Uncoupling Protein 2 Knockout Mice Have Enhanced Insulin Secretory Capacity After a High-Fat Diet

Joseph, Jamie W.; Koshkin, Vasilij; Zhang, Chenyu; Wang, Jing; Lowell, Bradford B.; Chan, Catherine B.; Wheeler, Michael B.

doi:10.2337/diabetes.51.11.3211

Cited by 190 publications

(206 citation statements)

References 48 publications

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“…The islet insulin secretion assay was performed as described previously (18,37). Islet insulin content was assessed after the secretion assay as described previously (41).…”

Section: Methodsmentioning

confidence: 99%

Mitochondrial Metabolism of Pyruvate Is Essential for Regulating Glucose-stimulated Insulin Secretion

Patterson

Cousteils

Lou

et al. 2014

Journal of Biological Chemistry

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Background: Pyruvate metabolism plays an essential role in pancreatic ␤-cells. Results: Pharmacological and siRNA-mediated inhibition of mitochondrial pyruvate carrier-1 and -2 inhibit ␤-cell metabolism and insulin secretion. Conclusion: Pyruvate entry into ␤-cell mitochondria is critical for regulating insulin release. Significance: Mitochondrial metabolism of pyruvate plays a key role in generating signals in response to nutrients that control insulin release.

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“…The islet insulin secretion assay was performed as described previously (18,37). Islet insulin content was assessed after the secretion assay as described previously (41).…”

Section: Methodsmentioning

confidence: 99%

Mitochondrial Metabolism of Pyruvate Is Essential for Regulating Glucose-stimulated Insulin Secretion

Patterson

Cousteils

Lou

et al. 2014

Journal of Biological Chemistry

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“…Indeed, several studies have associated an increase in UCP2 with inhibition of GSIS and indications of mitochondrial uncoupling [6][7][8]. An increase in UCP2 protein levels has been measured after long-term exposure of beta cells to high concentrations of fatty acids [9][10][11][12], with indications of mitochondrial uncoupling. Exposure of human islets to high glucose increases UCP2 expression, and alters GSIS [13].…”

Section: Introductionmentioning

confidence: 99%

Increasing uncoupling protein-2 in pancreatic beta cells does not alter glucose-induced insulin secretion but decreases production of reactive oxygen species

Produit-Zengaffinen¹,

Davis-Lameloise²,

Perreten³

et al. 2006

Diabetologia

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Aims/hypothesis Levels of uncoupling protein-2 (UCP2) are regulated in the pancreatic beta cells and an increase in the protein level has been associated with mitochondrial uncoupling and alteration in glucose-stimulated insulin secretion. However, it is not clear whether an increase in uncoupling protein-2 per se induces mitochondrial uncoupling and affects ATP generation and insulin secretion. Materials and methods Transgenic mice with beta cell-specific overexpression of the human UCP2 gene and INS-1 cells with doxycycline-inducible overproduction of the protein were generated and the consequences of increased levels of UCP2 on glucose-induced insulin secretion and on parameters reflecting mitochondrial uncoupling were determined.Results In transgenic mice, an increase in beta cell UCP2 protein concentration did not significantly modify plasma glucose and insulin levels. Glucose-induced insulin secretion and elevation in the ATP/ADP ratio were unaltered by an increase in UCP2 level. In INS-1 cells, a similar increase in UCP2 level did not modify glucose-induced insulin secretion, cytosolic ATP and ATP/ADP ratio, or glucose oxidation. Increased levels of UCP2 did not modify the mitochondrial membrane potential and oxygen consumption. Increased UCP2 levels decreased cytokine-induced production of reactive oxygen species. Conclusion/interpretation The results obtained in transgenic mice and in the beta cell line do not support the hypothesis that an increase in UCP2 protein per se uncouples the mitochondria and decreases glucose-induced insulin secretion. In contrast, the observation that increased UCP2 levels decrease cytokine-induced production of reactive oxygen species indicates a potential protective effect of the protein on beta cells, as observed in other cell types.

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“…Blood glucose levels were assessed before and 15, 30, 45, 60, and 90 min into the ITTs. 25 Electrophysiological Recording of K ATP Channel Currents Suspensions of dispersed cells from pancreatic islets were centrifuged at 100 r.p.m. for 3 min and the collected cells were then resuspended in Hepes-buffered RPMI 1640 (Sigma, USA).…”

Section: Glucose Tolerance Test and Insulin Tolerance Testmentioning

confidence: 99%

Pancreatic islet overproduction of H2S and suppressed insulin release in Zucker diabetic rats

Yang

Jia

et al. 2009

Laboratory Investigation

196

156

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Hydrogen sulfide (H 2 S) has been traditionally known for its toxic effects on living organisms. The role of H 2 S in the homeostatic regulation of pancreatic insulin metabolism has been unclear. The present study is aimed at elucidating the effect of endogenously produced H 2 S on pancreatic insulin release and its role in diabetes development. Diabetes development in Zucker diabetic fatty (ZDF) rats was evaluated in comparison with Zucker fatty (ZF) and Zucker lean (ZL) rats. Pancreatic H 2 S production and insulin release were also assayed. It was found that H 2 S was generated in rat pancreas islets, catalyzed predominantly by cystathionine g-lyase (CSE). Pancreatic CSE expression and H 2 S production were greater in ZDF rats than in ZF or ZL rats. ZDF rats exhibited reduced serum insulin level, hyperglycemia, and insulin resistance. Inhibition of pancreatic H 2 S production in ZDF rats by intraperitoneal injection of DL-propargylglycine (PPG) for 4 weeks increased serum insulin level, lowered hyperglycemia, and reduced hemoglobin A1c level (Po0.05). Although in ZF rats it also reduced pancreatic H 2 S production and serum H 2 S level, PPG treatment did not alter serum insulin and glucose level. Finally, H 2 S significantly increased K ATP channel activity in freshly isolated rat pancreatic b-cells. It appears that insulin release is impaired in ZDF because of abnormally high pancreatic production of H 2 S. New therapeutic approach for diabetes management can be devised based on our observation by inhibiting endogenous H 2 S production from pancreas. KEYWORDS: diabetes; hydrogen sulfide; insulin release; K ATP channel; pancreas; type 2 diabetes mellitus Known as a swamp gas or 'rotten egg' gas, hydrogen sulfide (H 2 S) has yielded a public image of air pollutant for centuries. Physiological importance of H 2 S as a gasotransmitter has been realized for less than a decade. Endogenous production of H 2 S from L-cysteine is catalyzed by cystathionine b-synthase (CBS) and/or cystathionine g-lyase (CSE) with ammonium and pyruvate as co-products. 1 This process occurs in different organs and tissues, such as neuronal, vascular, and intestinal tissues. 2 Physiological concentrations of circulating H 2 S have been reported in the range of 45-300 mM. 1 At this physiological range, exogenous H 2 S has been shown to relax different vascular tissues, including isolated rat aortae and perfused mesenteric artery bed. 3-5 Altered cell proliferation or apoptosis induced by H 2 S has also been widely reported. [6][7][8][9][10] Endogenous production and physiological function of H 2 S in pancreas have been studied with identification of both CBS and CSE in rat pancreatic tissues or cloned rat pancreatic b-cell line. 11,12 In recent years, pathophysiological implications of the CSE/H 2 S system in diabetes have been reported. 12 CSE mRNA expression and H 2 S formation in rat pancreas was significantly increased after diabetes induction by streptozotocin injection. 12 CBS expression was reported in pancreatic acinar cells. 13 Y...

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Uncoupling Protein 2 Knockout Mice Have Enhanced Insulin Secretory Capacity After a High-Fat Diet

Cited by 190 publications

References 48 publications

Mitochondrial Metabolism of Pyruvate Is Essential for Regulating Glucose-stimulated Insulin Secretion

Mitochondrial Metabolism of Pyruvate Is Essential for Regulating Glucose-stimulated Insulin Secretion

Increasing uncoupling protein-2 in pancreatic beta cells does not alter glucose-induced insulin secretion but decreases production of reactive oxygen species

Pancreatic islet overproduction of H2S and suppressed insulin release in Zucker diabetic rats

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