Role of cytosolic malic enzyme and isocitrate dehydrogenase in the regulation of insulin exocytosis from pancreatic beta-cells.

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A key pathway in the metabolic regulation of insulin exocytosis from pancreatic beta-cells involves an increase in ATP leading to membrane depolarization, calcium entry and insulin release. However, we and others have shown that there are other mitochondrial messenger(s), in addition to ATP, that are also involved in regulating insulin secretion. A strong link between NADPH and insulin release has been established in multiple tissue types including mouse, rat and human islets, however, the enzymatic source of this NADPH is still be being debated. Our previously funded NSERC research program focused on understanding the metabolic regulation of insulin granule exocytosis using the ß-cell as a model. In the current proposal, we will dissect further how nutrients play a unique role in regulating granule exocytosis. We have discovered a novel pathway for the metabolic regulation of insulin release involving pyruvate cycling through the pyruvate-isocitrate pathway. A key enzyme in this pathway is cytosolic isocitrate dehydrogenase (ICDc) which generates a-ketoglutarate and NADPH. NADPH is the likely key signaling molecule generated by this pathway that leads to insulin release. However, others have shown a role for pyruvate cycling through the pyruvate-malate pathway, with the key NADPH-producing enzyme in this case being cytosolic malic enzyme (MEc). There are