Insulin Regulation of the Adipocyte Glucose Transporter

脂肪细胞葡萄糖转运蛋白的胰岛素调节

• 批准号: 6771314
• 负责人: GUSTAV E. LIENHARD
• 金额: $ 37.13万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 1979
• 资助国家: 美国
• 起止时间: 1979-04-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6771314
• 关键词: SDS polyacrylamide gel electrophoresis; adipocytes; biological signal transduction; cell membrane; enzyme induction /repression; glucose transporter; guanosinetriphosphatase activating protein; hormone regulation /control mechanism; immunoprecipitation; insulin; insulin receptor; intracellular transport; membrane fusion; membrane transport proteins; molecular cloning; phosphorylation; protein kinase; protein purification; protein sequence; protein structure function; thin layer chromatography; vesicle /vacuole; western blottings

DESCRIPTION (provided by applicant): Insulin treatment of fat and muscle cells causes a rapid increase in the rate of glucose transport into these cells. This effect is a major contributor to the lowering of the blood glucose level by insulin. The basis of the effect is the movement to and fusion of specialized intracellular vesicles containing the glucose transporter GLUT4 with the plasma membrane. This process is known as GLUT4 translocation. Our overall goal is to elucidate at the molecular level how GLUT4 translocation occurs. The main focus in the coming grant period is to describe in detail how signaling from the insulin receptor causes GLUT4 translocation in adipocytes. Recently we have discovered and initially characterized a protein that is a likely key connection between insulin signaling and GLUT4 translocation. This protein is a Rab GTPase activating protein (Rab GAP) known as AS160. Our results indicate that insulin-stimulated phosphorylation of AS160, probably by the protein kinase Akt, is a trigger of GLUT4 translocation. They support the hypothesis that this phosphorylation of AS160 inactivates its GAP function, and that as a consequence the GTP form of a critical Rab is elevated. The GTP Rab is expected to be the initiating component in the GLUT4 translocation machinery. Our specific aims are: 1. To complete the characterization of AS160, We will identify the Rab(s) that is its substrate, determine how phosphorylation affects its GAP activity, define its sub cellular location, and assess its role in other membrane trafficking processes. 2. To characterize the Rab(s) that is required for GLUT4 translocation. We will identify this Rab, and examine its roles at the molecular level in both the movement of GLUT4 vesicles and their fusion with the plasma membrane. This research is directly relevant to diabetes. Detailed knowledge of GLUT4 translocation may lead to better therapeutic regimes or agents for both type 1 and type 2 diabetes.

描述（由申请方提供）：脂肪和肌肉细胞的胰岛素治疗导致葡萄糖转运到这些细胞中的速率快速增加。这种作用是胰岛素降低血糖水平的主要原因。该效应的基础是含有葡萄糖转运蛋白GLUT 4的特化细胞内囊泡与质膜的移动和融合。这个过程被称为GLUT4易位。我们的总体目标是在分子水平上阐明GLUT4易位如何发生。在即将到来的资助期内，主要重点是详细描述胰岛素受体的信号传导如何导致脂肪细胞中的GLUT4易位。最近，我们发现并初步鉴定了一种蛋白质，该蛋白质可能是胰岛素信号传导和GLUT4易位之间的关键联系。这种蛋白质是一种称为AS160的Rab GTP酶激活蛋白（Rab GAP）。我们的研究结果表明，胰岛素刺激的AS160磷酸化，可能是由蛋白激酶Akt，是GLUT4易位的触发器。他们支持这样的假设，即AS160的这种磷酸化使其GAP功能失活，因此关键Rab的GTP形式升高。预期GTP Rab是GLUT4易位机制中的起始组分。我们的具体目标是：1.为了完成AS160的表征，我们将鉴定作为其底物的Rab，确定磷酸化如何影响其GAP活性，确定其亚细胞位置，并评估其在其他膜运输过程中的作用。2.表征GLUT 4易位所需的Rab。我们将确定这种Rab，并在分子水平上研究其在GLUT4囊泡运动及其与质膜融合中的作用。这项研究与糖尿病直接相关。GLUT4易位的详细知识可能会导致更好的治疗方案或1型和2型糖尿病的药物。