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.

胰岛素的主要生物效应之一是刺激葡萄糖转运，并且详细了解胰岛素的作用。介导这种生物效应的分子事件将有助于加深对胰岛素机制的理解作用以及以胰岛素抵抗为特征的疾病状态。噻唑烷二酮 (TZD) 类胰岛素敏化剂与 PPARγ 受体结合，这一发现引起了人们对 PPARγ 受体的巨大兴趣生物学、TZD 作用和胰岛素抵抗的治疗。因此，本研究计划的总体目标是阐明导致 GLUT4 的胰岛素细胞内信号通路中的分子和生化事件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后信号传导事件。这些研究是由我们最近发现异源三聚体 G 蛋白 Gaq/11 是该过程中必要的信号分子，将信号从胰岛素受体传递至 PI3 激酶，从而刺激葡萄糖转运。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机制 2 型糖尿病以及许多其他病症的特征，我们提出了对此的新研究现象。 2 型糖尿病患者和其他人胰岛素中内皮素-I (ET-I) 水平升高抵抗状态，我们现在已经证明用 ET-I 处理 3T3-L1 脂肪细胞会产生一种状态胰岛素抵抗。我们现在提出一系列研究来检验异源性的基本机制 ET-I 使胰岛素刺激葡萄糖转运脱敏，因为它可能代表胰岛素的新机制人身上的抵抗力。 3) PPARγ 核受体是抗糖尿病 TZD 的假定靶标，这已引起了人们对这种核受体的生物学的极大兴趣。我们建议对 PPARy 进行详细研究生物学，以帮助阐明该受体及其下游靶基因在胰岛素作用和胰岛素抵抗。拟议的研究范围包括 PPARy 敲除 (KO) 的生理测量动物，对激动剂介导的 PPARγ 转录事件进行更基础的机制研究。综上所述，本申请中提出的实验将应用新的方法来提供机械信息和测试新的假设，这将进一步加深我们对胰岛素作用和胰岛素抵抗的理解。