METABOLICALLY COUPLED ION CHANNEL INTERACTIONS IN ISLETS

2型糖尿病(T2 DM)患者胰岛葡萄糖刺激胰岛素分泌(GSIS)功能受损。在……里面 健康的胰岛，GSIS是由以下细胞内信号(包括[钙]i)的复杂网络触发的 葡萄糖的摄取和代谢。振荡的胰岛素分泌对胰岛素的作用很重要，并且受到干扰。 T2 DM组。我们假设正常的胰岛振荡对于强健的血糖感应和胰岛素是至关重要的。 分泌物。个别胰岛表现出不同的振荡模式，可能是快的(10-60秒)，也可能是慢的(2-5分钟)。 尽管进行了深入的研究，但这些振荡背后的机制尚不清楚。缓慢的振荡是 尽管它们可能具有更大的意义，但人们对此知之甚少，正如我们最近的数据显示的那样 [Ca~(2+)]i振荡是体内胰岛素缓慢搏动的原因。我们假设缓慢的振荡反映了 磷酸果糖激酶驱动的糖酵解振荡。我们最近开发了一个“组合振荡模型”。 (COM)，其中振荡糖酵解定量地与更快的电子/[钙]i振荡相互作用。COM 解释了广泛的胰岛行为，包括不同的[Ca~(2+)]i模式。然而，小岛也展示了 氧利用、线粒体电位和NAD(P)H的缓慢振荡本提案的目的是：1) 确定代谢振荡对[钙]i振荡和分泌是否重要，以及是否 它们是线粒体或糖酵解；2)决定[Ca~(2+)]i和代谢如何相互作用；3)决定离子如何 通道(S)将β细胞的新陈代谢与电活动结合起来；以及4)了解 离子/代谢相互作用控制胰岛素的分泌。实验结果将用于测试COM和 目前关于胰岛功能的其他假说。膜片钳电生理学、安培法和[Ca~(2+)]i及 [Na+]I成像将与NAD(P)H、线粒体电位和氧气利用的测量相结合 野生型和SUR1基因敲除小鼠的胰岛来实现这些目标。执行这些研究测试a 新的全面的胰岛功能理论，可能会对改善胰岛产生翻译影响 移植和帮助糖尿病研究人员更合理地设计药物来改善胰岛素分泌和 2型糖尿病患者的胰岛活性。

Glucose-stimulated insulin secretion (GSIS) from pancreatic islets is defective in Type 2 diabetes (T2DM). In healthy islets, GSIS is triggered by a complex network of intracellular signals (including [Ca2+]i) following glucose uptake and metabolism. Oscillatory insulin secretion is important for insulin action, and is disrupted in T2DM. We hypothesize that normal islet oscillations are critical for robust glucose sensing and insulin secretion. Individual islets exhibit diverse oscillatory patterns which may be fast (10-60s) or slow (2-5 min.). Despite intensive study, the mechanisms underlying these oscillations are unclear. The slow oscillations are less understood despite their potentially greater significance, as evidence by our recent data showing islet [Ca2+]i oscillations account for slow pulsatile insulin in vivo. We hypothesize that slow oscillations reflect glycolytic oscillations driven by phosphofructokinase. We recently developed a 'Combined Oscillation Model' (COM) where oscillatory glycolysis quantitatively interacts with faster electrical/[Ca2+]i oscillations. COM accounts for a wide spectrum of islet behavior including diverse [Ca2+]i patterns. Islets, however, also exhibit slow oscillations in O2 usage, mitochondrial potential and NAD(P)H. The objectives of this proposal are to: 1) determine whether metabolic oscillations are important for [Ca2+]i oscillations and secretion, and whether they are mitochondrial or glycolytic; 2) determine how [Ca2+]i and metabolism interact; 3) determine how ion channel(s) couple metabolism to electrical activity in beta cells; and 4) understand how diverse ionic/metabolic interactions control insulin secretion. Experimental results will be used to test the COM and other current hypotheses of islet function. Patch clamp electrophysiology, amperometry, and [Ca2+]i and [Na+]i imaging will be combined with measurements of NAD(P)H, mitochondrial potential, and O2 usage in islets from wild type and SUR1 knockout mice to carry out these objectives. Performing these studies test a new comprehensive theory of islet function which may have translational impact to help improve islet transplantation and help diabetes researcher more rationally design drugs to improve insulin secretion and islet viability in T2DM.