The sulfonylurea glimepiride regulates intracellular routing of the insulin-receptor complexes through their interaction with specific protein kinaseC isoforms

Sulfonylureas may stimulate glucose metabolism by protein kinase C (PKC) ac tivation. Because interaction of insulin receptors with PKC plays an import ant role in controlling the intracellular sorting of the insulin-receptor c omplex, we investigated the possibility that the sulfonylurea glimepiride m ay influence intracellular routing of insulin and its receptor through a me chanism involving PKC, and that changes in these processes may be associate d with improved insulin action. Using human hepatoma Hep-G2 cells, we found that glimepiride did not affect insulin binding, insulin receptor isoform expression, and insulin-induced receptor internalization. By contrast, glim epiride significantly increased intracellular dissociation of the insulin-r eceptor complex, degradation of insulin, recycling of internalized insulin receptors, release of internalized radioactivity, and prevented insulin-ind uced receptor down-regulation. Association of PKC-beta II and -epsilon with insulin receptors was increased in glimepiride-treated cells. Selective de pletion of cellular PKC-beta II and -epsilon by exposure to 12-O-tetradecan oylphorbol-13-acetate (TPA) or treatment of cells with PKC-beta II inhibito r G06976 reversed the effect of glimepiride on intracellular insulin-recept or processing. Glimepiride increased the effects of insulin on glucose inco rporation into glycogen by enhancing both sensitivity and maximal efficacy of insulin. Exposing cells to TPA or G06976 inhibitor reversed these effect s. Results indicate that glimepiride increases intracellular sorting of the insulin-receptor complex toward the degradative route, which is associated with both an increased association of the insulin receptor with PKCs and i mproved insulin action. These data suggest a novel mechanism of action of s ulfonylurea, which may have a therapeutic impact on the treatment of type 2 diabetes.