Electrical Control of Insulin Secretion

描述（由申请人提供）：本项目的总体目标是了解电信号在胰岛素分泌中的作用。我们已经证明了β细胞KATP通道活性的遗传修饰对胰岛素分泌和葡萄糖耐量的巨大影响：KATP通道活性不足的动物显示出从分泌过多到分泌不足和糖尿病的复杂进展。相反，过度活跃的KATP通道导致分泌不足，严重时可导致新生儿死亡。这些动物模型预测并证实了人类的发现：KATP通道活性不足导致持续性低血糖高胰岛素血症，过度活跃的KATP通道现已被证明会导致永久性新生儿糖尿病。这些模型将使我们能够从机制上研究β细胞电活动的不平衡如何导致分泌缺陷。该提案将利用广泛的电生理学、转基因、基因组和细胞生物学方法来解决关于β细胞电兴奋性改变对葡萄糖耐量和疾病进展的体内后果的问题，无论是内在的还是对饮食操作的响应。所提出的实验将测试离子通道参与β细胞刺激分泌偶联以及高胰岛素血症和糖尿病病因学的机制假设。该项目的结果将提供可能影响糖尿病和高胰岛素血症新治疗方法开发的机制信息。

DESCRIPTION (provided by applicant): The overall goals of this project are to understand the role of electrical signaling in insulin secretion. We have demonstrated dramatic consequences of genetic modification of beta-cell KATP channel activity on insulin secretion and glucose tolerance: Animals with underactive KATP channels show a complex progression from hypersecretion to undersecretion and diabetes. In contrast overactive KATP channels cause undersecretion that can be severe enough to cause neonatal lethality. These animal models have both predicted and paralleled findings in humans: underactive KATP channels cause persistent hypoglycemic hyperinsulinemia, overactive KATP channels have now been shown to cause permanent neonatal diabetes. These models will allow us to examine mechanistically how imbalance in beta-cell electrical activity leads to secretory defects. This proposal will utilize a wide array of electrophysiological, transgenic, genomic and cellular biological approaches to address questions about the in vivo consequences of alterations of beta-cell electrical excitability for glucose tolerance and disease progression, both intrinsically and in response to dietary manipulations. The proposed experiments will test mechanistic hypotheses of the involvement of ion channels in stimulus-secretion coupling in beta-cells and in the etiology of hyperinsulinemia and diabetes. The results of this project will provide mechanistic information that may impact the development of new treatment approaches to both diabetes and hyperinsulinemia.