DESENSITIZATION OF THE INSULIN RECEPTOR AT AN EARLY POST-RECEPTOR STEP BY PROLONGED EXPOSURE TO ANTI-RECEPTOR ANTIBODY

We have used an adipocyte-like cell line, the 3T3-L1 fatty fibroblasts, to compare acute and chronic effects of autoantibodies directed against the insulin receptor. Acute exposure of the cells in tissue culture to the antibodies 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. Subsequently, the stimulatory response decayed and, after 6 hr in the continuous presence of the antibodies, basal glucose metabolism had returned to the level observed with unexposed cells and a state of severe insulin resistance prevailed. In contrast to the decay of bioresponse, 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 cell exposed to antibody for prolonged periods of time, although unresponsive to insulin and antireceptor antibodies, responded normally to both spermine and vitamin K5, agents that stimulate glucose metabolism independently of the insulin receptor. These data suggest that prolonged or continuous occupancy of the insulin receptor by a ligand, in this case antireceptor antibodies, does not produce an continuous biological response. Instead, there is 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 antibodies that react with membrane components.