Effects of metalloendoprotease inhibitors on insulin binding, internalization and processing in adipocytes

The effects of metalloendoprotease inhibitors on insulin binding, internalization, and processing were studied in isolated rat adipocytes. The metalloendoprotease inhibitor phosphoramidon caused a marked (threefold) increase in intracellular insulin accumulation without affecting surface binding. The dipeptide metalloendoprotease substrate analogues benzyloxycarbonyl-Gly-Phe-NH2 and benzyloxycarbonyl-Gly-Leu-NH2 caused similar large increases in intracellular insulin but also caused a doubling of cell surface bound insulin. The effect on surface binding was due to increased insulin receptor affinity as demonstrated by Scatchard analysis and the benzyloxycarbonyl-Gly-Phe NH2 induced inhibition of the dissociation of prebound insulin from the cell surface. These results suggest a role for endogenous metalloendoprotease-like enzymes in insulin processing by rat adipocytes.