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 i s accomplished through the tight coupling of glycolysis to mitochondrial ac tivation, 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, explainin g why overexpression of monocarboxylate transporters unravels pyruvate-stim ulated insulin secretion. NADH generated by glycolysis is efficiently reoxi dized by highly active mitochondrial shuttles rather than by lactate dehydr ogenase, Overexpression of this enzyme does not alter glucose-stimulated in sulin secretion, suggesting that NADH availability restricts the conversion of pyruvate to lactate in the beta cell. These metabolic features permit t he fuel function of glucose to be extended to the generation of signaling m olecules, which increases cytosolic Ca2+ and promotes insulin exocytosis.