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We have developed a model in the rat that leads to a predictable degree of severe uremia to study the role of the liver in the insulin-resistant state of uremia. The uremic animals were euglycemic and had increased serum immunoreactive insulin when compared with their pair-fed controls. Insulin action, binding, internalization, and degradation were characterized in freshly isolated hepatocytes from uremic animals, sham-operated pair-fed, and ad lib.-fed controls. The basal rate of aminoisobutyric acid (AIB) uptake was increased in hepatocytes from both uremic and pair-fed control rats. However, while hepatocytes from uremic animals were refractory to insulin with regard to AIB uptake, there was no significant difference in the absolute increment above basal AIB uptake by hepatocytes from pair-fed and fed ad lib. animals at any insulin concentration studied. 125I-Insulin binding at 24 degrees C was higher in hepatocytes from uremic rats at every insulin concentration studied when compared with fed ad lib. controls. The time course of 125I-insulin binding to the cell and to the fractions that were membrane bound or internalized were studied at 37 degrees C. An increase in membrane-bound 125I-insulin at 37 degrees C was present also in hepatocytes from uremic animals. The same fraction of membrane-bound 125I-insulin was internalized in hepatocytes from all groups of animals. Extracellular and receptor-mediated 125I-insulin degradation at the plasma membrane and after internalization was studied at 37 degrees C by gel chromatography. There was a delayed and decreased rate of 125I-insulin degradation in hepatocytes from uremic rats in the three compartments. We conclude: (a) In chronic uremia the liver is refractory to insulin with regard to AIB uptake. (b) Insulin resistance in uremic rat liver is not due to defects in insulin binding or internalization. (c) Despite the high level of circulating immunoreactive insulin, hepatocytes from uremic rats did not show the expected "down regulation" of their insulin receptors or an increased rate of insulin degradation. These studies further emphasize the primary role of postbinding events in the regulation of insulin binding and degradation. The mechanism as to how the coordinated steps of insulin metabolism in the liver are disrupted in a pathological state is presently unknown.

Insulin resistance in uremia. Characterization of insulin action, binding, and processing in isolated hepatocytes from chronic uremic rats.