METABOLICALLY COUPLED ION CHANNEL INTERACTIONS IN ISLETS

在2型糖尿病（T2 DM）中，胰岛的葡萄糖刺激胰岛素分泌（GSIS）存在缺陷。在 在健康的胰岛中，GSIS由细胞内信号（包括[Ca 2 +]i）的复杂网络触发， 葡萄糖摄取和代谢。振荡性胰岛素分泌对于胰岛素作用是重要的， 2型糖尿病我们假设正常的胰岛振荡对于稳定的葡萄糖感知和胰岛素分泌是至关重要的。 分泌物单个胰岛表现出不同的振荡模式，可能快（10- 60秒）或慢（2-5分钟）。 尽管深入研究，这些振荡的机制尚不清楚。慢振荡是 尽管其潜在的更大意义，但我们最近的数据表明， [Ca2+]i振荡解释了体内缓慢脉动的胰岛素。我们假设慢振荡反映了 由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/[Ca 2 +]i振荡相互作用。网 解释了广泛的胰岛行为，包括不同的[Ca 2 +]i模式。然而，胰岛也表现出 O2利用率、线粒体电位和NAD（P）H的缓慢振荡。本提案的目标是：1） 确定代谢振荡是否对[Ca 2 +]i振荡和分泌重要，以及是否 它们是线粒体的或糖酵解的; 2）确定[Ca 2 +]i和代谢如何相互作用; 3）确定离子如何相互作用。 通道将代谢与β细胞中的电活动偶联;以及4）了解β细胞中的多种 离子/代谢相互作用控制胰岛素分泌。实验结果将用于测试COM和 其他关于胰岛功能的假说。膜片钳电生理学、电流分析法和[Ca 2 +]i， [Na+]i成像将与NAD（P）H、线粒体电位和O2使用的测量相结合， 来自野生型和SUR 1敲除小鼠的胰岛来实现这些目的。执行这些研究测试a 新的胰岛功能综合理论，可能会产生翻译影响，以帮助改善胰岛功能 帮助糖尿病研究人员更合理地设计药物，改善胰岛素分泌， T2 DM中的胰岛活力。

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.