Regulation of insulin receptors: evidence for involvement of an endocytotic internalization pathway.

Cultured human fibroblasts degrade insulin by a receptor-mediated process. When intracellular hormone degradation is inhibited by chloroquine, 125I-labeled insulin internalizes and accumulates intracellularly. In contrast, cultured IM-9 lymphocytes do not degrade receptor-bound insulin or accumulate 125I-labeled insulin in the presence of chloroquine. Insulin-induced receptor loss occurs in both cell types, and chloroquine inhibits this process in fibroblasts but not in IM-9 lymphocytes. Transglutaminase is a membrane-associated enzyme thought to mediate the process of ligand-induced receptor aggregation and internalization; levels of this enzyme were high in fibroblasts but barely detectable in IM-9 lymphocytes. Furthermore, dansylcadaverine--a potent inhibitor of transglutaminase--blocked insulin-induced receptor loss in fibroblasts but was without effect in IM-9 lymphocytes. These results support the concept that insulin receptor regulation is mediated via an endocytotic internalization pathway in human fibroblasts and that the mechanisms of this process differ among cell types.