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

胰岛β细胞分泌胰岛素代谢调控的一个关键途径是细胞内三磷酸腺苷含量增加，导致细胞膜去极化、钙内流和胰岛素释放。然而，我们和其他人已经证明，除了三磷酸腺苷之外，还有其他线粒体信使(S)也参与调节胰岛素的分泌。在包括小鼠、大鼠和人的胰岛在内的多种组织类型中，NADPH和胰岛素释放之间已经建立了很强的联系，然而，这种NADPH的酶来源仍然存在争议。我们之前资助的NSERC研究项目重点是以？细胞为模型了解胰岛素颗粒胞吐的代谢调节。在目前的提案中，我们将进一步剖析营养物质如何在调节颗粒胞吐中发挥独特的作用。我们发现了一条通过丙酮酸-异柠檬酸途径代谢调节胰岛素释放的新途径，包括丙酮酸循环。胞质异柠檬酸脱氢酶(ICDC)是该途径中的一个关键酶，它能产生α-酮戊二酸和NADPH。NADPH可能是这一途径产生的导致胰岛素释放的关键信号分子。然而，其他研究表明，丙酮酸通过丙酮酸-苹果酸途径循环，在这种情况下，产生NADPH的关键酶是胞浆苹果酸酶(MEC)。确实有

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