INSULIN RECEPTORS AND THE GLUCOSE TRANSPORT SYSTEM

胰岛素的主要生物学作用之一是刺激葡萄糖转运，并详细了解胰岛素的作用。 介导这种生物效应的分子事件将导致对胰岛素机制的更好理解。 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 致敏剂与PPARy受体结合，这一发现引起了人们对PPARy受体的极大兴趣 生物学、TZD作用和胰岛素抵抗的治疗。因此，本研究提案的总体目标是 阐明胰岛素在导致GLUT 4的细胞信号通路中的分子和生化事件， 探讨胰岛素抵抗的新机制。1)我们会研究 受体后信号传导事件介导胰岛素刺激的葡萄糖转运。这些研究是由 我们最近发现异源三聚体G蛋白Gaq/11是这一过程中必需的信号分子， 将信号从胰岛素受体传递到PI 3激酶，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)胰岛素抵抗是一种主要的病理生理学 2型糖尿病的特点，以及其他条件的主机，我们提出了新的研究，这一点 现象2型糖尿病患者的内皮素-I（ET-I）水平升高， 我们现在已经证明用ET-I处理3 T3-L1脂肪细胞可以产生一种状态， 胰岛素抵抗。我们现在提出了一系列的研究，以检查异源的基本机制， ET-I对胰岛素刺激的葡萄糖转运的脱敏作用可能是胰岛素作用的一种新机制 3）PPARy核受体是抗糖尿病TZD的假定靶点，并且这已经 引起了人们对这种核受体生物学的极大兴趣。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中的作用， 胰岛素抵抗提出的研究范围从PPARy敲除（KO）中的生理测量， 动物，激动剂介导的PPARy转录事件的更基本的机制研究。总之， 本申请中提出的实验将应用新的方法来提供机械信息， 测试新的假设，这将进一步我们对胰岛素作用和胰岛素抵抗的理解。

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.