THIS IS A SHANNON AWARD PROVIDING PARTIAL SUPPORT FOR THE RESEARCH PROJECTS THAT FALL SHORT OF THE ASSIGNED INSTITUTE'S FUNDING RANGE BUT ARE IN THE MARGIN OF EXCELLENCE. THE SHANNON AWARD IS INTENDED TO PROVIDE SUPPORT TO TEST THE FEASIBILITY OF THE APPROACH; DEVELOP FURTHER TESTS AND REFINE RESEARCH TECHNIQUES; PERFORM SECONDARY ANALYSIS OR AVAILABLE DATA SETS; OR CONDUCT DISCRETE PROJECTS THAT CAN DEMONSTRATE THE PI'S RESEARCH CAPABILITIES OR LEND ADDITIONAL WEIGHT TO AN ALREADY MERITORIOUS APPLICATION. THE ABSTRACT BELOW IS TAKEN FROM THE ORIGINAL DOCUMENT SUBMITTED BY THE PRINCIPAL INVESTIGATOR. DESCRIPTION (Adapted from Applicant's abstract): Insulin resistance is a major feature of NIDDM. The investigators find that membrane glycoprotein PC- 1 is elevated in fibroblasts from individuals with NIDDM, muscle of both lean, insulin-resistant non-diabetic subjects, and obese, insulin-resistant subjects; and tissues from the insulin- resistant, Wistar fatty rat. In cultured cells, when PC-1 is over expressed, insulin receptor tyrosine kinase activity is reduced, (but not IGF-I or EGF receptor kinases), and stimulation of biological function by insulin are decreased. To enhance the investigators understanding of PC-1, the investigators plan several types of studies. First, the investigators will measure PC-1 levels in activity in muscle specimens from insulin-resistant subjects. The investigators will study muscle specimens from lean, non-obese insulin-resistant subjects. The investigators will study muscle specimens from obese patients. The investigators will investigate the effect of weight loss and exercise training on PC-1 levels. The investigators will investigate effects of adrenalectomy, exercise and weight reduction on both insulin resistance and elevated PC-1 levels in the Wistar fatty rat. Third, the investigators will investigate the relationship between the degree of PC-1 expression and IR function in cultured liver, adipose and muscle cells. The investigators will study the relationship between the level of PC-1 over-expression and the degree of inhibition of IR signaling. Fourth, the investigators will study hormone and cytokine regulation of PC-1 levels in cultured cells including glucocorticoids, TNF-alpha and insulin. Fifth, the investigators will study direct protein-protein interactions between the IR and PC-1 by both employing studies in vivo and purified IR and PC-1 in vitro. Sixth, the investigators will mutate major PC-1 domains. The above series of studies therefore should provide information concerning the role of PC-1 in insulin resistance.
