METABOLICALLY COUPLED ION CHANNEL INTERACTIONS IN ISLETS

胰岛中代谢耦合离子通道相互作用

基本信息

批准号：
8012957
负责人：
LESLIE S. SATIN
金额：
$ 5.28万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-02-04 至 2010-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8012957
关键词：
Accounting Acute Address Animal Model Attention Behavior Beta Cell Bucladesine Cell Survival Cell physiology Cells Complex Computational Biology Computer Simulation Consumption Coupled Coupling Cyclic AMP Data Defect Diabetes Mellitus Disease Drug Design Electrophysiology (science)Engineering Enzymes Exhibits Exocytosis Feedback Fructose Glucokinase Glucose Glycolysis Human Image In Situ In Vitro Individual Insulin Ion Channel Ions Islets of Langerhans Islets of Langerhans Transplantation Knock-out Knockout Mice Knowledge Measurement Mediating Membrane Potentials Metabolic Metabolism Mitochondria Modeling Monitor Mus Non-Insulin-Dependent Diabetes Mellitus Patients Pattern Phase Photometry Physiologic pulse Physiological Plasma Play Process Property Research Research Personnel Role Signal Transduction Staging Stimulus Tea Testing Time Tolbutamide Transplantation United States National Institutes of Health Wild Type Mouse Work base carbon fiber diabetic patient gene therapy glucagon-like peptide 1 glucose metabolism glucose uptake improved in vivo inhibitor/antagonist insulin granule insulin secretion insulin signaling islet mitochondrial membrane multidisciplinary patch clamp programs response theories voltage clamp

项目摘要

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.

胰岛中葡萄糖刺激的胰岛素分泌（GSI）在2型糖尿病（T2DM）中有缺陷。在健康的胰岛，GSI是由一个复杂的细胞内信号网络（包括[Ca2+] i）触发的葡萄糖摄取和代谢。振荡性胰岛素分泌对于胰岛素作用很重要，并且被破坏在T2DM中。我们假设正常的胰岛振荡对于鲁棒葡萄糖传感和胰岛素至关重要分泌。单个胰岛表现出可能是快速（10-60）或慢速（2-5分钟）的各种振荡模式。尽管进行了深入研究，但这些振荡的基础机制尚不清楚。缓慢的振荡是尽管我们最近的数据显示胰岛 [Ca2+] I振荡是体内缓慢脉动胰岛素的慢性胰岛素。我们假设缓慢的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）振荡性糖酵解与更快的电气/[Ca2+] I振荡相互作用。 com 包括各种胰岛行为，包括不同的[Ca2+] I模式。但是，胰岛也展出 O2使用，线粒体电位和NAD（P）h的缓慢振荡。该提议的目标是：1）确定代谢振荡对于[Ca2+] I振荡和分泌是否重要，以及是否重要它们是线粒体或糖酵解的； 2）确定[Ca2+] I和代谢如何相互作用； 3）确定离子的方式通道（S）夫妇代谢β细胞中的电活动； 4）了解多元化离子/代谢相互作用控制胰岛素分泌。实验结果将用于测试COM和胰岛功能的其他当前假设。斑块夹电生理学，安培计量学和[Ca2+] I和 [Na+] I成像将与NAD（P）H，线粒体电势和O2使用的测量结合来自野生型和SUR1敲除小鼠的胰岛来实现这些目标。进行这些研究测试胰岛功能的新综合理论可能会产生转化影响以帮助改善胰岛移植并帮助糖尿病研究人员更多地理性地设计药物，以改善胰岛素的分泌和 T2DM中的胰岛可行性。