Insulin Regulation of Adipocyte Microtubules

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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.