Insulinotropic Action of Methyl Pyruvate: Enzymatic and Metabolic Aspects

Jijakli, Hassan; Nadi, Abdellatif Bakkali; Cook, Lynda; Best, Leonard; Sener, Abdullah; Malaisse, Willy

doi:10.1006/abbi.1996.0505

Cited by 37 publications

(26 citation statements)

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“…Similar ATP\ADP ratios, and similar mitochondrial ATP production in the presence of pyruvate or MP, are corroborated by previous measurements of pyruvate or MP decarboxylation in intact islets showing no difference in decarboxylation efficacy between the two substrates [6].…”

Section: Discussionsupporting

confidence: 85%

“…Pyruvate and methyl pyruvate (MP) are equally well decarboxylated in isolated islets ; thus both substrates accumulate in the cytosol with similar concentrations [6]. However, only MP stimulates insulin secretion in itro [7][8][9][10] and in i o [11], whereas pyruvate, the main glycolytic intermediate of glucose metabolism, is not insulinogenic [12,13].…”

Section: Introductionmentioning

confidence: 99%

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Methyl pyruvate initiates membrane depolarization and insulin release by metabolic factors other than ATP

Lembert

Joos

Idahl

et al. 2001

Biochemical Journal

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The role of mitochondria in stimulus–secretion coupling of pancreatic β-cells was examined using methyl pyruvate (MP). MP stimulated insulin secretion in the absence of glucose, with maximal effect at 5mM. K+ (30mM) alone, or in combination with diazoxide (100µM), failed to enhance MP-induced secretion. Diazoxide (100µM) inhibited MP-induced insulin secretion. MP depolarized the β-cell in a concentration-dependent manner (5–20mM). The sustained depolarization induced by 20mM MP was not influenced by 100µM diazoxide, but the continuous spiking activity was suppressed by 500µM diazoxide. Pyruvate failed to initiate insulin release (5–20mM) or to depolarize the membrane potential. ATP production in isolated β-cell mitochondria was detected as accumulation of ATP in the medium during incubation in the presence of malate or glutamate in combination with pyruvate or MP. There was no difference in ATP production induced by pyruvate/malate or MP/malate in isolated β-cell mitochondria. ATP production by MP/glutamate was higher than that induced by pyruvate/glutamate, but it was much lower than that induced by α-ketoisocaproate/glutamate. Pyruvate (5mM) or MP (5mM) had no effect on the ATP/ADP ratio in whole islets, whereas glucose (20mM) significantly increased the whole islet ATP/ADP ratio. It is concluded that MP-induced β-cell membrane depolarization or insulin release does not relate directly to mitochondrial ATP production. Instead MP may exert a direct extramitochondrial effect, or it may stimulate β-cell mitochondria to produce coupling factors different from ATP to initiate insulin release.

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Section: Discussionsupporting

confidence: 85%

Section: Introductionmentioning

confidence: 99%

Methyl pyruvate initiates membrane depolarization and insulin release by metabolic factors other than ATP

Lembert

Joos

Idahl

et al. 2001

Biochemical Journal

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“…The methyl ester of pyruvate, a potent insulin secretagogue that generates large amounts of mitochondrial ATP (21,22), was used to specifically stimulate mitochondrial ATP production. Exposure of the HNF-1␣ (Ϫ/Ϫ) ␤-cells to 20 -50 mM methyl pyruvate induced an immediate (Ͻ20 s) suppression of I KATP (Fig.…”

Section: ␤-Cell Glycolytic Signaling In Mice Lacking Hnf-1␣mentioning

confidence: 99%

Defective Pancreatic β-Cell Glycolytic Signaling in Hepatocyte Nuclear Factor-1α-deficient Mice

Dukes¹,

Sreenan²,

Roe³

et al. 1998

Journal of Biological Chemistry

153

113

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Mutations in the hepatocyte nuclear factor-1␣ (HNF-1␣] i , and corrected the insulin secretion defect. NAD(P)H responses to glucose were substantially reduced, and inhibitors of glycolytic NADH generation reproduced the mutant phenotype in normal islets. Flux of glucose through glycolysis in islets from mutant mice was reduced, as a result of which ATP generation in response to glucose was impaired. We conclude that hepatocyte nuclear factor-1␣ diabetes results from defective ␤-cell glycolytic signaling, which is potentially correctable using substrates that bypass the defect.

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“…However, glyceraldehyde can be converted to the non-metabolizable intermediate glycerate-1-phosphate while still generating NADH (25) and can cause acidification of the cytosol (26 -28), making it difficult to fully interpret experiments with this secretagogue. Acidification has also been observed in studies with another widely used metabolite analog, methyl pyruvate (29,30). Since acidification alone can stimulate ATP generation in isolated mitochondria, the use of such compounds to dissect the role of cytosolic and mitochondrial signal generation could be misleading.…”

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confidence: 99%

Mitochondrial Metabolism Sets the Maximal Limit of Fuel-stimulated Insulin Secretion in a Model Pancreatic Beta Cell

Antinozzi¹,

Ishihara²,

Newgard

et al. 2002

Journal of Biological Chemistry

109

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The precise metabolic steps that couple glucose catabolism to insulin secretion in the pancreatic beta cell are incompletely understood. ATP generated from glycolytic metabolism in the cytosol, from mitochondrial metabolism, and/or from the hydrogen shuttles operating between cytosolic and mitochondrial compartments has been implicated as an important coupling factor. To identify the importance of each of these metabolic pathways, we have compared the fates of four fuel secretagogues (glucose, pyruvate, dihydroxyacetone, and glycerol) in the INS1-E beta cell line. Two of these fuels, dihydroxyacetone and glycerol, are normally ineffective as secretagogues but are enabled by adenovirus-mediated expression of glycerol kinase. Comparison of these two particular fuels allows the effect of redox state on insulin secretion to be evaluated since the phosphorylated products dihydroxyacetone phosphate and glycerol phosphate lie on opposite sides of the NADH-consuming glycerophosphate dehydrogenase reaction. Based upon measurements of glycolytic metabolites, mitochondrial oxidation, mitochondrial matrix calcium, and mitochondrial membrane potential, we find that insulin secretion most tightly correlates with mitochondrial metabolism for each of the four fuels. In the case of glucose stimulation, the high control strength of glucose phosphorylation sets the pace of glucose metabolism and thus the rate of insulin secretion. However, bypassing this reaction with pyruvate, dihydroxyacetone, or glycerol uncovers constraints imposed by mitochondrial metabolism, each of which attains a similar maximal limit of insulin secretion. More specifically, we found that the hyperpolarization of the mitochondrial membrane, related to the proton export from the mitochondrial matrix, correlates well with insulin secretion. Based on these findings, we propose that fuel-stimulated secretion is in fact limited by the inherent thermodynamic constraints of proton gradient formation.The pancreatic islet beta cell secretes insulin in response to several metabolic fuels, and this occurs via the metabolism of the stimulatory agents rather than their interaction with a ATP is generated by both cytosolic and mitochondrial reactions. Cytosolic ATP production comes from two reactions in the distal portion of glycolysis, 3-phosphoglycerate kinase and pyruvate kinase. Mitochondrial ATP is derived in part from hydrogen shuttles, primarily the malate-aspartate (5-7) and glycerophosphate shuttles, (8 -10) which are very active in islet beta cells. Finally, a major portion of ATP production comes from mitochondrial oxidation of glucose-derived pyruvate. There is evidence to support an important role of each of these discrete sources of ATP in the regulation of insulin secretion. Evidence for a role of glycolysis-derived ATP comes from studies in which inhibitors of glycolytic but not mitochondrial ATPproducing reactions inhibited GSIS (11). Evidence for an important role of hydrogen shuttles comes from studies showing near complete impairment of GSIS in islet...

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Insulinotropic Action of Methyl Pyruvate: Enzymatic and Metabolic Aspects

Cited by 37 publications

References 0 publications

Methyl pyruvate initiates membrane depolarization and insulin release by metabolic factors other than ATP

Methyl pyruvate initiates membrane depolarization and insulin release by metabolic factors other than ATP

Defective Pancreatic β-Cell Glycolytic Signaling in Hepatocyte Nuclear Factor-1α-deficient Mice

Mitochondrial Metabolism Sets the Maximal Limit of Fuel-stimulated Insulin Secretion in a Model Pancreatic Beta Cell

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