What couples glycolysis to mitochondrial signal generation in glucose-stimulated insulin secretion?
Pancreatic islet beta-cells are poised to generate metabolic messengers in the mitochondria that link glucose metabolism to insulin exocytosis. This is accomplished through the tight coupling of glycolysis to mitochondrial activation. The messenger molecules ATP and glutamate are produced after the metabolism of glycolysis-derived pyruvate in the mitochondria. The entry of monocarboxylates such as pyruvate into the beta cell is limited, explaining why overexpression of monocarboxylate transporters unravels pyruvate-stimulated insulin secretion. NADH generated by glycolysis is efficiently reoxidized by highly active mitochondrial shuttles rather than by lactate dehydrogenase. Overexpression of this enzyme does not alter glucose-stimulated insulin secretion, suggesting that NADH availability restricts the conversion of pyruvate to lactate in the beta cell. These metabolic features permit the fuel function of glucose to be extended to the generation of signaling molecules, which increases cytosolic Ca2+ and promotes insulin exocytosis.
Ishihara
H
H
Department of Internal Medicine, University Medical Center, Geneva 4, Switzerland.
Wollheim
C B
CB
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D002460:Cell Line; D002478:Cells, Cultured; D005947:Glucose / Q000378:metabolism*; D018698:Glutamic Acid / Q000378:metabolism; D006019:Glycolysis; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D008954:Models, Biological; D027501:Monocarboxylic Acid Transporters; D009243:NAD / Q000378:metabolism; D019289:Pyruvic Acid / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction
D002352:Carrier Proteins; D007328:Insulin; D027501:Monocarboxylic Acid Transporters; D009243:NAD; D018698:Glutamic Acid; D019289:Pyruvic Acid; D000255:Adenosine Triphosphate; D007770:L-Lactate Dehydrogenase; D005947:Glucose