METABOLIC REGULATION OF INSULIN SECRETION

胰岛素分泌的代谢调节

• 批准号: 2139673
• 负责人: BARBARA E. CORKEY
• 金额: $ 24.87万
• 依托单位: BOSTON MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-01-01 至 1996-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2139673
• 关键词: acyl coA; adenylate kinase; bioenergetics; calcium channel; diacylglycerols; fatty acid metabolism; fluorescent dye /probe; glucose metabolism; guanine nucleotide binding protein; hormone regulation /control mechanism; insulin; ion transport; laboratory rat; membrane channels; microelectrodes; oxygen consumption; pancreatic islet function; phosphatidylinositols; potassium channel; protein kinase C; secretion; tissue /cell culture; voltage /patch clamp

The first step in resolving abnormalities in insulin secretion is to understand how the beta-cell is normally stimulated by glucose to secrete insulin. Data obtained during the preceding grant period led us to propose a model linking oscillatory release of insulin from the pancreatic beta- cell with glucose metabolism. According to the model an increase in the ambient glucose concentration causes oscillatory changes in glucose phosphorylation and glycolysis leading to oscillations in the ATP/ADP ratio and O2 consumption. Peaks in ATP/ADP close ATP-sensitive K+-channels depolarizing the cell and causing opening of voltage regulated Ca2+- channels. As a consequence of the latter, oscillatory increases in cytosolic free Ca2+ occur in the beta-cell. A second change caused by enhanced glucose metabolism is an increase in malonyl CoA which leads to increases in diacylglycerol and cytosolic long chain acyl CoA. According to our model these may activate protein kinase C or cause the acylation of regulatory proteins. Finally, we have found that increases in glucose concentration increase the amplitude of oscillations in metabolism, cytosolic free Ca2+ and insulin release. This appears to be due to a synchronous recruitment of responding cells suggesting communication among cells and islets. The proposed studies will use methods and collaborative arrangements that have been established during the current grant period to test and extend the metabolic model and examine the phenomena of recruitment and synchronization. We will attempt to 1, substantiate that changes in the ATP/ADP ratio and O2 consumption precede those in cytosolic Ca2+; 2, identify the physiological changes in oscillating metabolites that regulate beta-cell ion channel activity; 3, establish whether isolated beta-cells are recruited to respond to glucose through cell contact, intracellular metabolites, or extracellular ions; 4, document how cells and islets are synchronized to respond to glucose in an oscillatory manner; 5, determine whether protein kinase C and GTP binding protein activity is regulated by acyl CoA esters in beta-cells; and 6, discover how fuels such as alpha-keto-isocaproic acid and glyceraldehyde cause ionic and metabolic changes in the beta-cell similar to those caused by glucose. These studies will address fundamental questions concerning metabolic events, electrical activity and Ca2+ levels in the framework of a complex model that includes both first and second phase insulin secretion.

解决胰岛素分泌异常的第一步是 了解通常如何通过葡萄糖刺激β细胞来分泌 胰岛素。 在上一个赠款期间获得的数据使我们提出了 将胰岛素从胰腺β-连接振荡释放的模型 具有葡萄糖代谢的细胞。 根据模型的增加 环境葡萄糖浓度会导致葡萄糖的振荡变化 磷酸化和糖酵解导致ATP/ADP比的振荡 和O2消耗。 ATP/ADP关闭ATP敏感的K+通道中的峰值 去极化电池并引起电压调节的Ca2+ - 频道。 由于后者，振荡增加 β细胞中发生胞质不含Ca2+。 由 增强的葡萄糖代谢是丙二酰氧COA的增加，导致 二酰基甘油和胞质长链酰基COA的增加。 根据 对于我们的模型，这些可能激活蛋白激酶C或引起酰化 调节蛋白。 最后，我们发现葡萄糖增加 浓度会增加代谢中振荡的振幅 胞质不含Ca2+和胰岛素释放。 这似乎是由于 同步募集响应单元的招募表明在 细胞和胰岛。 拟议的研究将使用方法和协作 在当前赠款期间已建立的安排 测试并扩展代谢模型并检查现象 招聘和同步。 我们将尝试1，证实 ATP/ADP比和O2消耗的变化之前 Ca2+; 2，确定振荡代谢产物的生理变化 调节β细胞离子通道活性； 3，确定是否孤立 招募β细胞通过细胞接触对葡萄糖做出反应， 细胞内代谢物或细胞外离子； 4，记录细胞和 胰岛同步以振荡方式对葡萄糖做出反应。 5， 确定蛋白激酶C和GTP结合蛋白活性是否是 由β细胞中的酰基COA酯调节；和6，发现如何燃料 作为α-酮 - 异思议酸和甘油醛会引起离子和代谢 β细胞的变化类似于葡萄糖引起的变化。 这些研究 将解决有关代谢事件的基本问题，电气 复杂模型的框架中的活动和Ca2+水平包括 第一阶段和第二阶段胰岛素分泌。