Metabolic coupling factors in pancreatic beta-cell signal transduction.
Metabolic coupling factors in pancreatic beta-cell signal transduction.
复制标题
DOI：
10.1146/annurev.bi.64.070195.003353
复制
发表时间：
1995
影响因子：
16.6
通讯作者：
C. B. Newgard;J. McGarry
中科院分区：
文献类型：
--
作者：
C. B. Newgard;J. McGarry
本章重点介绍介导朗格罕斯岛β细胞葡萄糖刺激胰岛素分泌（GSIS）的生化机制以及脂肪酸的增强作用。我们总结了支持以下观点的证据：GSIS 需要葡萄糖代谢，并且 GLUT-2 促进葡萄糖转运蛋白和葡萄糖磷酸化酶葡萄糖激酶在测量细胞外葡萄糖浓度的变化中发挥重要作用。葡萄糖代谢通过一系列事件与胰岛素分泌相关，这些事件涉及 ATP:ADP 比率的变化、ATP 敏感的 K+ 通道的抑制和电压门控 Ca2+ 通道的激活，这一观点得到了严格的审查，并评估了糖酵解与线粒体代谢产生的 ATP 的相对重要性。我们还提出了一个不断发展的概念，即胰岛素分泌的重要信号可能存在于葡萄糖和脂质代谢之间的联系，特别是促进脂肪酸酯化和抑制氧化的调节分子丙二酰辅酶A的产生。最后，我们发现，与其对 GSIS 的短期增强作用相反，胰岛长期暴露于高水平的脂肪酸会导致 β 细胞功能障碍，这表明与肥胖相关的高脂血症可能在非胰岛素依赖型糖尿病 (NIDDM) 的 GSIS 特征减弱中发挥因果作用。
This chapter focuses on the biochemical mechanisms that mediate glucose-stimulated insulin secretion (GSIS) from beta-cells of the islets of Langerhans and the potentiating role played by fatty acids. We summarize evidence supporting the idea that glucose metabolism is required for GSIS and that the GLUT-2 facilitated glucose transporter and the glucose phosphorylating enzyme glucokinase play important roles in measuring changes in extracellular glucose concentration. The idea that glucose metabolism is linked to insulin secretion through a sequence of events involving changes in ATP:ADP ratio, inhibition of ATP-sensitive K+ channels, and activation of voltage-gated Ca2+ channels is critically reviewed, and the relative importance of ATP generated from glycolytic versus mitochondrial metabolism is evaluated. We also present the growing concept that an important signal for insulin secretion may reside at the linkage between glucose and lipid metabolism, specifically the generation of the regulatory molecule malonyl CoA that promotes fatty acid esterification and inhibits oxidation. Finally, we show that in contrast to its short term potentiating effect on GSIS, long-term exposure of islets to high levels of fatty acids results in beta-cell dysfunction, suggesting that hyperlipidemia associated with obesity may play a causal role in the diminished GSIS characteristic of non insulin-dependent diabetes mellitus (NIDDM).