Direct demonstration that receptor crosslinking or aggregation is important in insulin action

作者：C. Ronald Kahn, Kathleen L. Baird, David B. Jarrett, Jeffrey S. Flier · 发表于：Proceedings of the National Academy of Sciences · 年份：1978 · DOI：10.1073/pnas.75.9.4209 · 被引用次数：391 · 研究领域：Receptor Mechanisms and Signaling、Metabolism, Diabetes, and Cancer、Pancreatic function and diabetes

Exposure of adipocytes to antibodies to the insulin receptor results in a blockade of (125)I-labeled insulin binding, stimulation of glucose oxidation, and many more insulin-like effects. Allowing for differences in purity, antireceptor antibody is equipotent with insulin on a molar basis. Both the bivalent F(ab')(2) and monovalent Fab' fragments of the antireceptor antibody are fully active in inhibiting (125)I-labeled insulin binding. Bivalent F(ab')(2) also retains its insulin-like effects. In contrast, the monovalent Fab' loses almost all ability to stimulate glucose oxidation and acts as a competitive antagonist of insulin-stimulated glucose oxidation. Addition of anti-F(ab')(2) antisera, which crosslink the Fab'-receptor complexes, results in a restoration of the insulin-like activity of the antibody. Similarly, when cells are exposed to submaximal doses of insulin, addition of anti-insulin antibodies at low concentration enhances the biological activity of insulin. These data suggest that receptor occupancy by ligand is not sufficient for signal generation and that the insulin-like effects of antireceptor antibody (and perhaps insulin itself) require receptor aggregation or clustering. This aggregation, however, appears to be independent of microfilaments or microtubules because the insulin-like effects of antireceptor antibody, and in fact, of insulin itself, are unaffected by agents that are known to disrupt these structures.