Desensitization of the insulin receptor at an early postreceptor step by prolonged exposure to antireceptor antibody

Abstract

An adipocyte-like cell line, the 3T3-L1 fatty fibroblasts, was used to compare acute and chronic effects of autoantibodies directed against the insulin receptor. Acute exposure of the cells in tissue culture to the antibodies [Ab] resulted in a blockade of insulin binding and stimulation of 2-deoxyglucose transport and glucose oxidation. Maximal acute effects were reached within 30-120 min. The stimulatory response decayed and, after 6 h in the continuous presence of the Ab, basal glucose metabolism had returned to the level observed with unexposed cells and a state of severe insulin resistance prevailed. No change in insulin binding was detectable over the same time period. The mechanism of desensitization seemed to involve events early after insulin binding to receptor because cells exposed to Ab for prolonged periods of time, although unresponsive to insulin and anti-receptor Ab, responded normally to spermine and vitamin K5, agents that stimulate glucose metabolism independently of the insulin receptor. Prolonged or continuous occupancy of the insulin receptor by a ligand, in this case anti-receptor Ab, may not produce a continuous biological response. There may be desensitization at some early step in the pathway for insulin action. These observations have important implications with respect to the mechanism of insulin action and to other situations in which there is long-term exposure of cells to Ab that react with membrane components.