UREMIA--EFFECTS ON INSULIN BINDING & RECEPTOR FUNCTION

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Uremia is a state characterized by muscle protein wasting and insulin resistance. It is not known how uremia impairs insulin action, but the uremia-induced defect(s) appear to involve processes other than the binding of insulin to its receptor. To study glucose metabolism and protein turnover, rat epitrochlearis muscles will be incubated in defined media supplemented with D-(U-14 C) glucose and D-(2-3 H) glucose and varying concentrations of insulin. These responses to insulin will be compared to ligand binding and stimulation of insulin receptor phosphorylation and tyrosine kinase activity from both partially purified muscle receptors and receptors present in sarcolemmal vesicles obtained from the same rats. Results from studies involving muscles of uremic and control rats will be compared to better understand how these functions related to the biologic functions of insulin and, in turn, whether they are affected by uremia. Since the metabolic acidosis accompanying uremia appears responsible for the muscle wasting and perhaps insulin resistance, parallel studies will be conducted on uremic rats receiving dietary NaHCO3 to define how acidosis contributes to the insulin resistance of uremia. Finally, the effects of varying dietary protein will be examined to assess how these interventions affect insulin response and insulin receptor function.