Fujimoto Shimpei, Nabe Koichiro, Takehiro Mihoko, Shimodahira Makiko, Kajikawa Mariko, Takeda Tomomi, Mukai Eri, Inagaki Nobuya, Seino Yutaka
Department of Diabetes and Clinical Nutrition, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.
Diabetes Res Clin Pract. 2007 Sep;77 Suppl 1:S2-10. doi: 10.1016/j.diabres.2007.01.026. Epub 2007 Apr 20.
Glucose-induced insulin secretion from beta-cells is often impaired in diabetic condition and by exposure to diabetogenic pharmacological agents. In pancreatic beta-cells, intracellular glucose metabolism regulates exocytosis of insulin granules, according to metabolism-secretion coupling in which glucose-induced mitochondrial ATP production plays an essential role. Impaired glucose-induced insulin secretion often results from impaired glucose-induced ATP elevation in beta-cells. Mitochondrial ATP production is driven by the proton-motive force including mitochondrial membrane potential (DeltaPsi(m)) generated by the electron transport chain. These electrons are derived from reducing equivalents, generated in the Krebs cycle and transferred from cytosol by the shuttles. Here, roles of the determinants of mitochondrial ATP production in impaired glucose-induced insulin secretion are discussed. Cytosolic alkalization, H(+) leak in the inner membrane by uncoupler (e.g. free fatty acid exposure), decrease in the supply of electron donors including NADH and FADH(2) to the respiratory chain, and endogenous mitochondrial ROS (e.g. Na(+)/K(+)-ATPase inhibition) all reduce hyperpolarlization of DeltaPsi(m) and ATP production, causing decresed glucose-induced insulin release. The decrease in the supply of NADH and FADH(2) to the respiratory chain derives from impairments in glucose metabolism including glycolysis (e.g. MODY2 and exposure to NO) and the shuttles (e.g. diabetic state and exposure to ketone body).
在糖尿病状态以及暴露于致糖尿病的药理剂时，β细胞中葡萄糖诱导的胰岛素分泌常常受损。在胰腺β细胞中，细胞内葡萄糖代谢根据代谢-分泌偶联调节胰岛素颗粒的胞吐作用，其中葡萄糖诱导的线粒体ATP生成起着至关重要的作用。葡萄糖诱导的胰岛素分泌受损通常是由于β细胞中葡萄糖诱导的ATP升高受损所致。线粒体ATP生成由质子动力驱动，包括电子传递链产生的线粒体膜电位（ΔΨm）。这些电子来源于三羧酸循环中产生并通过穿梭机制从细胞质转移的还原当量。在此，讨论线粒体ATP生成的决定因素在受损的葡萄糖诱导的胰岛素分泌中的作用。胞质碱化、解偶联剂（如游离脂肪酸暴露）导致内膜H⁺泄漏、呼吸链中包括NADH和FADH₂在内的电子供体供应减少以及内源性线粒体ROS（如钠钾ATP酶抑制）均会降低ΔΨm的超极化和ATP生成，导致葡萄糖诱导的胰岛素释放减少。呼吸链中NADH和FADH₂供应的减少源于葡萄糖代谢的受损，包括糖酵解（如MODY2和一氧化氮暴露）和穿梭机制（如糖尿病状态和酮体暴露）。
