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

AUTOR(ES)

Karlsson, F. Anders

RESUMO

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-deoxy-glucose 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 cells 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 a 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.

Documentos Relacionados

• Heterologous desensitization of bombesin-induced mitogenesis by prolonged exposure to vasopressin: a post-receptor signal transduction block.
• Effects of insulin incubation on insulin binding, glucose transport, and insulin degradation by isolated rat adipocytes. Evidence for hormone-induced desensitization at the receptor and postreceptor level.
• Desensitization of the insulin receptor by antireceptor antibodies in vivo is blocked by treatment of mice with beta-adrenergic agonists.
• Characterization of human rhinoviruses displaced by an anti-receptor monoclonal antibody.
• Analysis of the insulin receptor by anti-receptor antibodies and flow cytometry.