Regulation of insulin and insulin-like growth factor (IGF) responsiveness by IGFs in rat hepatoma cells.

We have previously reported that insulin induces a complete and reversible desensitization to the induction of tyrosine aminotransferase by insulin and insulin-like growth factors (IGFs) in HTC rat hepatoma cells. This loss of responsiveness cannot be accounted for by down-regulation of cell surface receptors, but occurs at a postbinding step in hormone action. Here we present evidence that IGF-I and IGF-II also induce desensitization to the actions of both IGFs and insulin and that this effect is mediated by IGF receptors. First, the concentration dependence for this effect is similar to that for the IGF-I and IGF-II induction of tyrosine aminotransferase, which has been shown to be mediated by IGF receptors. Second, antibody to the insulin receptor, which blocks insulin, but not IGF-II, binding to HTC cells, causes a rightward shift in the concentration dependence for insulin induction of desensitization, but does not significantly change the concentration dependence for IGF-II. These results indicate that IGF-II-induced desensitization to IGF-II is not mediated by the insulin receptor, but presumably by an IGF receptor. Although the IGFs do cause a moderate decrease in the binding of IGFs and insulin (to approximately 50-75% of the control value), this cannot account for the virtually complete desensitization to their actions. We conclude that IGFs, like insulin, induce a nearly complete loss of responsiveness to insulin and IGFs, that this effect is mediated via IGF receptors, and that desensitization occurs at a step distal to hormone binding which may be common to the actions of insulin and the IGFs.