Age-related changes in insulin receptor regulation in liver membranes from Zucker fatty rats

Hyperinsulinemic obese rodents have been shown to have reduced insulin binding to liver plasma membranes, a finding consistent with the model of down-regulation of insulin receptors by hyperinsulinemia. In contrast, hepatocytes from the hyperinsulinemic Zucker fatty rat were reported to have insulin binding equivalent to that of lean littermates. We have isolated liver plasma membranes from Zucker fatty rats 10 weeks, 5 months, and 1 yr of age and from fatty rats diet restricted until 5 months and 1 yr of age. We found no evidence for down-regulation of hepatic insulin receptors at 10 weeks of age. However, at 5 months and 1 yr of age there was marked down-regulation evident in isolated liver plasma membranes. Scatchard plots of the data are consistent with a decreased number of receptors rather than changes in receptor affinity accounting for the decreased binding. Diet restriction of the fatty rats resulted in lower plasma insulin levels and less marked down-regulation of hepatic insulin receptors. Our results are consistent with the hypothesis that in developing obesity there is a pattern of developing insulin resistance, first seen in muscle, later in fat, and finally in liver. Regulation of insulin receptors by hyperinsulinemia is probably less important than prior alterations in tissue metabolism by hyperinsulinemia in accounting for insulin resistance.