Noninsulin-dependent diabetes mellitus (NIDDM) is characterized by both insulin resistance and relative insulin deficiency. The insulin resistance is present early in the disease and in individuals at high risk for developing diabetes. A key component of insulin resistance is the inability of insulin to stimulate the uptake of glucose into insulin- sensitive tissues, primarily muscle and fat. This transport is primarily mediated by GLUT4, the insulin-responsive glucose transporter, that is retained in vesicles within the cell and translocated to the plasma membrane in response to insulin. At present, no drugs effectively overcome this insulin resistance and significantly enhance glucose transport, the primary defect in NIDDM. This program will establish several cell-based assays that will permit high-throughput screening of compound libraries to identify new molecules of potential therapeutic use in NIDDM. These assays will assess effects on glucose transport in an appropriate cellular model of insulin action and the translocation event directly. Surrogate markers of translocation as well as insertion of a marker directly into GLUT4 will be used to monitor the translocation process. Molecules that are identified that enhance or mimic insulin action on glucose transport will be attractive leads for drug development. As essentially no treatments currently available effectively deal with insulin resistance, drugs identified by this strategy are highly desirable and could substantially change the therapeutic options in NIDDM and insulin resistance. PROPOSED COMMERCIAL APPLICATION: A novel screening system will be developed to permit identification of molecules that could be used to treat noninsulin-dependent diabetes mellitus.