Previous studies have identified three types of cellular defects that can cause insulin resistance in tissues: a) defect in binding of insulin to its receptor; b) defect in phosphorylation of the insulin receptor by tyrosine kinase; and c) a post-receptor defect. The biochemical nature of the postreceptor defect or postreceptor insulin resistance in unknown, although it plays an important role in decreased responsiveness of tissues to insulin after severe trauma, in obesity, and in diabetes mellitus. We propose to test the hypothesis that the postreceptor insulin resistance is due to a defect in signal transduction between the insulin receptor and cellular effectors, and specifically that it is due to the inability to produce mediators (2nd messengers) of insulin action in cells from the precursor, glycosyl-phosphatidyl-inositol, in the cell membrane. The studies will be performed on soleus muscles of rats denervated on one hindlimb and on muscles of obese Zucker rats and their lean littermates. The denervated muscle represents a unique tool for these studies because it is the only clean model of postreceptor insulin resistance available. Its postreceptor insulin resistance is not complicated by defects in insulin binding and receptor phosphorylation. The findings in the denervated muscles will be compared to receptor phosphorylation. The findings in the denervated muscles will be compared to findings in muscles of obese Zucker rats in which both the insulin binding defect and the postreceptor defect contribute to tissue insulin resistance. The significance of this investigation is that it will explain for the first time the postreceptor insulin resistance in biochemical terms and in that way provide the scientific basis for similar, but more targeted, studies in human insulin-resistant states. In preparation for these future studies, we will develop the borhydride assay for quantitation of the mediator in human tissue biopsies. This investigation will also contribute to the understanding of the detailed structure of the phosphoinositol glycan mediator which may lead to the development of synthetic analogs for treatment of insulin resistance.
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