Autoantibodies to insulin receptors in man: immunological determinants and mechanism of action.

The insulin receptor is a membrane glycoprotein of high Mr which binds insulin with high affinity and specificity and transmits some intracellular signal(s) that initiate(s) insulin action. Antibodies to the receptor have been identified in patients with a syndrome characterized by severe resistance to endogenous and exogenous insulin, varying degrees of glucose intolerance, and the skin lesion acanthosis nigricans. The syndrome is most common in non-Caucasian, middle-aged women, but occurs in patients of all races, both sexes, and spanning the ages of 12-62. Most patients have evidence of other autoimmune disease with increased erythrocyte sedimentation rate and gamma globulins, anti-DNA and anti-nuclear antibodies, leucopenia, and other signs and symptoms of autoimmune disease. Antibodies to the insulin receptor are detected by their ability to inhibit 125I-insulin binding or to immunoprecipitate solubilized insulin receptors. In vitro these antibodies acutely mimic most of insulin's metabolic effects. This insulin-like activity depends on antibody bivalence; monovalent Fab fragments block insulin binding and action but lack intrinsic activity. With prolonged exposure of cells to anti-receptor antibody the insulin-like effect is lost and a state of insulin resistance ensues. This is due to both a blockage of insulin binding and a form of post-receptor desensitization. The possible causation of anti-receptor antibodies in this condition is discussed.