Insulin Regulation of Adipocyte Microtubules

描述(申请人提供)：在工业化国家和新兴国家，2型糖尿病的发病率都达到了流行的发展速度。了解该病的病理生理学机制是制定合理的治疗策略以预防或治疗该病的关键。2型糖尿病的发展往往先于胰岛素介导的葡萄糖转运缺陷，这一过程由胰岛素反应的促进性葡萄糖转运体GLUT4调节。GLUT4介导胰岛素促进外周组织葡萄糖摄取的重要生理效应，包括脂肪、心脏和骨骼肌。因此，必须彻底了解这一过程的分子细节，才能理解2型糖尿病的病理生理学。我们实验室和其他实验室最近的工作清楚地表明，微管细胞骨架在胰岛素通过GLUT4介导的葡萄糖摄取过程中发挥了作用，但微管在这一过程中的具体功能尚不清楚。我们实验室的新发现表明，胰岛素信号使细胞内的平衡从单体亚基(由α-和β-微管蛋白异二聚体组成)转移到聚合微管蛋白上，从而增加了细胞内微管网络的总尺寸。胰岛素依赖的聚合微管蛋白的增加不依赖于PI3-激酶的激活，需要完整的肌动蛋白细胞骨架。这项研究的目标是：1)确定胰岛素如何将其信号施加到微管细胞骨架上；2)开始确定胰岛素引起的微管聚合增加的生理作用。

DESCRIPTION (provided by applicant): Incidence of type 2 diabetes has reached epidemic rates of development in both industrialized and emerging nations. Understanding the pathophysiology of this disease is key to developing rational therapeutic strategies to prevent or treat this disease. Development of type 2 diabetes is often preceded by defects in insulin-mediated glucose transport, a process that is regulated by the insulin-responsive facilitative glucose transporter, GLUT4. GLUT4 mediates the important physiologic effect of insulin to enhance glucose uptake into peripheral tissues including fat, heart and skeletal muscle. The molecular details of this process must therefore be thoroughly understood to comprehend the pathophysiology of type 2 diabetes. Recent work from our laboratory and others clearly indicates that the microtubule cytoskeleton plays a role in the insulin-mediated glucose uptake via GLUT4, but the specific function of microtubules in this process is unknown. Novel findings from our laboratory indicate that insulin signaling shifts the equilibrium in the cell from monomeric subunits (consisting of alpha- and beta-tubulin heterodimers) to polymeric tubulin, thus increasing the total size of the microtubule network in the cell. The insulin-dependent increase in polymerized tubulin is independent of PI 3-kinase activation and requires an intact actin cytoskeleton. The goals of this research proposal are 1) to determine how insulin exerts its signal on the microtubule cytoskeleton and 2} to begin to define the physiologic role of increased microtubule polymerization in response to insulin.