scholarly journals Overexpression of the ped/pea-15 Gene Causes Diabetes by Impairing Glucose-Stimulated Insulin Secretion in Addition to Insulin Action

2004 ◽  
Vol 24 (11) ◽  
pp. 5005-5015 ◽  
Author(s):  
Giovanni Vigliotta ◽  
Claudia Miele ◽  
Stefania Santopietro ◽  
Giuseppe Portella ◽  
Anna Perfetti ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Secretion ◽  
Protein Kinase ◽  
Transgenic Mice ◽  
Insulin Action ◽  
Glucose Levels ◽  
Beta Cell Line ◽  
Protein Kinase Cα ◽  
Glucose Stimulated Insulin Secretion

ABSTRACT Overexpression of the ped/pea-15 gene is a common feature of type 2 diabetes. In the present work, we show that transgenic mice ubiquitously overexpressing ped/pea-15 exhibited mildly elevated random-fed blood glucose levels and decreased glucose tolerance. Treatment with a 60% fat diet led ped/pea-15 transgenic mice to develop diabetes. Consistent with insulin resistance in these mice, insulin administration reduced glucose levels by only 35% after 45 min, compared to 70% in control mice. In vivo, insulin-stimulated glucose uptake was decreased by almost 50% in fat and muscle tissues of the ped/pea-15 transgenic mice, accompanied by protein kinase Cα activation and block of insulin induction of protein kinase Cζ. These changes persisted in isolated adipocytes from the transgenic mice and were rescued by the protein kinase C inhibitor bisindolylmaleimide. In addition to insulin resistance, ped/pea-15 transgenic mice showed a 70% reduction in insulin response to glucose loading. Stable overexpression of ped/pea-15 in the glucose-responsive MIN6 beta-cell line also caused protein kinase Cα activation and a marked decline in glucose-stimulated insulin secretion. Antisense block of endogenous ped/pea-15 increased glucose sensitivity by 2.5-fold in these cells. Thus, in vivo, overexpression of ped/pea-15 may lead to diabetes by impairing insulin secretion in addition to insulin action.

PPARα activation reverses adverse effects induced by high-saturated-fat feeding on pancreatic β-cell function in late pregnancy

2007 ◽  
Vol 292 (4) ◽  
pp. E1087-E1094 ◽  
Author(s):  
Mark J. Holness ◽  
Nicholas D. Smith ◽  
Gemma K. Greenwood ◽  
Mary C. Sugden
Keyword(s):  
Insulin Resistance ◽  
Insulin Secretion ◽  
Insulin Action ◽  
Saturated Fat ◽  
Late Pregnancy ◽  
Islet Function ◽  
Perifused Islets ◽  
Fat Feeding ◽  
Long Chain

We examined whether the additional demand for insulin secretion imposed by dietary saturated fat-induced insulin resistance during pregnancy is accommodated at late pregnancy, already characterized by insulin resistance. We also assessed whether effects of dietary saturated fat are influenced by PPARα activation or substitution of 7% of dietary fatty acids (FAs) with long-chain ω-3 FA, manipulations that improve insulin action in the nonpregnant state. Glucose tolerance at day 19 of pregnancy in the rat was impaired by high-saturated-fat feeding throughout pregnancy. Despite modestly enhanced glucose-stimulated insulin secretion (GSIS) in vivo, islet perifusions revealed an increased glucose threshold and decreased glucose responsiveness of GSIS in the saturated-fat-fed pregnant group. Thus, insulin resistance evoked by dietary saturated fat is partially countered by augmented insulin secretion, but compensation is compromised by impaired islet function. Substitution of 7% of saturated FA with long-chain ω-3 FA suppressed GSIS in vivo but did not modify the effect of saturated-fat feeding to impair GSIS by perifused islets. PPARα activation (24 h) rescued impaired islet function that was identified using perifused islets, but GSIS in vivo was suppressed such that glucose tolerance was not improved, suggesting modification of the feedback loop between insulin action and secretion.

scholarly journals Cellular Mechanisms by Which FGF21 Improves Insulin Sensitivity in Male Mice

Endocrinology ◽  
2013 ◽  
Vol 154 (9) ◽  
pp. 3099-3109 ◽  
Author(s):  
João Paulo G. Camporez ◽  
François R. Jornayvaz ◽  
Max C. Petersen ◽  
Dominik Pesta ◽  
Blas A. Guigni ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Insulin Sensitivity ◽  
Protein Kinase ◽  
Insulin Action ◽  
Fibroblast Growth Factor 21 ◽  
Cellular Mechanisms ◽  
Novel Therapy

Fibroblast growth factor 21 (FGF21) is a potent regulator of glucose and lipid metabolism and is currently being pursued as a therapeutic agent for insulin resistance and type 2 diabetes. However, the cellular mechanisms by which FGF21 modifies insulin action in vivo are unclear. To address this question, we assessed insulin action in regular chow– and high-fat diet (HFD)–fed wild-type mice chronically infused with FGF21 or vehicle. Here, we show that FGF21 administration results in improvements in both hepatic and peripheral insulin sensitivity in both regular chow– and HFD-fed mice. This improvement in insulin responsiveness in FGF21-treated HFD-fed mice was associated with decreased hepatocellular and myocellular diacylglycerol content and reduced protein kinase Cϵ activation in liver and protein kinase Cθ in skeletal muscle. In contrast, there were no effects of FGF21 on liver or muscle ceramide content. These effects may be attributed, in part, to increased energy expenditure in the liver and white adipose tissue. Taken together, these data provide a mechanism by which FGF21 protects mice from lipid-induced liver and muscle insulin resistance and support its development as a novel therapy for the treatment of nonalcoholic fatty liver disease, insulin resistance, and type 2 diabetes.

Evidence for defective glucose sensing by islets of fa/fa obese Zucker rats

1993 ◽  
Vol 71 (1) ◽  
pp. 34-39 ◽  
Author(s):  
Catherine B. Chan ◽  
Ruth M. MacPhail ◽  
Katherine Mitton
Keyword(s):  
Insulin Secretion ◽  
Insulin Response ◽  
Glucose Sensing ◽  
Zucker Rats ◽  
Rat Islets ◽  
Glucose Levels ◽  
Half Maximal Effective Concentration ◽  
Glucose Stimulated Insulin Secretion

The hypothesis that a defect in glucose sensing by islets of fa/fa Zucker rats contributes to hyperinsulinemia in these animals was tested. Islets from lean and fa/fa rats were isolated by collagenase digestion and step-density gradient purification and then cultured overnight in Dulbecco's modified Eagle's medium containing 12.5 mM glucose. Obese rat islets were more sensitive to hypoglycemic glucose levels with half-maximal effective concentration (EC50) of 5.6 mM compared with an EC50 of 8.2 mM for lean rat islets. In contrast, responsiveness of both phenotypes to α-ketoisocaproate and quinine was similar. Mannoheptulose did not inhibit insulin secretion from fa/fa islets, although inhibitors of later events in the stimulus–secretion coupling pathway were normally inhibited by iodoacetate and diazoxide. Finally, starvation in vivo and culture of islets in low glucose concentrations (5 mM) in vitro both decreased glucose-stimulated insulin secretion from lean but not fa/fa rat islets. We conclude that fa/fa rat islets have an exaggerated insulin response to hypoglycemic stimuli, possibly as a result of a defect in B-cell glucokinase function.Key words: insulin secretion, obesity, glucose metabolism, starvation.

GABAB receptors and glucose homeostasis: evaluation in GABAB receptor knockout mice

2008 ◽  
Vol 294 (1) ◽  
pp. E157-E167 ◽  
Author(s):  
M. M. Bonaventura ◽  
P. N. Catalano ◽  
A. Chamson-Reig ◽  
E. Arany ◽  
D. Hill ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Secretion ◽  
Glucose Homeostasis ◽  
Gabab Receptors ◽  
Insulin Content ◽  
Western Blots ◽  
Pancreatic Insulin ◽  
Pancreatic Insulin Content ◽  
Glucose Stimulated Insulin Secretion

GABA has been proposed to inhibit insulin secretion through GABAB receptors (GABABRs) in pancreatic β-cells. We investigated whether GABABRs participated in the regulation of glucose homeostasis in vivo. The animals used in this study were adult male and female BALB/C mice, mice deficient in the GABAB1 subunit of the GABABR (GABAB−/−), and wild types (WT). Blood glucose was measured under fasting/fed conditions and in glucose tolerance tests (GTTs) with a Lifescan Glucose meter, and serum insulin was measured by ELISA. Pancreatic insulin content and islet insulin were released by RIA. Western blots for the GABAB1 subunit in islet membranes and immunohistochemistry for insulin and GABAB1 were performed in both genotypes. BALB/C mice preinjected with Baclofen (GABABR agonist, 7.5 mg/kg ip) presented impaired GTTs and decreased insulin secretion compared with saline-preinjected controls. GABAB−/− mice showed fasting and fed glucose levels similar to WT. GABAB−/− mice showed improved GTTs at moderate glucose overloads (2 g/kg). Baclofen pretreatment did not modify GTTs in GABAB−/− mice, whereas it impaired normal glycemia reinstatement in WT. Baclofen inhibited glucose-stimulated insulin secretion in WT isolated islets but was without effect in GABAB−/− islets. In GABAB−/− males, pancreatic insulin content was increased, basal and glucose-stimulated insulin secretion were augmented, and impaired insulin tolerance test and increased homeostatic model assessment of insulin resistance index were determined. Immunohistochemistry for insulin demonstrated an increase of very large islets in GABAB−/− males. Results demonstrate that GABABRs are involved in the regulation of glucose homeostasis in vivo and that the constitutive absence of GABABRs induces alterations in pancreatic histology, physiology, and insulin resistance.

scholarly journals MafA Is a Key Regulator of Glucose-Stimulated Insulin Secretion

2005 ◽  
Vol 25 (12) ◽  
pp. 4969-4976 ◽  
Author(s):  
Chuan Zhang ◽  
Takashi Moriguchi ◽  
Miwako Kajihara ◽  
Ritsuko Esaki ◽  
Ayako Harada ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Serum Glucose ◽  
Β Cells ◽  
Glucose Levels ◽  
Develop Diabetes Mellitus ◽  
Age Dependent ◽  
Glucose Stimulated Insulin Secretion ◽  
Deficient Mice

ABSTRACT MafA is a transcription factor that binds to the promoter in the insulin gene and has been postulated to regulate insulin transcription in response to serum glucose levels, but there is no current in vivo evidence to support this hypothesis. To analyze the role of MafA in insulin transcription and glucose homeostasis in vivo, we generated MafA-deficient mice. Here we report that MafA mutant mice display intolerance to glucose and develop diabetes mellitus. Detailed analyses revealed that glucose-, arginine-, or KCl-stimulated insulin secretion from pancreatic β cells is severely impaired, although insulin content per se is not significantly affected. MafA-deficient mice also display age-dependent pancreatic islet abnormalities. Further analysis revealed that insulin 1, insulin 2, Pdx1, Beta2, and Glut-2 transcripts are diminished in MafA-deficient mice. These results show that MafA is a key regulator of glucose-stimulated insulin secretion in vivo.

scholarly journals Effect of inhibition of glutathione synthesis on insulin action: in vivo and in vitro studies using buthionine sulfoximine

2000 ◽  
Vol 349 (2) ◽  
pp. 579-586 ◽  
Author(s):  
Mogher KHAMAISI ◽  
Oren KAVEL ◽  
Moti ROSENSTOCK ◽  
Michal PORAT ◽  
Michal YULI ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Adipose Tissue ◽  
Insulin Secretion ◽  
Insulin Action ◽  
Impaired Insulin ◽  
Insulin Responsiveness

Decreased cellular GSH content is a common finding in experimental and human diabetes, in which increased oxidative stress appears to occur. Oxidative stress has been suggested to play a causative role in the development of impaired insulin action on adipose tissue and skeletal muscle. In this study we undertook to investigate the potential of GSH depletion to induce insulin resistance, by utilizing the GSH synthesis inhibitor, L-buthionine-[S,R]-sulfoximine (BSO). GSH depletion (20-80% in various tissues), was achieved in vivo by treating rats for 20 days with BSO, and in vitro (80%) by treating 3T3-L1 adipocytes with BSO for 18 h. No demonstrable change in the GSH/GSSG ratio was observed following BSO treatment. GSH depletion was progressively associated with abnormal glucose tolerance test, which could not be attributed to impaired insulin secretion. Skeletal muscle insulin responsiveness was unaffected by GSH depletion, based on normal glucose response to exogenous insulin, 2-deoxyglucose uptake measurements in isolated soleus muscle, and on normal skeletal muscle expression of GLUT4 protein. Adipocyte insulin responsiveness in vitro was assessed in 3T3-L1 adipocytes, which displayed decreased insulin-stimulated tyrosine phosphorylation of insulin-receptor-substrate proteins and of the insulin receptor, but exaggerated protein kinase B phosphorylation. However, insulin-stimulated glucose uptake was unaffected by GSH depletion. In accordance, normal adipose tissue insulin sensitivity was observed in BSO-treated rats in vivo, as demonstrated by normal inhibition of circulating non-esterified fatty acid levels by endogenous insulin secretion. In conclusion, GSH depletion by BSO results in impaired glucose tolerance, but preserved adipocyte and skeletal muscle insulin responsiveness. This suggests that alternative oxidation-borne factors mediate the induction of peripheral insulin resistance by oxidative stress.

scholarly journals Glucose-dependent and Glucose-sensitizing Insulinotropic Effect of Nateglinide: Comparison to Sulfonylureas and Repaglinide

2001 ◽  
Vol 2 (1) ◽  
pp. 63-72 ◽  
Author(s):  
Shiling Hu ◽  
Shuya Wang ◽  
Beth E. Dunning
Keyword(s):  
Insulin Secretion ◽  
Mechanism Of Action ◽  
Basic Mechanism ◽  
Glucose Levels ◽  
Physiologic Effect ◽  
Glucose Sensitivity ◽  
Glucose Stimulated Insulin Secretion ◽  
Insulinotropic Effect

Nateglinide, a novel D-phenylalanine derivative, stimulates insulin releaseviaclosure ofKATPchannels in pancreaticβ-cell, a primary mechanism of action it shares with sulfonylureas (SUs) and repaglinide. This study investigated (1) the influence of ambient glucose levels on the insulinotropic effects of nateglinide, glyburide and repaglinide, and (2) the influence of the antidiabetic agents on glucose-stimulated insulin secretion (GSIS)in vitrofrom isolated rat islets. TheEC50of nateglinide to stimulate insulin secretion was 14 μM in the presence of 3mM glucose and was reduced by 6-fold in 8mM glucose and by 16-fold in 16mM glucose, indicating a glucose-dependent insulinotropic effect. The actions of glyburide and repaglinide failed to demonstrate such a glucose concentration-dependent sensitization. When tested at fixed and equipotent concentrations (~2xEC50in the presence of 8mM glucose) nateglinide and repaglinide shifted theEC50s for GSIS to the left by 1.7mM suggesting an enhancement of islet glucose sensitivity, while glimepiride and glyburide caused, respectively, no change and a right shift of theEC50. These data demonstrate that despite a common basic mechanism of action, the insulinotropic effects of different agents can be influenced differentially by ambient glucose and can differentially influence the islet responsiveness to glucose. Further, the present findings suggest that nateglinide may exert a more physiologic effect on insulin secretion than comparator agents and thereby have less propensity to elicit hypoglycemiain vivo.

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