DEFINING THE MOLECULAR COMPONENTS OF GLUT4 TRANSLOCATION

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In adipose tissue and skeletal muscle insulin induces the translocation o f GLUT4-containing vesicles to the ell surface resulting in an increase in glucose uptake. The mechanism of GLUT4 translocation is poorly understood. Recently several proteins involved in regulated exocytosis in neural and neuroendocrine tissues have been shown to be expressed in insulin-sensitive tissues. These proteins are components of the SNARE complex. In addition, members of the RAB family of small GTP-binding proteins that are involved in regulated endocytosis/exocytosis are also present in adipocytes and skeletal muscle. While these proteins have been implicated in insulin-regulated GLUT4 translocation no functional role has been determined. However, we have recently established that SNARE- complex proteins and specific members of the Rab family are necessary components in the GLUT4 translocation machinery. We have also identified a potentially novel protein that interacts with Rabs in adipocytes in an insulin-regulated manner. It is the purpose of this proposal to extend our preliminary observations to include a more detailed biochemical and cell biological analysis of these molecules. These studies will include experiments designed to investigate the specificity of protein-protein interactions between the SNARE proteins and their regulation by insulin, identification of other novel Rab-interacting proteins and pursuit of their molecular cloning. Data from these studies will allow us to define a more contemporary model of insulin-regulated glucose uptake.