0.05) in black rhinos managed in ex situ conditions compared to free-living counterparts. Findings indicate that the captive environment is contributing to increased inflammation and decreased insulin sensitivity in this endangered species. PMID:25980685

  5. Surgical removal of visceral fat decreases plasma free fatty acid and increases insulin sensitivity on liver and peripheral tissue in monosodium glutamate (MSG)-obese rats.

    PubMed

    Kim, Y W; Kim, J Y; Lee, S K

    1999-10-01

    In order to evaluate the role of visceral and subcutaneous fat tissue in insulin sensitivity and lipid metabolism, we measured the fasting levels of plasma free fatty acid (FFA) and insulin, glucose disappearance rate (Rd), and hepatic glucose production rate (HGP) after surgical removal of visceral (VF) or subcutaneous (SF) fat tissue in monosodium glutamate-obese (MSG-Ob) rats. Monosodium glutamate obesity was induced in rats by neonatal injection of MSG. Surgery to remove fat was done at 15 weeks of age. The experiments were done four weeks after the surgery. MSG-Ob rats showed increased levels of FFA, insulin, and HGP and decreased Rd compared to normal rats. In the VF group, the FFA level and HGP were decreased to normal values, Rd was partially normalized, but the level of insulin did not change significantly compared to MSG-Ob. In the SF group, FFA and Rd were partially normalized, but HGP was not suppressed significantly compared to MSG-Ob. These results suggest that visceral fat affects the insulin sensitivity of liver and FFA concentration more than subcutaneous fat; however, no significant difference was shown on whole body insulin sensitivity and fasting insulin concentration. PMID:10576150

  6. Developmental Programming: Impact of Gestational Steroid and Metabolic Milieus on Adiposity and Insulin Sensitivity in Prenatal Testosterone-Treated Female Sheep.

    PubMed

    Cardoso, Rodolfo C; Veiga-Lopez, Almudena; Moeller, Jacob; Beckett, Evan; Pease, Anthony; Keller, Erica; Madrigal, Vanessa; Chazenbalk, Gregorio; Dumesic, Daniel; Padmanabhan, Vasantha

    2016-02-01

    Prenatally testosterone (T)-treated sheep present metabolic disruptions similar to those seen in women with polycystic ovary syndrome. These females exhibit an increased ratio of small to large adipocytes, which may be the earliest event in the development of adult insulin resistance. Additionally, our longitudinal studies suggest the existence of a period of compensatory adaptation during development. This study tested whether 1) in utero cotreatment of prenatally T-treated sheep with androgen antagonist (flutamide) or insulin sensitizer (rosiglitazone) prevents juvenile insulin resistance and adult changes in adipocyte size; and 2) visceral adiposity and insulin sensitivity are both unaltered during early adulthood, confirming the predicted developmental trajectory in this animal model. Insulin sensitivity was tested during juvenile development and adipose tissue distribution, adipocyte size, and concentrations of adipokines were determined during early adulthood. Prenatal T-treated females manifested juvenile insulin resistance, which was prevented by prenatal rosiglitazone cotreatment. Neither visceral adiposity nor insulin sensitivity differed between groups during early adulthood. Prenatal T-treated sheep presented an increase in the relative proportion of small adipocytes, which was not substantially prevented by either prenatal intervention. A large effect size was observed for increased leptin concentrations in prenatal T-treated sheep compared with controls, which was prevented by prenatal rosiglitazone. In conclusion, gestational alterations in insulin-glucose homeostasis likely play a role in programming insulin resistance, but not adipocyte size distribution, in prenatal T-treated sheep. Furthermore, these results support the notion that a period of compensatory adaptation of the metabolic system to prenatal T exposure occurs between puberty and adulthood. PMID:26650569

  7. Time and position sensitive single photon detector for scintillator read-out

    NASA Astrophysics Data System (ADS)

    Schössler, S.; Bromberger, B.; Brandis, M.; Schmidt, L. Ph H.; Tittelmeier, K.; Czasch, A.; Dangendorf, V.; Jagutzki, O.

    2012-02-01

    We have developed a photon counting detector system for combined neutron and γ radiography which can determine position, time and intensity of a secondary photon flash created by a high-energy particle or photon within a scintillator screen. The system is based on a micro-channel plate photomultiplier concept utilizing image charge coupling to a position- and time-sensitive read-out anode placed outside the vacuum tube in air, aided by a standard photomultiplier and very fast pulse-height analyzing electronics. Due to the low dead time of all system components it can cope with the high throughput demands of a proposed combined fast neutron and dual discrete energy γ radiography method (FNDDER). We show tests with different types of delay-line read-out anodes and present a novel pulse-height-to-time converter circuit with its potential to discriminate γ energies for the projected FNDDER devices for an automated cargo container inspection system (ACCIS).

  8. eIF6 coordinates insulin sensitivity and lipid metabolism by coupling translation to transcription

    PubMed Central

    Brina, Daniela; Miluzio, Annarita; Ricciardi, Sara; Clarke, Kim; Davidsen, Peter K.; Viero, Gabriella; Tebaldi, Toma; Offenhäuser, Nina; Rozman, Jan; Rathkolb, Birgit; Neschen, Susanne; Klingenspor, Martin; Wolf, Eckhard; Gailus-Durner, Valerie; Fuchs, Helmut; Hrabe de Angelis, Martin; Quattrone, Alessandro; Falciani, Francesco; Biffo, Stefano

    2015-01-01

    Insulin regulates glycaemia, lipogenesis and increases mRNA translation. Cells with reduced eukaryotic initiation factor 6 (eIF6) do not increase translation in response to insulin. The role of insulin-regulated translation is unknown. Here we show that reduction of insulin-regulated translation in mice heterozygous for eIF6 results in normal glycaemia, but less blood cholesterol and triglycerides. eIF6 controls fatty acid synthesis and glycolysis in a cell autonomous fashion. eIF6 acts by exerting translational control of adipogenic transcription factors like C/EBPβ, C/EBPδ and ATF4 that have G/C rich or uORF sequences in their 5′ UTR. The outcome of the translational activation by eIF6 is a reshaping of gene expression with increased levels of lipogenic and glycolytic enzymes. Finally, eIF6 levels modulate histone acetylation and amounts of rate-limiting fatty acid synthase (Fasn) mRNA. Since obesity, type 2 diabetes, and cancer require a Fasn-driven lipogenic state, we propose that eIF6 could be a therapeutic target for these diseases. PMID:26383020

  9. eIF6 coordinates insulin sensitivity and lipid metabolism by coupling translation to transcription.

    PubMed

    Brina, Daniela; Miluzio, Annarita; Ricciardi, Sara; Clarke, Kim; Davidsen, Peter K; Viero, Gabriella; Tebaldi, Toma; Offenhäuser, Nina; Rozman, Jan; Rathkolb, Birgit; Neschen, Susanne; Klingenspor, Martin; Wolf, Eckhard; Gailus-Durner, Valerie; Fuchs, Helmut; Hrabe de Angelis, Martin; Quattrone, Alessandro; Falciani, Francesco; Biffo, Stefano

    2015-01-01

    Insulin regulates glycaemia, lipogenesis and increases mRNA translation. Cells with reduced eukaryotic initiation factor 6 (eIF6) do not increase translation in response to insulin. The role of insulin-regulated translation is unknown. Here we show that reduction of insulin-regulated translation in mice heterozygous for eIF6 results in normal glycaemia, but less blood cholesterol and triglycerides. eIF6 controls fatty acid synthesis and glycolysis in a cell autonomous fashion. eIF6 acts by exerting translational control of adipogenic transcription factors like C/EBPβ, C/EBPδ and ATF4 that have G/C rich or uORF sequences in their 5' UTR. The outcome of the translational activation by eIF6 is a reshaping of gene expression with increased levels of lipogenic and glycolytic enzymes. Finally, eIF6 levels modulate histone acetylation and amounts of rate-limiting fatty acid synthase (Fasn) mRNA. Since obesity, type 2 diabetes, and cancer require a Fasn-driven lipogenic state, we propose that eIF6 could be a therapeutic target for these diseases. PMID:26383020

  10. Decreased insulin sensitivity due to continuous nutrient administration in neonatal pigs

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Chronic TPN compared to intermittent formula feeding has been shown to induce hepatic insulin resistance and steatosis in neonatal pigs. We hypothesized that the route of feeding (IV vs. enteral) rather than the nature of the diet (elemental vs polymeric) or the feeding regimen (continuous vs interm...

  11. TEA INCREASES INSULIN SENSITIVITY AND DECREASES OXIDATIVE STRESS IN RATS WITH METABOLIC SYNDROME

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Cinnamon has been shown to improve glycemic control in people with non-insulin dependent diabetes. Fifty-one patients with gestational diabetes diagnosed between 24 and 32 weeks of gestation were randomized to 6 weeks of either 1 gram of cinnamon per day or an identical-appearing capsule containing...

  12. Docosahexaenoic acid supplementation improved lipocentric but not glucocentric markers of insulin sensitivity in hypertriglyceridemic men

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Background: Obesity and metabolic syndrome are associated with increases in insulin resistance (IR) and type 2 diabetes mellitus. Results from animal intervention studies and human epidemiological studies suggest that n-3 polyunsaturated fatty acids can prevent and reverse IR, but results from huma...

  13. 5-HT2CRs expressed by pro-opiomelanocortin neurons regulate insulin sensitivity in liver

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Mice lacking 5-HT 2C receptors displayed hepatic insulin resistance, a phenotype normalized by re-expression of 5-HT2CRs only in pro-opiomelanocortin (POMC) neurons. 5-HT2CR deficiency also abolished the anti-diabetic effects of meta-chlorophenylpiperazine (a 5-HT2CR agonist); these effects were re...

  14. Biosimilar insulins.

    PubMed

    Heinemann, Lutz

    2012-08-01

    Until now most insulin used in developed countries is manufactured and distributed by a small number of multinational companies. Other pharmaceutical companies - many of these are located in countries such as India or China - are also able to manufacture insulin with modern biotechnological methods. Additionally, the patents for many insulin formulations have expired or are going to expire soon. This enables such companies to produce insulins and to apply for market approval of these as biosimilar insulins (BIs) in highly regulated markets such as the EU or the US. To understand the complexity of BIs' approval and usage, scientific and regulatory aspects have to be discussed. Differences in the manufacturing process (none of the insulin-manufacturing procedures are identical) result in the fact that all insulin that might become BIs differ from the originator insulin to some extent. The question is, have such differences in the structure of the insulin molecule and or the purity and so on clinically relevant consequences for the biological effects induced or not. The guidelines already in place in the EU for market approval require that the manufacturer demonstrates that his insulin has a safety and efficacy profile that is similar to that of the 'original' insulin formulation. Recently guidelines for biosimilars were issued in the US; however, these do not cover insulin. Although a challenging approval process for insulins to become BI might be regarded as a hurdle to keep companies out of certain markets, it is fair to say that the potential safety and efficacy issues surrounding BI are substantial and relevant, and do warrant a careful and evidence-driven approval process. Nevertheless, it is very likely that in the next years, BIs will come to the market also in highly regulated markets. PMID:22583127

  15. Fault-sensitivity and wear-out analysis of VLSI systems

    NASA Astrophysics Data System (ADS)

    Choi, Gwan S.

    1995-06-01

    This thesis describes simulation approaches to conduct fault sensitivity and wear-out failure analysis of VLSI systems. A fault-injection approach to study transient impact in VLSI systems is developed. Through simulated fault injection at the device level and subsequent fault propagation at the gate, functional and software levels, it is possible to identify critical bottlenecks in dependability. Techniques to speed up the fault simulation and to perform statistical analysis of fault impact are developed. A wear-out simulation environment is also developed to closely mimic dynamic sequences of wear-out events in a device through time, to localize weak location/aspect of target chip and to allow generation of Time-to-Failure (TTF) distribution of a VLSI chip as whole. First, an accurate simulation of a target chip and its application code is performed to acquire real workload trace data on switch activity. Then, using this switch activity information, wear-out of the each component of the chip is simulated using Monte Carlo techniques.

  16. CMHX008, a Novel Peroxisome Proliferator-Activated Receptor γ Partial Agonist, Enhances Insulin Sensitivity In Vitro and In Vivo

    PubMed Central

    Song, Ying; Liu, Zhiguo; Li, Jibin; Gao, Rufei; Zhang, Yuyao; Mei, Hu; Guo, Tingwang; Xiao, Ling; Wang, Bochu; Wu, Chaodong; Xiao, Xiaoqiu

    2014-01-01

    The peroxisome proliferator-activated receptor γ (PPARγ) plays an important role in adipocyte differentiation and insulin sensitivity. Its ligand rosiglitazone has anti-diabetic effect but is frequently accompanied with some severe unwanted effects. The aim of the current study was to compare the anti-diabetic effect of CMHX008, a novel thiazolidinedione-derivative, with rosiglitazone. A luciferase assay was used to evaluate in vitro PPARγ activation. 3T3-L1 cells were used to examine adipocyte differentiation. High fat diet (HFD) mice were used to examine in vivo insulin sensitivity. The mRNA levels were evaluated by real-time RT-PCR. Serum biochemical and hormonal variables were assessed using a clinical chemistry analyser. CMHX008 displayed a moderate PPARγ agonist activity, and promoted 3T3-L1 preadipocyte differentiation with lower activity than rosiglitazone. CMHX008 regulated the expression of PPARγ target genes in a different manner from rosiglitazone. CMHX008 increased the expression and secretion of adiponectin with the similar efficacy as rosiglitazone, but only 25% as potent as rosiglitazone for the induction of adipocyte fatty acid binding protein. Treatment of CMHX008 and rosiglitazone protected mice from high fat diet (HFD)-induced glucose intolerance, hyperinsulinemia and inflammation. CMHX008 reduced the mRNA expression of M1 macrophage markers, and significantly increased the expressions of M2 markers. In conclusion, CMHX008 shared the comparable insulin-sensitizing effects as rosiglitazone with lower adipogenic capacity and might potentially be developed into an effective agent for the treatment of diabetes and metabolic disorders. PMID:25004107

  17. Temporal Relationship Between Insulin Sensitivity and the Pubertal Decline in Physical Activity in Peripubertal Hispanic and African American Females

    PubMed Central

    Spruijt-Metz, Donna; Belcher, Britni R.; Hsu, Ya-Wen; McClain, Arianna D.; Chou, Chih-Ping; Nguyen-Rodriguez, Selena; Weigensberg, Marc J.; Goran, Michael I.

    2013-01-01

    OBJECTIVE Little attention has been paid to possible intrinsic biological mechanisms for the decline in physical activity that occurs during puberty. This longitudinal observational study examined the association between baseline insulin sensitivity (SI) and declines in physical activity and increases in sedentary behavior in peripubertal minority females over a year. RESEARCH DESIGN AND METHODS Participants were Hispanic and African American girls (n = 55; 76% Hispanic; mean age 9.4 years; 36% obese). SI and other insulin indices were measured at baseline using the frequently sampled intravenous glucose tolerance test. Physical activity was measured on a quarterly basis by accelerometry and self-report. RESULTS Physical activity declined by 25% and time spent in sedentary behaviors increased by ∼13% over 1 year. Lower baseline SI predicted the decline in physical activity measured by accelerometry, whereas higher baseline acute insulin response to glucose predicted the decline in physical activity measured by self-report. Time spent in sedentary behavior increased by ~13% over 1 year, and this was predicted by lower baseline SI. All models controlled for adiposity, age, pubertal stage, and ethnicity. CONCLUSIONS When evaluated using a longitudinal design with strong outcome measures, this study suggests that lower baseline SI predicts a greater decline in physical activity in peripubertal minority females. PMID:23846812

  18. Curcumin rescues high fat diet-induced obesity and insulin sensitivity in mice through regulating SREBP pathway.

    PubMed

    Ding, Lili; Li, Jinmei; Song, Baoliang; Xiao, Xu; Zhang, Binfeng; Qi, Meng; Huang, Wendong; Yang, Li; Wang, Zhengtao

    2016-08-01

    Obesity and its major co-morbidity, type 2 diabetes, have reached an alarming epidemic prevalence without an effective treatment available. It has been demonstrated that inhibition of SREBP pathway may be a useful strategy to treat obesity with type 2 diabetes. Sterol regulatory element-binding proteins (SREBPs) are major transcription factors regulating the expression of genes involved in biosynthesis of cholesterol, fatty acid and triglyceride. In current study, we identified a small molecule, curcumin, inhibited the SREBP expression in vitro. The inhibition of SREBP by curcumin decreased the biosynthesis of cholesterol and fatty acid. In vivo, curcumin ameliorated HFD-induced body weight gain and fat accumulation in liver or adipose tissues, and improved serum lipid levels and insulin sensitivity in HFD-induced obese mice. Consistently, curcumin regulates SREBPs target genes and metabolism associated genes in liver or adipose tissues, which may directly contribute to the lower lipid level and improvement of insulin resistance. Take together, curcumin, a major active component of Curcuma longa could be a potential leading compound for development of drugs for the prevention of obesity and insulin resistance. PMID:27208389

  19. Mitochondrial dysfunction leads to impairment of insulin sensitivity and adiponectin secretion in adipocytes.

    PubMed

    Wang, Chih-Hao; Wang, Ching-Chu; Huang, Hsin-Chang; Wei, Yau-Huei

    2013-02-01

    Adipocytes play an integrative role in the regulation of energy metabolism and glucose homeostasis in the human body. Functional defects in adipocytes may cause systemic disturbance of glucose homeostasis. Recent studies revealed mitochondrial abnormalities in the adipose tissue of patients with type 2 diabetes. In addition, patients with mitochondrial diseases usually manifest systemic metabolic disorder. However, it is unclear how mitochondrial dysfunction in adipocytes affects the regulation of glucose homeostasis. In this study, we induced mitochondrial dysfunction and overproduction of reactive oxygen species (ROS) by addition of respiratory inhibitors oligomycin A and antimycin A and by knockdown of mitochondrial transcription factor A (mtTFA), respectively. We found an attenuation of the insulin response as indicated by lower glucose uptake and decreased phosphorylation of Akt upon insulin stimulation of adipocytes with mitochondrial dysfunction. Furthermore, the expression of glucose transporter 4 (Glut4) and secretion of adiponectin were decreased in adipocytes with increased ROS generated by defective mitochondria. Moreover, the severity of insulin insensitivity was correlated with the extent of mitochondrial dysfunction. These results suggest that higher intracellular ROS levels elicited by mitochondrial dysfunction resulted in impairment of the function of adipocytes in the maintenance of glucose homeostasis through attenuation of insulin signaling, downregulation of Glut4 expression, and decrease in adiponectin secretion. Our findings substantiate the important role of mitochondria in the regulation of glucose homeostasis in adipocytes and also provide a molecular basis for the explanation of the manifestation of diabetes mellitus or insulin insensitivity in a portion of patients with mitochondrial diseases such as MELAS or MERRF syndrome. PMID:23253816

  20. Vitamin E and vitamin C do not reduce insulin sensitivity but inhibit mitochondrial protein expression in exercising obese rats

    PubMed Central

    Picklo, Matthew J.; Thyfault, John P.

    2016-01-01

    Controversy exists as to whether supplementation with the antioxidants vitamin E and vitamin C blocks adaptation to exercise. Exercise is a first-line means to treat obesity and its complications. While diet-induced obesity alters mitochondrial function and induces insulin resistance (IR), no data exist as to whether supplementation with vitamin E and vitamin C modify responses to exercise in pre-existing obesity. We tested the hypothesis that dietary supplementation with vitamin E (0.4 g α-tocopherol acetate/kg) and vitamin C (0.5 g/kg) blocks exercise-induced improvements on IR and mitochondrial content in obese rats maintained on a high-fat (45% fat energy (en)) diet. Diet-induced obese, sedentary rats had a 2-fold higher homeostasis model assessment of insulin resistance and larger insulin area under the curve following glucose tolerances test than rats fed a low-fat (10% fat en) diet. Exercising (12 weeks at 5 times per week in a motorized wheel) of obese rats normalized IR indices, an effect not modified by vitamin E and vitamin C. Vitamin E and vitamin C supplementation with exercise elevated mtDNA content in adipose and skeletal muscle to a greater extent (20%) than exercise alone in a depot-specific manner. On the other hand, vitamin C and vitamin E decreased exercise-induced increases in mitochondrial protein content for complex I (40%) and nicotinamide nucleotide transhydrogenase (35%) in a muscle-dependent manner. These data indicate that vitamin E and vitamin C supplementation in obese rodents does not modify exercise-induced improvements in insulin sensitivity but that changes in mitochondrial biogenesis and mitochondrial protein expression may be modified by antioxidant supplementation. PMID:25761734

  1. Vitamin E and vitamin C do not reduce insulin sensitivity but inhibit mitochondrial protein expression in exercising obese rats.

    PubMed

    Picklo, Matthew J; Thyfault, John P

    2015-04-01

    Controversy exists as to whether supplementation with the antioxidants vitamin E and vitamin C blocks adaptation to exercise. Exercise is a first-line means to treat obesity and its complications. While diet-induced obesity alters mitochondrial function and induces insulin resistance (IR), no data exist as to whether supplementation with vitamin E and vitamin C modify responses to exercise in pre-existing obesity. We tested the hypothesis that dietary supplementation with vitamin E (0.4 g α-tocopherol acetate/kg) and vitamin C (0.5 g/kg) blocks exercise-induced improvements on IR and mitochondrial content in obese rats maintained on a high-fat (45% fat energy (en)) diet. Diet-induced obese, sedentary rats had a 2-fold higher homeostasis model assessment of insulin resistance and larger insulin area under the curve following glucose tolerances test than rats fed a low-fat (10% fat en) diet. Exercising (12 weeks at 5 times per week in a motorized wheel) of obese rats normalized IR indices, an effect not modified by vitamin E and vitamin C. Vitamin E and vitamin C supplementation with exercise elevated mtDNA content in adipose and skeletal muscle to a greater extent (20%) than exercise alone in a depot-specific manner. On the other hand, vitamin C and vitamin E decreased exercise-induced increases in mitochondrial protein content for complex I (40%) and nicotinamide nucleotide transhydrogenase (35%) in a muscle-dependent manner. These data indicate that vitamin E and vitamin C supplementation in obese rodents does not modify exercise-induced improvements in insulin sensitivity but that changes in mitochondrial biogenesis and mitochondrial protein expression may be modified by antioxidant supplementation. PMID:25761734

  2. Glutamate Cysteine Ligase—Modulatory Subunit Knockout Mouse Shows Normal Insulin Sensitivity but Reduced Liver Glycogen Storage

    PubMed Central

    Lavoie, Suzie; Steullet, Pascal; Kulak, Anita; Preitner, Frederic; Do, Kim Q.; Magistretti, Pierre J.

    2016-01-01

    Glutathione (GSH) deficits have been observed in several mental or degenerative illness, and so has the metabolic syndrome. The impact of a decreased glucose metabolism on the GSH system is well-known, but the effect of decreased GSH levels on the energy metabolism is unclear. The aim of the present study was to investigate the sensitivity to insulin in the mouse knockout (KO) for the modulatory subunit of the glutamate cysteine ligase (GCLM), the rate-limiting enzyme of GSH synthesis. Compared to wildtype (WT) mice, GCLM-KO mice presented with reduced basal plasma glucose and insulin levels. During an insulin tolerance test, GCLM-KO mice showed a normal fall in glycemia, indicating normal insulin secretion. However, during the recovery phase, plasma glucose levels remained lower for longer in KO mice despite normal plasma glucagon levels. This is consistent with a normal counterregulatory hormonal response but impaired mobilization of glucose from endogenous stores. Following a resident-intruder stress, during which stress hormones mobilize glucose from hepatic glycogen stores, KO mice showed a lower hyperglycemic level despite higher plasma cortisol levels when compared to WT mice. The lower hepatic glycogen levels observed in GCLM-KO mice could explain the impaired glycogen mobilization following induced hypoglycemia. Altogether, our results indicate that reduced liver glycogen availability, as observed in GCLM-KO mice, could be at the origin of their lower basal and challenged glycemia. Further studies will be necessary to understand how a GSH deficit, typically observed in GCLM-KO mice, leads to a deficit in liver glycogen storage. PMID:27148080

  3. Macrophage Metalloelastase (MMP12) Regulates Adipose Tissue Expansion, Insulin Sensitivity, and Expression of Inducible Nitric Oxide Synthase

    PubMed Central

    Lee, Jung-Ting; Pamir, Nathalie; Liu, Ning-Chun; Kirk, Elizabeth A.; Averill, Michelle M.; Becker, Lev; Larson, Ilona; Hagman, Derek K.; Foster-Schubert, Karen E.; van Yserloo, Brian; Bornfeldt, Karin E.; LeBoeuf, Renee C.; Kratz, Mario

    2014-01-01

    Macrophage metalloelastase, a matrix metallopeptidase (MMP12) predominantly expressed by mature tissue macrophages, is implicated in pathological processes. However, physiological functions for MMP12 have not been described. Because mRNA levels for the enzyme increase markedly in adipose tissue of obese mice, we investigated the role of MMP12 in adipose tissue expansion and insulin resistance. In humans, MMP12 expression correlated positively and significantly with insulin resistance, TNF-α expression, and the number of CD14+CD206+ macrophages in adipose tissue. MMP12 was the most abundant matrix metallopeptidase detected by proteomic analysis of conditioned medium of M2 macrophages and dendritic cells. In contrast, it was detected only at low levels in bone marrow derived macrophages and M1 macrophages. When mice received a high-fat diet, adipose tissue mass increased and CD11b+F4/80+CD11c−macrophages accumulated to a greater extent in MMP12-deficient (Mmp12−/−) mice than in wild-type mice (Mmp12+/+). Despite being markedly more obese, fat-fed Mmp12−/− mice were more insulin sensitive than fat-fed Mmp12+/+ mice. Expression of inducible nitric oxide synthase (Nos2) by Mmp12−/− macrophages was significantly impaired both in vivo and in vitro, suggesting that MMP12 might mediate nitric oxide production during inflammation. We propose that MMP12 acts as a double-edged sword by promoting insulin resistance while combatting adipose tissue expansion. PMID:24914938

  4. Long-chain omega-3 fatty acids regulate bovine whole-body protein metabolism by promoting muscle insulin signalling to the Akt–mTOR–S6K1 pathway and insulin sensitivity

    PubMed Central

    Gingras, Andrée-Anne; White, Phillip James; Chouinard, P Yvan; Julien, Pierre; Davis, Teresa A; Dombrowski, Luce; Couture, Yvon; Dubreuil, Pascal; Myre, Alexandre; Bergeron, Karen; Marette, André; Thivierge, M Carole

    2007-01-01

    The ability of the skeletal musculature to use amino acids to build or renew constitutive proteins is gradually lost with age and this is partly due to a decline in skeletal muscle insulin sensitivity. Since long-chain omega-3 polyunsaturated fatty acids (LCn–3PUFA) from fish oil are known to improve insulin-mediated glucose metabolism in insulin-resistant states, their potential role in regulating insulin-mediated protein metabolism was investigated in this study. Experimental data are based on a switchback design composed of three 5 week experimental periods using six growing steers to compare the effect of a continuous abomasal infusion of LCn–3PUFA-rich menhaden oil with an iso-energetic control oil mixture. Clamp and insulin signalling observations were combined with additional data from a second cohort of six steers. We found that enteral LCn–3PUFA potentiate insulin action by increasing the insulin-stimulated whole-body disposal of amino acids from 152 to 308 μmol kg−1 h−1 (P = 0.006). The study further showed that in the fed steady-state, chronic adaptation to LCn–3PUFA induces greater activation (P < 0.05) of the Akt–mTOR–S6K1 signalling pathway. Simultaneously, whole-body total flux of phenylalanine was reduced from 87 to 67 μmol kg−1 h−1 (P = 0.04) and oxidative metabolism was decreased (P = 0.05). We conclude that chronic feeding of menhaden oil provides a novel nutritional mean to enhance insulin-sensitive aspects of protein metabolism. PMID:17158167

  5. Long-chain omega-3 fatty acids regulate bovine whole-body protein metabolism by promoting muscle insulin signalling to the Akt-mTOR-S6K1 pathway and insulin sensitivity.

    PubMed

    Gingras, Andrée-Anne; White, Phillip James; Chouinard, P Yvan; Julien, Pierre; Davis, Teresa A; Dombrowski, Luce; Couture, Yvon; Dubreuil, Pascal; Myre, Alexandre; Bergeron, Karen; Marette, André; Thivierge, M Carole

    2007-02-15

    The ability of the skeletal musculature to use amino acids to build or renew constitutive proteins is gradually lost with age and this is partly due to a decline in skeletal muscle insulin sensitivity. Since long-chain omega-3 polyunsaturated fatty acids (LCn-3PUFA) from fish oil are known to improve insulin-mediated glucose metabolism in insulin-resistant states, their potential role in regulating insulin-mediated protein metabolism was investigated in this study. Experimental data are based on a switchback design composed of three 5 week experimental periods using six growing steers to compare the effect of a continuous abomasal infusion of LCn-3PUFA-rich menhaden oil with an iso-energetic control oil mixture. Clamp and insulin signalling observations were combined with additional data from a second cohort of six steers. We found that enteral LCn-3PUFA potentiate insulin action by increasing the insulin-stimulated whole-body disposal of amino acids from 152 to 308 micromol kg(-1) h(-1) (P=0.006). The study further showed that in the fed steady-state, chronic adaptation to LCn-3PUFA induces greater activation (P<0.05) of the Akt-mTOR-S6K1 signalling pathway. Simultaneously, whole-body total flux of phenylalanine was reduced from 87 to 67 micromol kg(-1) h(-1) (P=0.04) and oxidative metabolism was decreased (P=0.05). We conclude that chronic feeding of menhaden oil provides a novel nutritional mean to enhance insulin-sensitive aspects of protein metabolism. PMID:17158167

  6. Effects of High vs Low Glycemic Index of Dietary Carbohydrate on Cardiovascular Disease Risk Factors and Insulin Sensitivity

    PubMed Central

    Sacks, Frank M.; Carey, Vincent J.; Anderson, Cheryl A. M.; Miller, Edgar R.; Copeland, Trisha; Charleston, Jeanne; Harshfield, Benjamin J.; Laranjo, Nancy; McCarron, Phyllis; Swain, Janis; White, Karen; Yee, Karen; Appel, Lawrence J.

    2015-01-01

    IMPORTANCE Foods that have similar carbohydrate content can differ in the amount they raise blood glucose. The effects of this property, called the glycemic index, on risk factors for cardiovascular disease and diabetes are not well understood. OBJECTIVE To determine the effect of glycemic index and amount of total dietary carbohydrate on risk factors for cardiovascular disease and diabetes. DESIGN, SETTING, AND PARTICIPANTS Randomized crossover-controlled feeding trial conducted in research units in academic medical centers, in which 163 overweight adults (systolic blood pressure, 120–159 mm Hg) were given 4 complete diets that contained all of their meals, snacks, and calorie-containing beverages, each for 5 weeks, and completed at least 2 study diets. The first participant was enrolled April 1, 2008; the last participant finished December 22, 2010. For any pair of the 4 diets, there were 135 to 150 participants contributing at least 1 primary outcome measure. INTERVENTIONS (1) A high–glycemic index (65% on the glucose scale), high-carbohydrate diet (58% energy); (2) a low–glycemic index (40%), high-carbohydrate diet; (3) a high–glycemic index, low-carbohydrate diet (40% energy); and (4) a low–glycemic index, low-carbohydrate diet. Each diet was based on a healthful DASH-type diet. MAIN OUTCOMES AND MEASURES The 5 primary outcomes were insulin sensitivity, determined from the areas under the curves of glucose and insulin levels during an oral glucose tolerance test; levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides; and systolic blood pressure. RESULTS At high dietary carbohydrate content, the low– compared with high–glycemic index level decreased insulin sensitivity from 8.9 to 7.1 units (−20%, P = .002); increased LDL cholesterol from 139 to 147 mg/dL (6%, P ≤ .001); and did not affect levels of HDL cholesterol, triglycerides, or blood pressure. At low carbohydrate content, the

  7. Relationship between insulin sensitivity and the triglyceride-HDL-C ratio in overweight and obese postmenopausal women: a MONET study.

    PubMed

    Karelis, Antony D; Pasternyk, Stephanie M; Messier, Lyne; St-Pierre, David H; Lavoie, Jean-Marc; Garrel, Dominique; Rabasa-Lhoret, Rémi

    2007-12-01

    The objective of this cross-sectional study was to examine the relationship between the triglyceride-HDL-cholesterol ratio (TG:HDL-C) and insulin sensitivity in overweight and obese sedentary postmenopausal women. The study population consisted of 131 non-diabetic overweight and obese sedentary postmenopausal women (age; 57.7+/-5.0 y; body mass index (BMI), 32.2+/-4.3 kg/m2). Subjects were characterized by dividing the entire cohort into tertiles based on the TG:HDL-C (T1<0.86 vs. T2=0.86 to 1.35 vs. T3>1.35, respectively). We measured (i) insulin sensitivity (using the hyperinsulinenic-euglycemic clamp and homeostasis model assessment (HOMA)), (ii) body composition (using dual-energy X-ray absorptiometry), (iii) visceral fat (using computed tomography), (iv) plasma lipids, C-reactive protein, 2 h glucose concentration during an oral glucose tolerance test (2 h glucose), as well as fasting glucose and insulin, (v) peak oxygen consumption, and (vi) lower-body muscle strength (using weight training equipment). Significant correlations were observed between the TG:HDL-C and the hyperinsulinemic-euglycemic clamp (r=-0.45; p<0.0001), as well as with HOMA (r=0.42; p<0.0001). Moreover, the TG:HDL-C significantly correlated with lean body mass, visceral fat, 2 h glucose, C-reactive protein, and muscle strength. Stepwise regression analysis showed that the TG:HDL-C explained 16.4% of the variation in glucose disposal in our cohort, which accounted for the greatest source of unique variance. Other independent predictors of glucose disposal were 2 h glucose (10.1%), C-reactive protein (CRP; 7.6%), and peak oxygen consumption (5.8%), collectively (including the TG:HDL-C) explaining 39.9% of the unique variance. In addition, the TG:HDL-C was the second predictor for HOMA, accounting for 11.7% of the variation. High levels of insulin sensitivity were associated with low levels of the TG:HDL-C. In addition, the TG:HDL-C was a predictor for glucose disposal rates and HOMA values

  8. Anti-myostatin antibody increases muscle mass and strength and improves insulin sensitivity in old mice

    PubMed Central

    Camporez, João-Paulo G.; Petersen, Max C.; Abudukadier, Abulizi; Moreira, Gabriela V.; Jurczak, Michael J.; Friedman, Glenn; Haqq, Christopher M.; Petersen, Kitt Falk; Shulman, Gerald I.

    2016-01-01

    Sarcopenia, or skeletal muscle atrophy, is a debilitating comorbidity of many physiological and pathophysiological processes, including normal aging. There are no approved therapies for sarcopenia, but the antihypertrophic myokine myostatin is a potential therapeutic target. Here, we show that treatment of young and old mice with an anti-myostatin antibody (ATA 842) for 4 wk increased muscle mass and muscle strength in both groups. Furthermore, ATA 842 treatment also increased insulin-stimulated whole body glucose metabolism in old mice, which could be attributed to increased insulin-stimulated skeletal muscle glucose uptake as measured by a hyperinsulinemic-euglycemic clamp. Taken together, these studies provide support for pharmacological inhibition of myostatin as a potential therapeutic approach for age-related sarcopenia and metabolic disease. PMID:26858428

  9. Increased GIP signaling induces adipose inflammation via a HIF-1α-dependent pathway and impairs insulin sensitivity in mice.

    PubMed

    Chen, Shu; Okahara, Fumiaki; Osaki, Noriko; Shimotoyodome, Akira

    2015-03-01

    Glucose-dependent insulinotropic polypeptide (GIP) is a gut hormone secreted in response to dietary fat and glucose. The blood GIP level is elevated in obesity and diabetes. GIP stimulates proinflammatory gene expression and impairs insulin sensitivity in cultured adipocytes. In obesity, hypoxia within adipose tissue can induce inflammation. The aims of this study were 1) to examine the proinflammatory effect of increased GIP signaling in adipose tissues in vivo and 2) to clarify the association between GIP and hypoxic signaling in adipose tissue inflammation. We administered GIP intraperitoneally to misty (lean) and db/db (obese) mice and examined adipose tissue inflammation and insulin sensitivity. We also examined the effects of GIP and hypoxia on expression of the GIP receptor (GIPR) gene and proinflammatory genes in 3T3-L1 adipocytes. GIP administration increased monocyte chemoattractant protein-1 (MCP-1) expression and macrophage infiltration into adipose tissue and increased blood glucose in db/db mice. GIPR and hypoxia-inducible factor-1α (HIF-1α) expressions were positively correlated in the adipose tissue in mice. GIPR expression increased dramatically in differentiated adipocytes. GIP treatment of adipocytes increased MCP-1 and interleukin-6 (IL-6) production. Adipocytes cultured either with RAW 264 macrophages or under hypoxia expressed more GIPR and HIF-1α, and GIP treatment increased gene expression of plasminogen activator inhibitor 1 and IL-6. HIF-1α gene silencing diminished both macrophage- and hypoxia-induced GIPR expression and GIP-induced IL-6 expression in adipocytes. Thus, increased GIP signaling plays a significant role in adipose tissue inflammation and thereby insulin resistance in obese mice, and HIF-1α may contribute to this process. PMID:25537494

  10. Insulin-sensitizing and anti-proliferative effects of Argania spinosa seed extracts.

    PubMed

    Samane, Samira; Noël, Josette; Charrouf, Zoubida; Amarouch, Hamid; Haddad, Pierre Selim

    2006-09-01

    Argania spinosa is an evergreen tree endemic of southwestern Morocco. Many preparations have been used in traditional Moroccan medicine for centuries to treat several illnesses including diabetes. However, scientific evidence supporting these actions is lacking. Therefore, we prepared various extracts of the argan fruit, namely keel, cake and argan oil extracts, which we tested in the HTC hepatoma cell line for their potential to affect cellular insulin responses. Cell viability was measured by Trypan Blue exclusion and the response to insulin evaluated by the activation of the extracellular regulated kinase (ERK1/2), ERK kinase (MEK1/2) and protein kinase B (PKB/Akt) signaling components. None of the extracts demonstrated significant cytotoxic activity. Certain extracts demonstrated a bi-phasic effect on ERK1/2 activation; low doses of the extract slightly increased ERK1/2 activation in response to insulin, whereas higher doses completely abolished the response. In contrast, none of the extracts had any significant effect on MEK whereas only a cake saponin subfraction enhanced insulin-induced PKB/Akt activation. The specific action of argan oil extracts on ERK1/2 activation made us consider an anti-proliferative action. We have thus tested other transformed cell lines (HT-1080 and MSV-MDCK-INV cells) and found similar results. Inhibition of ERK1/2 activation was also associated with decreased DNA synthesis as evidenced by [(3)H]thymidine incorporation experiments. These results suggest that the products of Argania spinosa may provide a new therapeutic avenue against proliferative diseases. PMID:16951716

  11. Insulin-sensitizing and Anti-proliferative Effects of Argania spinosa Seed Extracts

    PubMed Central

    Samane, Samira; Noël, Josette; Charrouf, Zoubida; Amarouch, Hamid; Haddad, Pierre Selim

    2006-01-01

    Argania spinosa is an evergreen tree endemic of southwestern Morocco. Many preparations have been used in traditional Moroccan medicine for centuries to treat several illnesses including diabetes. However, scientific evidence supporting these actions is lacking. Therefore, we prepared various extracts of the argan fruit, namely keel, cake and argan oil extracts, which we tested in the HTC hepatoma cell line for their potential to affect cellular insulin responses. Cell viability was measured by Trypan Blue exclusion and the response to insulin evaluated by the activation of the extracellular regulated kinase (ERK1/2), ERK kinase (MEK1/2) and protein kinase B (PKB/Akt) signaling components. None of the extracts demonstrated significant cytotoxic activity. Certain extracts demonstrated a bi-phasic effect on ERK1/2 activation; low doses of the extract slightly increased ERK1/2 activation in response to insulin, whereas higher doses completely abolished the response. In contrast, none of the extracts had any significant effect on MEK whereas only a cake saponin subfraction enhanced insulin-induced PKB/Akt activation. The specific action of argan oil extracts on ERK1/2 activation made us consider an anti-proliferative action. We have thus tested other transformed cell lines (HT-1080 and MSV-MDCK-INV cells) and found similar results. Inhibition of ERK1/2 activation was also associated with decreased DNA synthesis as evidenced by [3H]thymidine incorporation experiments. These results suggest that the products of Argania spinosa may provide a new therapeutic avenue against proliferative diseases. PMID:16951716

  12. The Role of Skeletal Muscle Glycogen Breakdown for Regulation of Insulin Sensitivity by Exercise

    PubMed Central

    Jensen, Jørgen; Rustad, Per Inge; Kolnes, Anders Jensen; Lai, Yu-Chiang

    2011-01-01

    Glycogen is the storage form of carbohydrates in mammals. In humans the majority of glycogen is stored in skeletal muscles (∼500 g) and the liver (∼100 g). Food is supplied in larger meals, but the blood glucose concentration has to be kept within narrow limits to survive and stay healthy. Therefore, the body has to cope with periods of excess carbohydrates and periods without supplementation. Healthy persons remove blood glucose rapidly when glucose is in excess, but insulin-stimulated glucose disposal is reduced in insulin resistant and type 2 diabetic subjects. During a hyperinsulinemic euglycemic clamp, 70–90% of glucose disposal will be stored as muscle glycogen in healthy subjects. The glycogen stores in skeletal muscles are limited because an efficient feedback-mediated inhibition of glycogen synthase prevents accumulation. De novo lipid synthesis can contribute to glucose disposal when glycogen stores are filled. Exercise physiologists normally consider glycogen’s main function as energy substrate. Glycogen is the main energy substrate during exercise intensity above 70% of maximal oxygen uptake (Vo2max⁡) and fatigue develops when the glycogen stores are depleted in the active muscles. After exercise, the rate of glycogen synthesis is increased to replete glycogen stores, and blood glucose is the substrate. Indeed insulin-stimulated glucose uptake and glycogen synthesis is elevated after exercise, which, from an evolutional point of view, will favor glycogen repletion and preparation for new “fight or flight” events. In the modern society, the reduced glycogen stores in skeletal muscles after exercise allows carbohydrates to be stored as muscle glycogen and prevents that glucose is channeled to de novo lipid synthesis, which over time will causes ectopic fat accumulation and insulin resistance. The reduction of skeletal muscle glycogen after exercise allows a healthy storage of carbohydrates after meals and prevents development of type 2

  13. A Randomized Controlled Exercise Training Trial on Insulin Sensitivity in African American Men: The ARTIIS study

    PubMed Central

    Newton, Robert L.; Johnson, William D.; Hendrick, Chelsea; Harris, Melissa; Andrews, Emanuel; Johannsen, Neil; Rodarte, Ruben Q.; Hsia, Daniel S.; Church, Timothy S.

    2015-01-01

    Background Lack of regular physical activity at prescribed intensity levels is a modifiable risk factor for insulin resistance and the development of diabetes. African American men are at increased risk for developing diabetes and most African American men are not meeting the current recommended levels of physical activity. The primary objective of the Aerobic Plus Resistance Training and Insulin Resistance in African American Men (ARTIIS) study is to determine the effectiveness of an exercise training intervention aimed at reducing diabetes risk factors in African American men at risk for developing diabetes. Methods Insufficiently active 35–70 year old African American men with a family history of diabetes were eligible for the study. The 5-month randomized controlled trial assigns 116 men to an exercise training or healthy living control arm. The exercise training arm combines aerobic and resistance training according to the current national physical activity recommendations and is conducted in community (YMCA) facilities. The healthy living arm receives information promoting healthy lifestyle changes. Outcomes Insulin response to an oral glucose load is the primary outcome measure, and changes in physiological parameters, cardiorespiratory fitness, strength, body composition, and psychological well-being comprise the secondary outcomes. Conclusions The ARTIIS study is one of the first adequately powered, rigorously designed studies to investigate the effects of an aerobic plus resistance exercise training program and to assess adherence to exercise training in community facilities, in African American men. PMID:25979318

  14. INSR gene variation is associated with decreased insulin sensitivity in Iraqi women with PCOs

    PubMed Central

    T. Mutib, Manal; B. Hamdan, Farqad; R. Al-Salihi, Anam

    2014-01-01

    Background: Polycystic ovarian syndrome (PCOS) is a complex, heterogeneous disorder of uncertain etiology with strong genetic background. Insulin resistance is present in the majority of PCOS cases with linkage and association between single nucleotide polymorphisms of insulin receptor (INSR) gene and PCOS. Objective: To examine whether the exon 17 of INSR gene contributes to genetic susceptibility to PCOS in Iraqi women and its effects on glucose tolerance test and lipid profile. Materials and Methods: Sixty-five healthy Iraqi women and eighty-four infertile women with PCOS, divided into two subgroups depending on the BMI were studied. Restriction fragment length polymorphism (RFLP-PCR) analysis was performed to determine the genotypes for the His 1058 C/T polymorphism at the tyrosine kinase domain in the INSR gene. Clinical, anthropometric and biochemical parameters were also estimated. Results: The C/T polymorphism at His 1058 in exon 17 of INSR was associated with PCOS (obese and non-obese). CC genotype frequency was higher in PCOS patients whereas TT genotype was higher in control women. Those with CC genotype had higher BMI, GTT and lipid profile than those with TT genotype. Conclusion: An association of C/T polymorphism at His1058 of INSR with PCOS in Iraqi women was observed. Its association with indices of insulin resistance and dyslipidemia were also noticed. PMID:25114673

  15. Effects of Aerobic Versus Resistance Exercise Without Caloric Restriction on Abdominal Fat, Intrahepatic Lipid, and Insulin Sensitivity in Obese Adolescent Boys

    PubMed Central

    Lee, SoJung; Bacha, Fida; Hannon, Tamara; Kuk, Jennifer L.; Boesch, Chris; Arslanian, Silva

    2012-01-01

    The optimal exercise modality for reductions of abdominal obesity and risk factors for type 2 diabetes in youth is unknown. We examined the effects of aerobic exercise (AE) versus resistance exercise (RE) without caloric restriction on abdominal adiposity, ectopic fat, and insulin sensitivity and secretion in youth. Forty-five obese adolescent boys were randomly assigned to one of three 3-month interventions: AE, RE, or a nonexercising control. Abdominal fat was assessed by magnetic resonance imaging, and intrahepatic lipid and intramyocellular lipid were assessed by proton magnetic resonance spectroscopy. Insulin sensitivity and secretion were evaluated by a 3-h hyperinsulinemic-euglycemic clamp and a 2-h hyperglycemic clamp. Both AE and RE prevented the significant weight gain that was observed in controls. Compared with controls, significant reductions in total and visceral fat and intrahepatic lipid were observed in both exercise groups. Compared with controls, a significant improvement in insulin sensitivity (27%) was observed in the RE group. Collapsed across groups, changes in visceral fat were associated with changes in intrahepatic lipid (r = 0.72) and insulin sensitivity (r = −0.47). Both AE and RE alone are effective for reducing abdominal fat and intrahepatic lipid in obese adolescent boys. RE but not AE is also associated with significant improvements in insulin sensitivity. PMID:22751691

  16. Muscle-specific deletion of comparative gene identification-58 (CGI-58) causes muscle steatosis but improves insulin sensitivity in male mice.

    PubMed

    Xie, Ping; Kadegowda, Anil K G; Ma, Yinyan; Guo, Feng; Han, Xianlin; Wang, Miao; Groban, Leanne; Xue, Bingzhong; Shi, Hang; Li, Huihua; Yu, Liqing

    2015-05-01

    Intramyocellular accumulation of lipids is often associated with insulin resistance. Deficiency of comparative gene identification-58 (CGI-58) causes cytosolic deposition of triglyceride (TG)-rich lipid droplets in most cell types, including muscle due to defective TG hydrolysis. It was unclear, however, whether CGI-58 deficiency-induced lipid accumulation in muscle influences insulin sensitivity. Here we show that muscle-specific CGI-58 knockout mice relative to their controls have increased glucose tolerance and insulin sensitivity on a Western-type high-fat diet, despite TG accumulation in both heart and oxidative skeletal muscle and cholesterol deposition in heart. Although the intracardiomyocellular lipid deposition results in cardiac ventricular fibrosis and systolic dysfunction, muscle-specific CGI-58 knockout mice show increased glucose uptake in heart and soleus muscle, improved insulin signaling in insulin-sensitive tissues, and reduced plasma concentrations of glucose, insulin, and cholesterol. Hepatic contents of TG and cholesterol are also decreased in these animals. Cardiac steatosis is attributable, at least in part, to decreases in cardiac TG hydrolase activity and peroxisome proliferator-activated receptor-α/peroxisome proliferator-activated receptor-γ coactivator-1-dependent mitochondrial fatty acid oxidation. In conclusion, muscle CGI-58 deficiency causes cardiac dysfunction and fat deposition in oxidative muscles but induces a series of favorable metabolic changes in mice fed a high-fat diet. PMID:25751639

  17. Insulin sensitivity following agent orange exposure in Vietnam veterans with high blood levels of 2,3,7,8-tetrachlorodibenzo-p-dioxin.

    PubMed

    Kern, Philip A; Said, Sufyan; Jackson, William G; Michalek, Joel E

    2004-09-01

    Our objective was to determine whether insulin sensitivity was related to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in Vietnam veterans exposed to Agent Orange. Air Force veterans of Operation Ranch Hand, the unit responsible for spraying Agent Orange and other herbicides in Vietnam from 1962 to 1971, and comparison veterans who did not spray herbicides were included. We measured insulin sensitivity (S(I)) using a frequently sampled iv glucose tolerance test in a matched study of 29 matched pairs of veterans and a quantitative insulin sensitivity check index (QUICKI) based on fasting glucose and insulin in 71 matched pairs. No group differences were found with regard to the mean values of S(I), QUICKI, TNFalpha, adiponectin, and two measures of insulin secretion. However, S(I) and QUICKI decreased significantly with regard to TCDD (P = 0.01 and 0.02). A corresponding pattern (although not significant) was found for blood levels of TNFalpha and adiponectin. These data suggest that high blood TCDD levels may promote an insulin-resistant state, but the magnitude of this effect appeared to be small, such that an 18-fold increase in blood TCDD due to increased exposure resulted in only a 10% change in S(I) in the 29 matched pairs. PMID:15356078

  18. Acupoint-specific, frequency-dependent, and improved insulin sensitivity hypoglycemic effect of electroacupuncture applied to drug-combined therapy studied by a randomized control clinical trial.

    PubMed

    Lin, Rong-Tsung; Tzeng, Chung-Yuh; Lee, Yu-Chen; Chen, Ying-I; Hsu, Tai-Hao; Lin, Jaung-Geng; Chang, Shih-Liang

    2014-01-01

    The application of electroacupuncture (EA) to specific acupoints can induce a hypoglycemic effect in streptozotocin-induced rats, normal rats, and rats with steroid-induced insulin resistance. EA combined with the oral insulin sensitizer rosiglitazone improved insulin sensitivity in rats and humans with type II diabetes mellitus (DM). There are different hypoglycemic mechanisms between Zhongwan and Zusanli acupoints by EA stimulation. On low-frequency (2 Hz) stimulation at bilateral Zusanli acupoints, serotonin was involved in the hypoglycemic effect in normal rats. Moreover, after 15 Hz EA stimulation at the bilateral Zusanli acupoints, although enhanced insulin activity mainly acts on the insulin-sensitive target organs, the muscles must be considered. In addition, 15 Hz EA stimulation at the bilateral Zusanli acupoints has the combined effect of enhancing cholinergic nerve activity and increasing nitric oxide synthase (NOS) activity to enhance insulin activity. Despite the well-documented effect of pain control by EA in many systemic diseases, there are few high-quality long-term clinical trials on the hypoglycemic effect of EA in DM. Combination treatment with EA and other medications seems to be an alternative treatment to achieve better therapeutic goals that merit future investigation. PMID:25024728

  19. Osteocalcin reverses endoplasmic reticulum stress and improves impaired insulin sensitivity secondary to diet-induced obesity through nuclear factor-κB signaling pathway.

    PubMed

    Zhou, Bo; Li, Huixia; Xu, Lin; Zang, Weijin; Wu, Shufang; Sun, Hongzhi

    2013-03-01

    Osteocalcin, a synthetic osteoblast-specific protein, has recently emerged as an important regulator of energy metabolism, but the underlying mechanisms are not fully understood. In the present study, mice fed a high-fat diet and receiving osteocalcin showed reduced body weight gain, less fat pad gain, and improved insulin sensitivity as well as increased energy expenditure compared with mice fed a high-fat diet and receiving vehicle. Meanwhile, increased endoplasmic reticulum (ER) stress, defective insulin signaling, and mitochondrial dysfunction induced by obesity were also effectively alleviated by treatment with osteocalcin. Consistent with these findings, the addition of osteocalcin to the culture medium of 3T3-L1 adipocytes, Fao liver cells, and L6 muscle cells markedly reduced ER stress and restored insulin sensitivity. These effects were nullified by blockade of nuclear factor-κB (NF-κB) or phosphatidylinositol 3-kinase but not by U0126, a mitogen-activated protein kinase inhibitor, indicating the causative role of phosphatidylinositol 3-kinase/NF-κB in action of osteocalcin. In addition, the reversal effects of osteocalcin in cells deficient in X-box-binding protein-1, a transcription factor that modulates ER stress response, further confirmed its protective role against ER stress and insulin resistance. Our findings suggest that osteocalcin attenuates ER stress and rescues impaired insulin sensitivity in insulin resistance via the NF-κB signaling pathway, which may offer novel opportunities for treatment of obesity and diabetes. PMID:23407450

  20. Impact of hypovitaminosis D on clinical, hormonal and insulin sensitivity parameters in normal body mass index polycystic ovary syndrome women.

    PubMed

    Ganie, Mohd Ashraf; Marwaha, Raman Kumar; Nisar, Sobia; Farooqi, Khalid Jamal; Jan, Rafi Ahmed; Wani, Saleem Ahmed; Gojwari, Tariq; Shah, Zaffar Amin

    2016-05-01

    Earlier data on the relationship of 25 hydroxyvitamins (25OHD) levels with various components of polycystic ovary syndrome (PCOS) has been conflicting. We studied 122 normal body mass index (BMI) women with PCOS (cases) and 46 age and BMI-matched healthy women (controls) and assessed the impact of serum 25OHD levels on clinical, biochemical and insulin sensitivity parameters in these lean Indian women with PCOS. The mean age and BMI of the cases and controls were comparable. Mean serum 25OHD levels respectively were 10.1 ± 9.9 and 7.9 ± 6.8 ng/ml with 87.7% and 91.1% vitamin D (VD) deficient. No significant correlation was noted between 25OHD levels and clinical, biochemical and insulin sensitivity parameters except with the total testosterone levels (p = 0.007). Also, no significant difference in these parameters was observed once the PCOS women were stratified into various subgroups based on the serum 25OHD levels. We conclude that VD deficiency being common in normal BMI Indian women with or without PCOS does not seem to alter the metabolic phenotype in these women. PMID:26772667

  1. Improvement of Insulin Sensitivity by Isoenergy High Carbohydrate Traditional Asian Diet: A Randomized Controlled Pilot Feasibility Study

    PubMed Central

    Hsu, William C.; Lau, Ka Hei Karen; Matsumoto, Motonobu; Moghazy, Dalia; Keenan, Hillary; King, George L.

    2014-01-01

    The prevalence of diabetes is rising dramatically among Asians, with increased consumption of the typical Western diet as one possible cause. We explored the metabolic responses in East Asian Americans (AA) and Caucasian Americans (CA) when transitioning from a traditional Asian diet (TAD) to a typical Western diet (TWD), which has not been reported before. This 16-week randomized control pilot feasibility study, included 28AA and 22CA who were at risk of developing type 2 diabetes. Eight weeks of TAD were provided to all participants, followed by 8 weeks of isoenergy TWD (intervention) or TAD (control). Anthropometric measures, lipid profile, insulin resistance and inflammatory markers were assessed. While on TAD, both AA and CA improved in insulin AUC (−960.2 µU/mL×h, P = 0.001) and reduced in weight (−1.6 kg; P<0.001), body fat (−1.7%, P<0.001) and trunk fat (−2.2%, P<0.001). Comparing changes from TAD to TWD, AA had a smaller weight gain (−1.8 to 0.3 kg, P<0.001) than CA (−1.4 to 0.9 kg, P = 0.001), but a greater increase in insulin AUC (AA: −1402.4 to 606.2 µU/mL×h, P = 0.015 vs CA: −466.0 to 223.5 µU/mL×h, P = 0.034) and homeostatic static model assessment-insulin resistance (HOMA-IR) (AA: −0.3 to 0.2, P = 0.042 vs CA: −0.1 to 0.0, P = 0.221). Despite efforts to maintain isoenergy state and consumption of similar energy, TAD induced weight loss and improved insulin sensitivity in both groups, while TWD worsened the metabolic profile. Trial Registration: ClinicalTrials.gov NCT00379548 PMID:25226279

  2. Molecular predictors of sensitivity to the insulin-like growth factor 1 receptor inhibitor Figitumumab (CP-751,871).

    PubMed

    Pavlicek, Adam; Lira, Maruja E; Lee, Nathan V; Ching, Keith A; Ye, Jingjing; Cao, Joan; Garza, Scott J; Hook, Kenneth E; Ozeck, Mark; Shi, Stephanie T; Yuan, Jing; Zheng, Xianxian; Rejto, Paul A; Kan, Julie L C; Christensen, James G

    2013-12-01

    Figitumumab (CP-751,871), a potent and fully human monoclonal anti-insulin-like growth factor 1 receptor (IGF1R) antibody, has been investigated in clinical trials of several solid tumors. To identify biomarkers of sensitivity and resistance to figitumumab, its in vitro antiproliferative activity was analyzed in a panel of 93 cancer cell lines by combining in vitro screens with extensive molecular profiling of genomic aberrations. Overall response was bimodal and the majority of cell lines were resistant to figitumumab. Nine of 15 sensitive cell lines were derived from colon cancers. Correlations between genomic characteristics of cancer cell lines with figitumumab antiproliferative activity revealed that components of the IGF pathway, including IRS2 (insulin receptor substrate 2) and IGFBP5 (IGF-binding protein 5), played a pivotal role in determining the sensitivity of tumors to single-agent figitumumab. Tissue-specific differences among the top predictive genes highlight the need for tumor-specific patient selection strategies. For the first time, we report that alteration or expression of the MYB oncogene is associated with sensitivity to IGF1R inhibitors. MYB is dysregulated in hematologic and epithelial tumors, and IGF1R inhibition may represent a novel therapeutic opportunity. Although growth inhibitory activity with single-agent figitumumab was relatively rare, nine combinations comprising figitumumab plus chemotherapeutic agents or other targeted agents exhibited properties of synergy. Inhibitors of the ERBB family were frequently synergistic and potential biomarkers of drug synergy were identified. Several biomarkers of antiproliferative activity of figitumumab both alone and in combination with other therapies may inform the design of clinical trials evaluating IGF1R inhibitors. PMID:24107449

  3. Relationships between muscle morphology and insulin sensitivity are improved after adjustment for intra-individual variability in 70-year-old men.

    PubMed

    Hedman, A; Berglund, L; Essén-Gustavsson, B; Reneland, R; Lithell, H

    2000-06-01

    The purpose of this investigation was to examine to what extent variability in the muscle morphology and insulin sensitivity influence the correlation between them. Reproducibility of muscle characteristics was estimated in duplicate biopsies from the same thigh of 23 subjects from a cohort of 70-year-old men. The coefficient of variation (CV) for different characteristics of muscle morphology was between 11 and 42% in duplicate biopsies. Coefficient of variation for markers of insulin sensitivity ranged between 12 and 39%. The variability reflected by intra-class correlation ranged from 0.23 to 0.60 for muscle morphology and from 0.68 to 0.96 for estimates of insulin sensitivity. The correlation analysis between muscle morphology and insulin resistance was performed in a sample of 515 men from the cohort, correlation coefficients were calculated with (rtrue) and without (r) adjustment for intra-individual variation. Insulin sensitivity showed a positive relationship with percentage of type I fibres (rtrue=0.33, r=0.21; P < 0.0001) and capillary density (rtrue=0.43, r=0.21; P < 0. 0001) and negative correlations with percentage of type IIB fibres (rtrue=-0.35, r=-0.24; P < 0.0001). Capillary density was inversely correlated to insulin. Thus, an obvious improvement of the correlation was seen after correcting intra-individual variation. In conclusion, owing to the low degree of reproducibility of muscle morphology variables and insulin sensitivity, implying a noticeable underestimation of correlations, the r-values should be adjusted for within-subject variation in order to demonstrate a more accurate estimate of the strength of the relationships studied. PMID:10848642

  4. Ursolic acid and rosiglitazone combination improves insulin sensitivity by increasing the skeletal muscle insulin-stimulated IRS-1 tyrosine phosphorylation in high-fat diet-fed C57BL/6J mice.

    PubMed

    Sundaresan, Arjunan; Radhiga, Thangaiyan; Pugalendi, Kodukkur Viswanathan

    2016-06-01

    The aim of this present study was to investigate the effect of ursolic acid (UA) and rosiglitazone (RSG) on insulin sensitivity and proximal insulin signaling pathways in high-fat diet (HFD)-fed C57/BL/6J mice. Male C57BL/6J mice were fed either normal diet or HFD for 10 weeks, after which animals in each dietary group were divided into the following six groups (normal diet, normal diet plus UA and RSG, HFD alone, HFD plus UA, HFD plus RSG, and HFD plus UA and RSG) for the next 5 weeks. UA (5 mg/kg BW) and RSG (4 mg/kg BW) were administered as suspensions directly into the stomach using a gastric tube. The HFD diet elevated fasting plasma glucose, insulin, and homeostasis model assessment index. The expression of insulin receptor substrate (IRS)-1, phosphoinositide 3-kinase (PI3-kinase), Akt, and glucose transporter (GLUT) 4 were determined by Western blot analyses. The results demonstrated that combination treatment (UA/RSG) ameliorated HFD-induced glucose intolerance and insulin resistance by improving the homeostatic model assessment (HOMA) index. Further, combination treatment (UA/RSG) stimulated the IRS-1, PI3-kinase, Akt, and GLUT 4 translocation. These results strongly suggest that combination treatment (UA/RSG) activates IRS-PI3-kinase-Akt-dependent signaling pathways to induce GLUT 4 translocation and increases the expression of insulin receptor to improve glucose intolerance. PMID:27090933

  5. Green tea extract decreases oxidative stress and improves insulin sensitivity in an animal model of insulin resistance, the fructose- fed rat

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Metabolic syndrome is characterized by insulin resistance, dyslipidemia, and increased oxidative stress. Tea polyphenols, as both insulin potentiating factors and antioxidants, might act in preventing the metabolic syndrome. We aimed to determine the effects of green tea extract consumption on oxida...

  6. Do We Know Who Will Drop out?: A Review of the Predictors of Dropping out of High School--Precision, Sensitivity, and Specificity

    ERIC Educational Resources Information Center

    Bowers, Alex J.; Sprott, Ryan; Taff, Sherry A.

    2013-01-01

    The purpose of this study is to review the literature on the most accurate indicators of students at risk of dropping out of high school. We used Relative Operating Characteristic (ROC) analysis to compare the sensitivity and specificity of 110 dropout flags across 36 studies. Our results indicate that 1) ROC analysis provides a means to compare…

  7. Long-chain omega-3 fatty acids regulate bovine whole-body protein metabolism by promoting muscle insulin signalling to the Akt-mTOR-S6K1 pathway and insulin sensitivity.

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The ability of the skeletal musculature to use amino acids to build or renew constitutive proteins is gradually lost with age and this is partly due to a decline in skeletal muscle insulin sensitivity. Since long-chain omega-3 polyunsaturated fatty acids (LC"n"-3PUFA) from fish oil are known to impr...

  8. Resistin, visfatin and insulin sensitivity in selected phases of annual training cycle of triathletes.

    PubMed

    Sliwicka, Ewa; Pilaczyńska-Szcześniak, L; Nowak, A; Zieliński, J

    2012-03-01

    The purpose of the study was to examine the effects of sport training on carbohydrate metabolic indices and adipokines concentrations in young male triathletes (n=10). Athletes performed the incremental running test in two periods of the training cycle: in the transitory and preparatory phases. In both analyzed terms, physical exercise was reflected by a significant increase in lactate (p≤0.01), insulin (p≤0.01), visfatin concentrations (p≤0.01, p<0.05, respectively) and only during transitory phase in glucose (p≤0.01) and resistin concentrations (p<0.05). Significant inter-period differences were noted in the pre-exercise insulin (p≤0.01) and also in pre- and post-exercise visfatin concentrations (p<0.05). Additionally, the differences (Δ) between post- and pre-exercise values of glucose (p<0.05) and visfatin (p≤0.01) significantly decreased in the preparatory phase comparing to the transitory phase. The inverse correlations between pre-exercise concentrations of visfatin and peak oxygen uptake (p<0.05) in the transitory phase and between post- and pre-exercise differences (Δ) of visfatin and lactate concentrations (p<0.05) in the preparatory phase were noted. During preparatory phase, pre-exercise visfatin concentrations inversely correlated with pre-exercise resistin, insulin and glucose levels (p<0.05). In conclusion, systematic training in elite triathletes modulates basal adipokine concentrations only to a small extent, however, influences on these molecules response on the acute exercise. PMID:22425808

  9. Insulin sensitivity and glucose effectiveness from three minimal models: effects of energy restriction and body fat in adult male rhesus monkeys.

    PubMed

    Gresl, Theresa A; Colman, Ricki J; Havighurst, Thomas C; Byerley, Lauri O; Allison, David B; Schoeller, Dale A; Kemnitz, Joseph W

    2003-12-01

    The minimal model of glucose disappearance (MINMOD version 3; MM3) and both the one-compartment (1CMM) and the two-compartment (2CMM) minimal models were used to analyze stable isotope-labeled intravenous glucose tolerance test (IVGTT) data from year 10 of a study of the effect of dietary restriction (DR) in male rhesus monkeys. Adult monkeys were energy restricted (R; n = 12) on a semipurified diet to approximately 70% of control (C) intake (ad libitum-fed monkeys; n = 12). Under ketamine anesthesia, fasting insulin levels were greater among C monkeys. Insulin sensitivity estimates from all models were greater in R than C monkeys, whereas glucose effectiveness estimates were not consistently greater in R monkeys. Fasting plasma glucose as well as hepatic glucose production and clearance rates did not differ between groups. Body fat, in part, statistically mediated the effect of DR to enhance insulin sensitivity indexes. Precision of estimation and intermodel relationships among insulin sensitivity and glucose effectiveness estimates were in the ranges of those reported previously for humans and dogs, suggesting that the models may provide valid estimates for rhesus monkeys as well. The observed insulin sensitivity indexes from all models, elevated among R vs. C monkeys, may be explained, at least in part, by the difference in body fat content between these groups after chronic DR. PMID:12842866

  10. Beneficial role of vitamin K supplementation on insulin sensitivity, glucose metabolism, and the reduced risk of type 2 diabetes: A review.

    PubMed

    Manna, Prasenjit; Kalita, Jatin

    2016-01-01

    Micronutrients are gaining acceptance as an important nutritional therapy for the prevention and/or management of diabetes and its associated health risks. Although a very small quantity of micronutrients are required for specific functions in our bodies, moderate deficiencies can lead to serious health issues. Impaired insulin sensitivity and glucose intolerance play a major role in the development of diabetic pathophysiology. Vitamin K is well known for its function in blood coagulation. Moreover, several human studies reported the beneficial role of vitamin K supplementation in improving insulin sensitivity and glucose tolerance, preventing insulin resistance, and reducing the risk of type 2 diabetes (T2 D). Both animal and human studies have suggested that vitamin K-dependent protein (osteocalcin [OC]), regulation of adipokine levels, antiinflammatory properties, and lipid-lowering effects may mediate the beneficial function of vitamin K in insulin sensitivity and glucose tolerance. This review for the first time provides an overview of the currently available preclinical and clinical evidences on the effect of vitamin K supplementation in the management of insulin sensitivity and glucose tolerance. The outcome of this review will increase understanding for the development of a novel adjuvant therapy to achieve better control of glycemia and improve the lives of diabetic patients. PMID:27133809

  11. The Prostaglandin E2 Receptor EP4 Regulates Obesity-Related Inflammation and Insulin Sensitivity

    PubMed Central

    Yasui, Mika; Tamura, Yukinori; Minami, Manabu; Higuchi, Sei; Fujikawa, Risako; Ikedo, Taichi; Nagata, Manabu; Arai, Hidenori; Murayama, Toshinori; Yokode, Masayuki

    2015-01-01

    With increasing body weight, macrophages accumulate in adipose tissue. There, activated macrophages secrete numerous proinflammatory cytokines and chemokines, giving rise to chronic inflammation and insulin resistance. Prostaglandin E2 suppresses macrophage activation via EP4; however, the role of EP4 signaling in insulin resistance and type 2 diabetes mellitus remains unknown. In this study, we treated db/db mice with an EP4-selective agonist, ONO-AE1-329, for 4 weeks to explore the role of EP4 signaling in obesity-related inflammation in vivo. Administration of the EP4 agonist did not affect body weight gain or food intake; however, in the EP4 agonist–treated group, glucose tolerance and insulin resistance were significantly improved over that of the vehicle–treated group. Additionally, administration of the EP4 agonist inhibited the accumulation of F4/80-positive macrophages and the formation of crown-like structures in white adipose tissue, and the adipocytes were significantly smaller. The treatment of the EP4 agonist increased the number of anti-inflammatory M2 macrophages, and in the stromal vascular fraction of white adipose tissue, which includes macrophages, it markedly decreased the levels of proinflammatory cytokines and chemokines. Further, EP4 activation increased the expression of adiponectin and peroxidase proliferator–activated receptors in white adipose tissue. Next, we examined in vitro M1/M2 polarization assay to investigate the impact of EP4 signaling on determining the functional phenotypes of macrophages. Treatment with EP4 agonist enhanced M2 polarization in wild-type peritoneal macrophages, whereas EP4-deficient macrophages were less susceptible to M2 polarization. Notably, antagonizing peroxidase proliferator–activated receptor δ activity suppressed EP4 signaling-mediated shift toward M2 macrophage polarization. Thus, our results demonstrate that EP4 signaling plays a critical role in obesity-related adipose tissue inflammation

  12. Natural supplements for improving insulin sensitivity and glucose uptake in skeletal muscle.

    PubMed

    Kouzi, Samir A; Yang, Sendra; Nuzum, Donald S; Dirks-Naylor, Amie J

    2015-01-01

    Type 2 diabetes is a common metabolic disorder characterized by resistance to the actions of insulin to stimulate skeletal muscle glucose disposal. In light of the staggering financial/human cost of type 2 diabetes, there is considerable need for safe and effective agents that can be used to prevent and/or adjunctively treat the disease. Available evidence suggests that a number of natural supplements, including cinnamon, biotin, fenugreek, ginseng, banaba, and alpha-lipoic acid, have the potential to reduce the risk for type 2 diabetes in the large at-risk population. The evidence also suggests that, when used adjunctively, these natural products are likely to help clinicians achieve optimal glycemic control, improve long-term prognosis, and/or minimize the need for insulin therapy in type 2 diabetics. More research, particularly well-designed, long-term human clinical trials, is certainly needed to accurately define the value and place of these supplements in diabetes prevention and management. PMID:25553366

  13. Distinct growth hormone receptor signaling modes regulate skeletal muscle development and insulin sensitivity in mice

    PubMed Central

    Mavalli, Mahendra D.; DiGirolamo, Douglas J.; Fan, Yong; Riddle, Ryan C.; Campbell, Kenneth S.; van Groen, Thomas; Frank, Stuart J.; Sperling, Mark A.; Esser, Karyn A.; Bamman, Marcas M.; Clemens, Thomas L.

    2010-01-01

    Skeletal muscle development, nutrient uptake, and nutrient utilization is largely coordinated by growth hormone (GH) and its downstream effectors, in particular, IGF-1. However, it is not clear which effects of GH on skeletal muscle are direct and which are secondary to GH-induced IGF-1 expression. Thus, we generated mice lacking either GH receptor (GHR) or IGF-1 receptor (IGF-1R) specifically in skeletal muscle. Both exhibited impaired skeletal muscle development characterized by reductions in myofiber number and area as well as accompanying deficiencies in functional performance. Defective skeletal muscle development, in both GHR and IGF-1R mutants, was attributable to diminished myoblast fusion and associated with compromised nuclear factor of activated T cells import and activity. Strikingly, mice lacking GHR developed metabolic features that were not observed in the IGF-1R mutants, including marked peripheral adiposity, insulin resistance, and glucose intolerance. Insulin resistance in GHR-deficient myotubes derived from reduced IR protein abundance and increased inhibitory phosphorylation of IRS-1 on Ser 1101. These results identify distinct signaling pathways through which GHR regulates skeletal muscle development and modulates nutrient metabolism. PMID:20921627

  14. High Protein Intake Improves Insulin Sensitivity but Exacerbates Bone Resorption in Immobility (WISE Study)

    NASA Technical Reports Server (NTRS)

    Heer, Martina; Smith, Scott M.; Frings-Meuthen, Petra; Zwart, Sara R.; Baecker, Natalie

    2012-01-01

    Inactivity, like bed rest (BR), causes insulin resistance (IR) and bone loss even in healthy subjects. High protein intake seems to mitigate this IR but might exacerbate bone loss. We hypothesized that high protein intake (animal:vegetable protein ratio: 60:40), isocaloric, compared to the control group plus high potassium intake would prevent IR without affecting bone turnover. After a 20-day ambulatory adaptation to controlled confinement and diet, 16 women participated in a 60-day, 6 deg head-down-tilt BR and were assigned randomly to one of the two groups. Control subjects (CON, n=8) received 1g/kg body mass/d dietary protein. Nutrition subjects (NUT, n=8) received 1.45g/kg body mass/d dietary protein plus 7.2g branched chain amino acids per day during BR. All subjects received 1670 kcal/d. Bed rest decreased glucose disposal by 35% (p<0.05) in CON. Isocaloric high protein intake prevented insulin resistance, but exacerbated bed rest induced increase in bone resorption markers C-telopeptide (> 30%) and Ntelopeptide (>20%) (both: p<0.001). Bone formation markers were unaffected by high protein intake. We conclude from these results that high protein intake might positively affect glucose tolerance, but might also foster bone loss. Further long-duration studies are mandatory before high protein intake for diabetic patients, who have an increased fracture risk, might be recommended.

  15. Muscle insulin sensitivity and glucose metabolism are controlled by the intrinsic muscle clock★

    PubMed Central

    Dyar, Kenneth A.; Ciciliot, Stefano; Wright, Lauren E.; Biensø, Rasmus S.; Tagliazucchi, Guidantonio M.; Patel, Vishal R.; Forcato, Mattia; Paz, Marcia I.P.; Gudiksen, Anders; Solagna, Francesca; Albiero, Mattia; Moretti, Irene; Eckel-Mahan, Kristin L.; Baldi, Pierre; Sassone-Corsi, Paolo; Rizzuto, Rosario; Bicciato, Silvio; Pilegaard, Henriette; Blaauw, Bert; Schiaffino, Stefano

    2013-01-01

    Circadian rhythms control metabolism and energy homeostasis, but the role of the skeletal muscle clock has never been explored. We generated conditional and inducible mouse lines with muscle-specific ablation of the core clock gene Bmal1. Skeletal muscles from these mice showed impaired insulin-stimulated glucose uptake with reduced protein levels of GLUT4, the insulin-dependent glucose transporter, and TBC1D1, a Rab-GTPase involved in GLUT4 translocation. Pyruvate dehydrogenase (PDH) activity was also reduced due to altered expression of circadian genes Pdk4 and Pdp1, coding for PDH kinase and phosphatase, respectively. PDH inhibition leads to reduced glucose oxidation and diversion of glycolytic intermediates to alternative metabolic pathways, as revealed by metabolome analysis. The impaired glucose metabolism induced by muscle-specific Bmal1 knockout suggests that a major physiological role of the muscle clock is to prepare for the transition from the rest/fasting phase to the active/feeding phase, when glucose becomes the predominant fuel for skeletal muscle. PMID:24567902

  16. Synthesis and evaluation of temperature- and glucose-sensitive nanoparticles based on phenylboronic acid and N-vinylcaprolactam for insulin delivery.

    PubMed

    Wu, Jun-Zi; Bremner, David H; Li, He-Yu; Sun, Xiao-Zhu; Zhu, Li-Min

    2016-12-01

    Poly N-vinylcaprolactam-co-acrylamidophenylboronic acid p(NVCL-co-AAPBA) was prepared from N-vinylcaprolactam (NVCL) and 3-acrylamidophenylboronic acid (AAPBA), using 2,2-azobisisobutyronitrile (AIBN) as initiator. The synthesis and structure of the polymer were examined by Fourier Transform infrared spectroscopy (FT-IR) and (1)H-NMR. Dynamic light scattering (DLS), lower critical solution temperature (LCST) and transmission electron microscopy (TEM) were utilized to characterize the nanoparticles, CD spectroscopy was used to determine if there were any changes to the conformation of the insulin, and cell and animal toxicity were also investigated. The prepared nanoparticles were found to be monodisperse submicron particles and were glucose- and temperature-sensitive. In addition, the nanoparticles have good insulin-loading characteristics, do not affect the conformation of the insulin and show low-toxicity to cells and animals. These p(NVCL-co-AAPBA) nanoparticles may have some value for insulin or other hypoglycemic protein delivery. PMID:27612799

  17. Hepatocyte NADPH Oxidase 4 Regulates Stress Signaling, Fibrosis, and Insulin Sensitivity During Development of Steatohepatitis in Mice

    PubMed Central

    Bettaieb, Ahmed; Jiang, Joy X.; Sasaki, Yu; Chao, Tzu-I; Kiss, Zsofia; Chen, Xiangling; Tian, Jijing; Katsuyama, Masato; Yabe-Nishimura, Chihiro; Xi, Yannan; Szyndralewiez, Cedric; Schröder, Kathrin; Shah, Ajay; Brandes, Ralph P.; Haj, Fawaz G.; Török, Natalie J.

    2015-01-01

    Background & Aims Reactive oxidative species (ROS) are believed to be involved in the progression of non-alcoholic steatohepatitis (NASH). However, little is known about the sources of ROS in hepatocytes or their role in disease progression. We studied the effects of NADPH oxidase 4 (NOX4) in liver tissues from patients with NASH and mice with steatohepatitis. Methods Liver biopsy samples were obtained from 5 patients with NASH, as well as 4 patients with simple steatosis and 5 patients without steatosis (controls) from the University of California, Davis Cancer Center Biorepository. Mice with hepatocyte-specific deletion of NOX4 (NOX4hepKO) and NOX4floxp+/+ C57BL/6 mice (controls) were given fast food diets (supplemented with high-fructose corn syrup) or choline-deficient L-amino acid-defined to induce steatohepatitis, or control diets, for 20 weeks. A separate group of mice were given the NOX4 inhibitor (GKT137831). Liver tissues were collected and immunoblot analyses were performed determine levels of NOX4, markers of inflammation and fibrosis, double-stranded RNA-activated protein kinase (PKR), and phospho-eIF-2alpha kinase (PERK)-mediated stress signaling pathways. We performed hyperinsulinemic-euglycemic clamp studies and immunoprecipitation analyses to determine the oxidation and phosphatase activity of PP1C. Results Levels of NOX4 were increased in patients with NASH, compared with controls. Hepatocyte-specific deletion of NOX4 reduced oxidative stress, lipid peroxidation, and liver fibrosis in mice with diet-induced steatohepatitis. A small molecule inhibitor of NOX4 reduced liver inflammation and fibrosis and increased insulin sensitivity in mice with diet-induced steatohepatitis. In primary hepatocytes, NOX4 reduced the activity of the phosphatase PP1C, prolonging activation of PKR and PERK-mediated stress signaling. Mice with hepatocyte-specific deletion of NOX4 and mice given GKT137831had increased insulin sensitivity. Conclusion NOX4 regulates

  18. Energy deficit after exercise augments lipid mobilization but does not contribute to the exercise-induced increase in insulin sensitivity

    PubMed Central

    Newsom, Sean A.; Schenk, Simon; Thomas, Kristin M.; Harber, Matthew P.; Knuth, Nicolas D.; Goldenberg, Naila

    2010-01-01

    The content of meals consumed after exercise can impact metabolic responses for hours and even days after the exercise session. The purpose of this study was to compare the effect of low dietary carbohydrate (CHO) vs. low energy intake in meals after exercise on insulin sensitivity and lipid metabolism the next day. Nine healthy men participated in four randomized trials. During the control trial (CON) subjects remained sedentary. During the other three trials, subjects exercised [65% peak oxygen consumption (V̇o2peak); cycle ergometer and treadmill exercise] until they expended ∼800 kcal. Dietary intake during CON and one exercise trial (BAL) was designed to provide sufficient energy and carbohydrate to maintain nutrient balance. In contrast, the diets after the other two exercise trials were low in either CHO (LOW-CHO) or energy (LOW-EN). The morning after exercise we obtained a muscle biopsy, assessed insulin sensitivity (Si; intravenous glucose tolerance test) and measured lipid kinetics (isotope tracers). Although subjects were in energy balance during both LOW-CHO and CON, the lower muscle glycogen concentration during LOW-CHO vs. CON (402 ± 29 vs. 540 ± 33 mmol/kg dry wt, P < 0.01) coincided with a significant increase in Si [5.2 ± 0.7 vs. 3.8 ± 0.7 (mU/l)−1·min−1; P < 0.05]. Conversely, despite ingesting several hundred fewer kilocalories after exercise during LOW-EN compared with BAL, this energy deficit did not affect Si the next day [4.9 ± 0.9, and 5.0 ± 0.8 (mU/l)−1·min−1]. Maintaining an energy deficit after exercise had the most potent effect on lipid metabolism, as measured by a higher plasma triacylglycerol concentration, and increased plasma fatty acid mobilization and oxidation compared with when in nutrient balance. Carbohydrate deficit after exercise, but not energy deficit, contributed to the insulin-sensitizing effects of acute aerobic exercise, whereas maintaining an energy deficit after exercise augmented lipid

  19. Aerobic exercise training improves insulin sensitivity without changes in body weight, body fat, adiponectin, and inflammatory markers in overweight and obese girls.

    PubMed

    Nassis, George P; Papantakou, Katerina; Skenderi, Katerina; Triandafillopoulou, Maria; Kavouras, Stavros A; Yannakoulia, Mary; Chrousos, George P; Sidossis, Labros S

    2005-11-01

    The aim of this study was to examine the effect of aerobic exercise training on insulin sensitivity in overweight and obese girls. Nineteen overweight and obese girls (mean +/- SD: age, 13.1+/-1.8 years; body mass index, 26.8+/-3.9 kg/m(2)) volunteered for this study. Body composition (dual-energy x-ray absorptiometry), insulin sensitivity (oral glucose tolerance test and homeostasis model assessment estimate of insulin resistance; n=15), adiponectin, C-reactive protein (CRP), interleukin (IL) 6, insulin-like growth factor-1, soluble intercellular adhesion molecule-1 and soluble vascular cell adhesion molecule-1 serum levels, and blood lipids and lipoproteins were assessed before and after 12 weeks of aerobic training. Cardiorespiratory fitness increased by 18.8% (P<.05) as a result of training. The area under the insulin concentration curve (insulin area under the curve) decreased by 23.3% (12781.7+/-7454.2 vs 9799.0+/-4918.6 microU.min/mL before and after intervention, respectively; P=.03). Insulin sensitivity was improved without changes in body weight (pre-intervention, 67.9+/-14.5 kg; post-intervention, 68.3+/-14.0 kg) or percent body fat (pre-intervention, 41.4% +/- 4.8%; post-intervention, 40.7%+/-5.2%). The lower limb fat-free mass increased by 6.2% (P<.01) as a result of training, and changes in lower limb fat-free mass were correlated with changes in the insulin area under the curve (r= -.68; P< .01). Serum adiponectin, IL-6, and CRP concentrations did not change (pre-intervention vs post-intervention: adiponectin, 9.57+/-3.01 vs 9.08+/-2.32 microg/mL; IL-6, 1.67+/-1.29 vs 1.65+/-1.25 pg/mL, CRP, 3.21+/-2.48 vs 2.73+/-1.88 mg/L) whereas insulin-like growth factor-1 was lower after training (pre-intervention, 453.8 +/- 159.3 ng/mL; post-intervention, 403.2+/- 155.1 ng/mL; P<.05). In conclusion, 12 weeks of aerobic training improved insulin sensitivity in overweight and obese girls without change in body weight, percent body fat, and circulating

  20. Acetyl-CoA carboxylase inhibition by ND-630 reduces hepatic steatosis, improves insulin sensitivity, and modulates dyslipidemia in rats

    PubMed Central

    Harriman, Geraldine; Greenwood, Jeremy; Bhat, Sathesh; Huang, Xinyi; Wang, Ruiying; Paul, Debamita; Tong, Liang; Saha, Asish K.; Westlin, William F.; Kapeller, Rosana; Harwood, H. James

    2016-01-01

    Simultaneous inhibition of the acetyl-CoA carboxylase (ACC) isozymes ACC1 and ACC2 results in concomitant inhibition of fatty acid synthesis and stimulation of fatty acid oxidation and may favorably affect the morbidity and mortality associated with obesity, diabetes, and fatty liver disease. Using structure-based drug design, we have identified a series of potent allosteric protein–protein interaction inhibitors, exemplified by ND-630, that interact within the ACC phosphopeptide acceptor and dimerization site to prevent dimerization and inhibit the enzymatic activity of both ACC isozymes, reduce fatty acid synthesis and stimulate fatty acid oxidation in cultured cells and in animals, and exhibit favorable drug-like properties. When administered chronically to rats with diet-induced obesity, ND-630 reduces hepatic steatosis, improves insulin sensitivity, reduces weight gain without affecting food intake, and favorably affects dyslipidemia. When administered chronically to Zucker diabetic fatty rats, ND-630 reduces hepatic steatosis, improves glucose-stimulated insulin secretion, and reduces hemoglobin A1c (0.9% reduction). Together, these data suggest that ACC inhibition by representatives of this series may be useful in treating a variety of metabolic disorders, including metabolic syndrome, type 2 diabetes mellitus, and fatty liver disease. PMID:26976583

  1. Insulin-sensitizing and beneficial lipid-metabolic effects of the water-soluble melanin complex extracted from Inonotus obliquus.

    PubMed

    Lee, Jung-Han; Hyun, Chang-Kee

    2014-09-01

    Inonotus obliquus has been traditionally used for treatment of metabolic diseases; however, the mechanism remains to be elucidated. In this study, we found that the water-soluble melanin complex extracted from I. obliquus improved insulin sensitivity and reduced adiposity in high fat (HF)-fed obese mice. When the melanin complex was treated to 3T3-L1 adipocytes, insulin-stimulated glucose uptake was increased significantly, and its phosphoinositide 3-kinase-dependent action was proven with wortmannin treatment. Additionally, dose-dependent increases in Akt phosphorylation and glucose transporter 4 translocation into the plasma membrane were observed in melanin complex-treated cells. Adiponectin gene expression in 3T3-L1 cells incubated with melanin complex increased which was corroborated by increased AMP-activated protein kinase phosphorylation in HepG2 and C2C12 cells treated with conditioned media from the 3T3-L1 culture. Melanin complex-treated 3T3-L1 cells showed no significant change in expression of several lipogenic genes, whereas enhanced expressions of fatty acid oxidative genes were observed. Similarly, the epididymal adipose tissue of melanin complex-treated HF-fed mice had higher expression of fatty acid oxidative genes without significant change in lipogenic gene expression. Together, these results suggest that the water-soluble melanin complex of I. obliquus exerts antihyperglycemic and beneficial lipid-metabolic effects, making it a candidate for promising antidiabetic agent. PMID:24615848

  2. Antioxidant treatment normalizes mitochondrial energetics and myocardial insulin sensitivity independently of changes in systemic metabolic homeostasis in a mouse model of the metabolic syndrome.

    PubMed

    Ilkun, Olesya; Wilde, Nicole; Tuinei, Joseph; Pires, Karla M P; Zhu, Yi; Bugger, Heiko; Soto, Jamie; Wayment, Benjamin; Olsen, Curtis; Litwin, Sheldon E; Abel, E Dale

    2015-08-01

    Cardiac dysfunction in obesity is associated with mitochondrial dysfunction, oxidative stress and altered insulin sensitivity. Whether oxidative stress directly contributes to myocardial insulin resistance remains to be determined. This study tested the hypothesis that ROS scavenging will improve mitochondrial function and insulin sensitivity in the hearts of rodent models with varying degrees of insulin resistance and hyperglycemia. The catalytic antioxidant MnTBAP was administered to the uncoupling protein-diphtheria toxin A (UCP-DTA) mouse model of insulin resistance (IR) and obesity, at early and late time points in the evolution of IR, and to db/db