Regulation of insulin secretion by uncoupling protein

2006 ◽  
Vol 34 (5) ◽  
pp. 802-805 ◽  
Author(s):  
C.B. Chan ◽  
N. Kashemsant
Keyword(s):  
Insulin Secretion ◽  
Fatty Acid ◽  
Uncoupling Protein ◽  
Physiological Role ◽  
Atp Production ◽  
Ucp2 Expression ◽  
Increased Sensitivity ◽  
Glucose Stimulated Insulin Secretion

UCPs (uncoupling proteins) can regulate cellular ATP production by uncoupling oxidative phosphorylation. UCP2 is expressed in islet β-cells and its induction reduces glucose-stimulated insulin secretion. Under physiological conditions, superoxide, formed as a by-product of respiration, activates UCP2. This leads to reduced ATP production, which impairs closure of the ATP-dependent K+ channels to prevent insulin secretion. It is suggested that the physiological role of UCP2 is to prevent excessive superoxide generation through a feedback loop. UCP2 induction may also alter fatty acid metabolism by altering NAD/NADH or by facilitating cycling of fatty acid anions. Recently, UCP2 has been proposed to keep insulin secretion low during starvation, a function under the control of the transcription co-repressor, surtuin-1, which has been shown to bind to the UCP2 promoter. Pathological UCP2 expression or activation may suppress glucose-stimulated insulin secretion to the extent that diabetes onset is hastened. In ob/ob mice, induction of UCP2 at age 5 weeks precedes development of insulin secretion defects and hyperglycaemia. Activating protein kinase A-dependent pathways can normalize insulin secretion in UCP2-overexpressing islets. Conversely, lowering UCP2 expression may promote increased insulin secretion. UCP2 knockout mice were protected from the diabetogenic effects of a high-fat diet and their islets exhibited increased sensitivity to glucose and elevated ATP/ADP. These results support a role for UCP2 as a gene contributing to the pathogenesis of Type 2 diabetes.

scholarly journals Metabolic cycling in control of glucose-stimulated insulin secretion

2008 ◽  
Vol 295 (6) ◽  
pp. E1287-E1297 ◽  
Author(s):  
Mette V. Jensen ◽  
Jamie W. Joseph ◽  
Sarah M. Ronnebaum ◽  
Shawn C. Burgess ◽  
A. Dean Sherry ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Β Cells ◽  
Pyruvate Metabolism ◽  
Coupling Factors ◽  
Stimulus Secretion Coupling ◽  
Channel Dependent ◽  
Glucose Stimulated Insulin Secretion ◽  
Dependent Mechanism

Glucose-stimulated insulin secretion (GSIS) is central to normal control of metabolic fuel homeostasis, and its impairment is a key element of β-cell failure in type 2 diabetes. Glucose exerts its effects on insulin secretion via its metabolism in β-cells to generate stimulus/secretion coupling factors, including a rise in the ATP/ADP ratio, which serves to suppress ATP-sensitive K+ (KATP) channels and activate voltage-gated Ca2+ channels, leading to stimulation of insulin granule exocytosis. Whereas this KATP channel-dependent mechanism of GSIS has been broadly accepted for more than 30 years, it has become increasingly apparent that it does not fully describe the effects of glucose on insulin secretion. More recent studies have demonstrated an important role for cyclic pathways of pyruvate metabolism in control of insulin secretion. Three cycles occur in islet β-cells: the pyruvate/malate, pyruvate/citrate, and pyruvate/isocitrate cycles. This review discusses recent work on the role of each of these pathways in control of insulin secretion and builds a case for the particular relevance of byproducts of the pyruvate/isocitrate cycle, NADPH and α-ketoglutarate, in control of GSIS.

scholarly journals Uncoupling protein-2 modulates the lipid metabolic response to fasting in mice

2008 ◽  
Vol 294 (4) ◽  
pp. G1017-G1024 ◽  
Author(s):  
Anthony R. Sheets ◽  
Péter Fülöp ◽  
Zoltán Derdák ◽  
Andrea Kassai ◽  
Edmond Sabo ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Insulin Secretion ◽  
Metabolic Response ◽  
Uncoupling Protein ◽  
Serum Insulin ◽  
Uncoupling Protein 2 ◽  
Cell Dysfunction ◽  
Hepatic Fat ◽  
Glucose Stimulated Insulin Secretion

Uncoupling protein-2 (UCP2) regulates insulin secretion by controlling ATP levels in β-cells. Although UCP2 deficiency improves glycemic control in mice, increased expression of UCP2 interferes with glucose-stimulated insulin secretion. These observations link UCP2 to β-cell dysfunction in type 2 diabetes with a perplexing evolutionary role. We found higher residual serum insulin levels and blunted lipid metabolic responses in fasted ucp2−/− mice, supporting the concept that UCP2 evolved to suppress insulin effects and to accommodate the fuel switch to fatty acids during starvation. In the absence of UCP2, fasting initially promotes peripheral lipolysis and hepatic fat accumulation at less than expected rates but culminates in protracted steatosis, indicating diminished hepatic utilization and clearance of fatty acids. We conclude that UCP2-mediated control of insulin secretion is a physiologically relevant mechanism of the metabolic response to fasting.

scholarly journals Free Fatty Acid Induced Reduction in Glucose-Stimulated Insulin Secretion: Evidence for a Role of Oxidative Stress In Vitro and In Vivo

Diabetes ◽  
2007 ◽  
Vol 56 (12) ◽  
pp. 2927-2937 ◽  
Author(s):  
A. I. Oprescu ◽  
G. Bikopoulos ◽  
A. Naassan ◽  
E. M. Allister ◽  
C. Tang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Insulin Secretion ◽  
Fatty Acid ◽  
Free Fatty Acid ◽  
Glucose Stimulated Insulin Secretion

scholarly journals In vivo phosphoproteomics reveals pathogenic signaling changes in diabetic islets

2018 ◽  
Author(s):  
Francesca Sacco ◽  
Anett Seelig ◽  
Sean J. Humphrey ◽  
Natalie Krahmer ◽  
Francesco Volta ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Beta Cells ◽  
Pancreatic Beta Cells ◽  
Drug Targets ◽  
High Sensitivity ◽  
Glucose Stimulated Insulin Secretion

SUMMARYProgressive decline of pancreatic beta cells function is key to the pathogenesis of type 2 diabetes. Protein phosphorylation is the central mechanism controlling glucose-stimulated insulin secretion in beta cells. However, if and how signaling networks are remodeled in diabetic isletsin vivoremain unknowns. Here we applied high-sensitivity mass spectrometry-based proteomics and quantified the levels of about 6,500 proteins and 13,000 phosphopeptides in islets of obese diabetic mice and matched controls. This highlighted drastic remodeling of key kinase hubs and signaling pathways. We integrated our phosphoproteomic dataset with a literature-derived signaling network, which revealed a crucial and conserved role of GSK3 kinase in the control of the beta cells-specific transcription factor PDX1 and insulin secretion, which we functionally verified. Our resource will enable the community to investigate potential mechanisms and drug targets in type 2 diabetes.

scholarly journals Prevention of Adipose Tissue Depletion during Food Deprivation in Angiotensin Type 2 Receptor-Deficient Mice

Endocrinology ◽  
2006 ◽  
Vol 147 (11) ◽  
pp. 5078-5086 ◽  
Author(s):  
Laurent Yvan-Charvet ◽  
Patrick Even ◽  
Noël Lamandé ◽  
Pascal Ferré ◽  
Annie Quignard-Boulangé
Keyword(s):  
Adipose Tissue ◽  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Physiological Role ◽  
Acid Oxidation ◽  
Ang Ii ◽  
Wild Type ◽  
Angiotensin Type 2 Receptor

Angiotensin (Ang) II is produced locally in various tissues, but its role in the regulation of tissue metabolism is still unclear. Recent studies have revealed the role of type 2 Ang II receptor (AT2R) in the control of energy homeostasis and lipid metabolism. The contribution of the AT2R to adaptation to starvation was tested using AT2R-deficient (AT2Ry/−) mice. Fasted AT2Ry/− mice exhibited a lower loss of adipose tissue weight associated to a decreased free fatty acid (FFA) release from stored lipids than the controls. In vitro studies show that Ang II causes an AT1R-mediated antilipolytic effect in isolated adipocytes. AT1R expression is up-regulated by fasting in both genotypes, but the increase is more pronounced in AT2Ry/− mice. In addition, the increased muscle β-oxidation displayed in AT2Ry/− mice on a fed state, persists after fasting compared with wild-type mice. In liver from fed mice, AT2R deficiency did not modify the expression of genes involved in fatty acid oxidation. However, in response to fasting, the large increase of the expression of this subset of genes exhibited by wild-type mice, was impaired in AT2Ry/− mice. Taken together, decreased lipolytic capacity and increased muscle fatty acid oxidation participate in the decreased plasma FFA observed in fasted AT2Ry/− mice and could account for the lower FFA metabolism in the liver. These data reveal an important physiological role of AT2R in metabolic adaptations to fasting.

scholarly journals Impact of uncoupling protein-2 overexpression on proinsulin processing

2006 ◽  
Vol 37 (3) ◽  
pp. 517-526 ◽  
Author(s):  
Narudee Kashemsant ◽  
Catherine B Chan
Keyword(s):  
Insulin Secretion ◽  
Uncoupling Protein ◽  
Diabetic Patients ◽  
Uncoupling Protein 2 ◽  
Atp Content ◽  
Type 2 Diabetic Patients ◽  
Atp Production ◽  
High K ◽  
Proinsulin Processing ◽  
Glucose Stimulated Insulin Secretion

Hyperproinsulinemia is observed in type 2 diabetic patients. We hypothesized that the induction of uncoupling protein-2 (UCP2) would impair processing of proinsulin to mature insulin and potentially contribute to hyperproinsulinemia, based on the evidence that hormone processing is an ATP-dependent process and UCP2 up-regulation can suppress cellular ATP production. UCP2 was overexpressed (UCP2-OE) by twofold in INS-1 cells by means of plasmid transfection. Although UCP2-OE reduced glucose-stimulated insulin secretion and cellular ATP content, no effects on proinsulin processing, as measured by western blotting, were observed. To increase the demand for insulin, we then cultured UCP2-OE and control INS-1 cells in medium containing 20 mM KCl for 24 h. High K+ markedly reduced glucose-stimulated insulin secretion from control cells, indicating inability of cells to meet secretory demand. Independent of UCP2 expression, high K+ reduced preproinsulin mRNA expression but had no effect on ATP content despite increasing ATP synthase expression. In UCP2-OE cells, high K+decreased total cellular insulin species content and increased the ratio of proinsulin to insulin, indicating an impairment of processing. We conclude that UCP2-OE can negatively impact proinsulin processing, possibly by ATP-dependent alteration of the granule environment or reduction of Ca2+availability, particularly when cells are chronically stimulated to secrete insulin.

scholarly journals The Role of Fatty Acid Signaling in Islet Beta-Cell Adaptation to Normal Pregnancy

2022 ◽  
Vol 12 ◽  
Author(s):  
Jee-Hye Kim ◽  
Viviane Delghingaro-Augusto ◽  
Jeng Yie Chan ◽  
D. Ross Laybutt ◽  
Joseph Proietto ◽  
...  
Keyword(s):  
Insulin Secretion ◽  
Fatty Acid ◽  
Beta Cell ◽  
Liver Glycogen ◽  
Oral Glucose ◽  
Pregnant Rat ◽  
Islet Beta Cell ◽  
Glucose Stimulated Insulin Secretion ◽  
Beta Cell Adaptation

BackgroundMaintenance of a normal fetal nutrient supply requires major adaptations in maternal metabolic physiology, including of the islet beta-cell. The role of lipid signaling processes in the mechanisms of islet beta-cell adaptation to pregnancy has been minimally investigated.ObjectiveTo determine the effects of pregnancy on islet fatty acid (FA) metabolic partitioning and FA augmentation of glucose-stimulated insulin secretion (GSIS).MethodsAge matched virgin, early pregnant (gestational day-11, G11) and late pregnant (G19) Sprague-Dawley rats were studied. Fasted and fed state biochemistry, oral glucose tolerance tests (OGTT), and fasted and post-OGTT liver glycogen, were determined to assess in vivo metabolic characteristics. In isolated islets, FA (BSA-bound palmitate 0.25 mmol/l) augmentation of GSIS, FA partitioning into esterification and oxidation processes using metabolic tracer techniques, lipolysis by glycerol release, triacylglycerols (TG) content, and the expression of key beta-cell genes were determined.ResultsPlasma glucose in pregnancy was lower, including during the OGTT (glucose area under the curve 0-120 min (AUC0-120); 655±24 versus 849±13 mmol.l-1.min; G19 vs virgin; P<0.0001), with plasma insulin concentrations equivalent to those of virgin rats (insulin AUC0-120; 97±7 versus 83±7 ng.ml-1.min; G19 vs virgin; not significant). Liver glycogen was depleted in fasted G19 rats with full recovery after oral glucose. Serum TG increased during pregnancy (4.4±0.4, 6.7±0.5; 17.1±1.5 mmol/l; virgin, G11, G19, P<0.0001), and islet TG content decreased (147±42, 172±27, 73±13 ng/µg protein; virgin, G11, G19; P<0.01). GSIS in isolated islets was increased in G19 compared to virgin rats, and this effect was augmented in the presence of FA. FA esterification into phospholipids, monoacylglycerols and TG were increased, whereas FA oxidation was reduced, in islets of pregnant compared to virgin rats, with variable effects on lipolysis dependent on gestational age. Expression of Ppargc1a, a key regulator of mitochondrial metabolism, was reduced by 51% in G11 and 64% in G19 pregnant rat islets compared to virgin rat islets (P<0.001).ConclusionA lowered set-point for islet and hepatic glucose homeostasis in the pregnant rat has been confirmed. Islet adaptation to pregnancy includes increased FA esterification, reduced FA oxidation, and enhanced FA augmentation of glucose-stimulated insulin secretion.

Sign in / Sign up

Export Citation Format

Share Document