ELECTRICAL CONTROL OF INSULIN SECRETION

 描述(申请人提供)：本项目的长期目标是了解电控制胰岛素分泌和糖尿病发展的机制、作用和意义。许多以前的工作已经证明了K-ATP通道在胰腺β细胞电活动中的中心作用，并揭示了K-ATP通道活性缺陷是如何 会对胰岛素的分泌产生深远的影响，并导致新生儿糖尿病。这导致这些患者从胰岛素治疗转向磺脲类药物治疗，生活方式和疾病结局得到显著改善。基于新的初步数据，我们认为，由于电活动改变而导致的胰岛素分泌障碍可能比以前认识到的更突出，并且多种未知的分子成分可能与兴奋分泌控制和糖尿病的发展有关。为了追求这些想法，我们将利用独特的动物模型来评估胰岛K-ATP活性和胰岛素分泌控制之间的定量关系，并将利用模式生物中创新的正向遗传方法来寻找新陈代谢-兴奋耦合的新调节因子。在这个过程中，拟议的实验将测试关于胰岛代谢-兴奋-分泌耦合的机械性假说以及不同形式糖尿病的病因，并将提供影响治疗方法的机械性信息。

 DESCRIPTION (provided by applicant): The long-term goals of this project are to understand the mechanisms, role and significance of electrical control of insulin secretion and development of diabetes. Much previous work has demonstrated the central role of the K-ATP channel in electrical activity of the pancreatic β-cell and has revealed how defective K-ATP channel activity can have profound effects on insulin secretion and cause neonatal diabetes. This has led to transfer of these patients from insulin to sulfonylurea therapy, with marked improvements in lifestyle and disease outcome. Based on new preliminary data, we propose that failure of insulin secretion due to altered electrical activity may be more prominent than previously realized, and that multiple unrecognized molecular components are likely to be relevant to excitation-secretion control and the development of diabetes. To pursue these ideas, we will utilize unique animal models to assess quantitative relationships between islet K-ATP activity and insulin secretory control, and we will utilize innovative forward genetic approaches in model organisms to search for novel regulators of metabolism-excitation coupling. In the process, the proposed experiments will test mechanistic hypotheses regarding metabolism-excitation-secretion coupling in islets and in the etiology of different forms of diabetes and will provide mechanistic information that will impact treatment approaches.