INSULIN RECEPTORS AND THE GLUCOSE TRANSPORT SYSTEM

胰岛素受体和葡萄糖转运系统

基本信息

批准号：
8004368
负责人：
jerrold Michael OLEFSKY
金额：
$ 9.37万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
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：
2010-02-01 至 2010-04-30
项目状态：
已结题

项目摘要

One of insulin's major biologic effects is stimulation of glucose transport, and detailed knowledge of the molecular events which mediate this bioeffect will lead to improved understanding of mechanisms of insulin action as well as disease states characterized by insulinresistance. The thiazoladinedione (TZD) class ofinsulin sensitizers binds to the PPARy receptor, and this finding has led to an enormous interest into PPARy receptor biology, TZD action, and the treatment of insulin resistance. Thus, the overall goals of this research proposal are to elucidate the molecular and biochemical events in insulin'sintracellularsignalingpathway leading to GLUT4 translocation and glucose transport and to explore new mechanisms of insulin resistance. 1) We will study the post receptor signaling events which mediate insulin stimulated glucose transport. These studies are driven by our recent findings that the heterotrimeric G protein, Gaq/11, is a necessary signaling molecule in this process, conveying signals from the insulin receptor to PI3 kinase, leading to glucose transport stimulation. We will further study the role of Gaq/11 in this insulin bioeffect. 2) Insulin resistance is a major pathophysiologic feature of Type 2 diabetes mellitus, as well as a host of other conditions, and we propose novel studies of this phenomenon. Endothelin-I (ET-I) levels are elevated in Type 2 diabetic patients and other human insulin resistant states, and we have now demonstrated that treatment of 3T3-L1 adipocytes with ET-Iproduces a state of insulin resistance. We now propose a series of studies to examine the basic mechanisms of heterologous desensitization of insulin stimulated glucose transport by ET-I, as it may represent a new mechanism ofinsulin resistance in man. 3) PPARy nuclear receptors are the presumed target for anti-diabetic TZDs, and this has generated an enormous interest in the biology of this nuclear receptor. We propose detailed studies of PPARy biology, in order to help elucidate the role of this receptor, and its downstream target genes, in insulin action and insulin resistance. The proposed studies range from physiologic measurements in PPARy knockout (KO) animals, to more basic mechanistic studies of agonist mediated PPARy transcriptional events. In summary, the experiments proposed in this application will apply new methodologies to provide mechanistic information and test novel hypotheses, which will further our understanding of insulin action and insulin resistance.

胰岛素的主要生物学作用之一是刺激葡萄糖转运，并详细了解介导这种生物效应的分子事件将导致对胰岛素机制的理解提高作用以及以胰岛抗性为特征的疾病状态。噻唑烷二酮（TZD）类的insuinsuins 敏化剂与PPARY受体结合，这一发现引起了PPARY受体的极大关注生物学，TZD作用和胰岛素抵抗的治疗。因此，该研究建议的总体目标是为了阐明胰岛素的细胞信号路径中的分子和生化事件，导致GLUT4 易位和葡萄糖转运，并探索胰岛素抵抗的新机制。 1）我们将研究介导胰岛素刺激葡萄糖转运的受体信号事件。这些研究是由我们最近的发现，在此过程中，异三聚体G蛋白Gaq/11是必要的信号分子。将信号从胰岛素受体传递到PI3激酶，从而导致葡萄糖转运刺激。我们将进一步研究GAQ/11在这种胰岛素生物效应中的作用。 2）胰岛素抵抗是主要的病理生理学 2型糖尿病的特征以及许多其他疾病的特征，我们提出了新的研究现象。 2型糖尿病患者和其他人类胰岛素的内皮素-I（ET-I）水平升高抗性状态，我们现在已经证明了用ET-IPRODUCE的3T3-L1脂肪细胞的处理状态胰岛素抵抗。现在，我们提出了一系列研究，以检查异源的基本机制 ET-I刺激葡萄糖转运的脱敏，因为它可能代表了一种新机制人类的抵抗。 3）PPARY核受体是抗糖尿病TZD的推测目标，这具有对该核受体的生物学产生了巨大的兴趣。我们提出了PPARY的详细研究生物学，以帮助阐明该受体及其下游靶基因的作用，在胰岛素作用和胰岛素抵抗。拟议的研究范围从PPARY敲除（KO）的生理测量值（KO）动物，对激动剂介导的PPARY转录事件的更基本的机械研究。总而言之，本应用程序中提出的实验将采用新的方法来提供机械信息和测试新的假设，这将进一步了解我们对胰岛素作用和胰岛素抵抗的理解。