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运输，并详细了解 介导这种生物效应的分子事件将有助于更好地理解胰岛素的作用机制 行为以及以胰岛素抵抗为特征的疾病状态。噻唑二酮(TZD)类胰岛素 增敏剂与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，这项研究提案的总体目标是 阐明导致GLUT4的胰岛素信号通路中的分子和生化事件 并探索胰岛素抵抗的新机制。1)我们会研究 介导胰岛素刺激葡萄糖转运的受体后信号转导事件。这些研究是由 我们最近的研究发现，异三聚体G蛋白Gaq/11是这一过程中必要的信号分子， 将信号从胰岛素受体传递到PI3激酶，导致葡萄糖转运刺激。我们会 进一步研究Gaq/11在这一胰岛素生物效应中的作用。2)胰岛素抵抗是胰岛素抵抗的主要病理生理机制。 2型糖尿病的特征，以及许多其他情况，我们建议对此进行新的研究 现象。2型糖尿病患者和其他人的胰岛素水平升高 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基因的基本机制。 胰岛素脱敏可通过ET-I促进葡萄糖转运，这可能是胰岛素的一种新机制 人类的抵抗力。3)PPARy核受体被认为是抗糖尿病TZD的靶点，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进行详细的研究 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。建议的研究范围从PPARy基因敲除(KO)的生理测量。 动物，到激动剂介导的PPARy转录事件的更基本的机制研究。总而言之， 本申请中提出的实验将应用新的方法来提供机械信息和 测试新的假说，这将加深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.