Jensen Mette V, Joseph Jamie W, Ronnebaum Sarah M, Burgess Shawn C, Sherry A Dean, Newgard Christopher B
Sarah W. Stedman Nutrition and Metabolism Center, Duke Univ. Medical Center, Durham, NC 27704, USA.
Am J Physiol Endocrinol Metab. 2008 Dec;295(6):E1287-97. doi: 10.1152/ajpendo.90604.2008. Epub 2008 Aug 26.
Glucose-stimulated insulin secretion (GSIS) is central to normal control of metabolic fuel homeostasis, and its impairment is a key element of beta-cell failure in type 2 diabetes. Glucose exerts its effects on insulin secretion via its metabolism in beta-cells to generate stimulus/secretion coupling factors, including a rise in the ATP/ADP ratio, which serves to suppress ATP-sensitive K(+) (K(ATP)) channels and activate voltage-gated Ca(2+) channels, leading to stimulation of insulin granule exocytosis. Whereas this K(ATP) channel-dependent mechanism of GSIS has been broadly accepted for more than 30 years, it has become increasingly apparent that it does not fully describe the effects of glucose on insulin secretion. More recent studies have demonstrated an important role for cyclic pathways of pyruvate metabolism in control of insulin secretion. Three cycles occur in islet beta-cells: the pyruvate/malate, pyruvate/citrate, and pyruvate/isocitrate cycles. This review discusses recent work on the role of each of these pathways in control of insulin secretion and builds a case for the particular relevance of byproducts of the pyruvate/isocitrate cycle, NADPH and alpha-ketoglutarate, in control of GSIS.
葡萄糖刺激的胰岛素分泌（GSIS）是正常代谢燃料稳态控制的核心，其受损是2型糖尿病β细胞功能衰竭的关键因素。葡萄糖通过在β细胞中的代谢发挥其对胰岛素分泌的作用，产生刺激/分泌偶联因子，包括ATP/ADP比值的升高，这有助于抑制ATP敏感性钾（K(ATP)）通道并激活电压门控钙（Ca(2+)）通道，从而刺激胰岛素颗粒胞吐作用。尽管这种依赖K(ATP)通道的GSIS机制已被广泛接受30多年，但越来越明显的是，它并不能完全描述葡萄糖对胰岛素分泌的影响。最近的研究表明，丙酮酸代谢的循环途径在胰岛素分泌控制中起重要作用。胰岛β细胞中存在三个循环：丙酮酸/苹果酸循环、丙酮酸/柠檬酸循环和丙酮酸/异柠檬酸循环。本综述讨论了这些途径各自在胰岛素分泌控制中的作用的最新研究，并阐述了丙酮酸/异柠檬酸循环的副产物NADPH和α-酮戊二酸在GSIS控制中的特殊相关性。
