Insulin resistance and hypoglycemia in a patient with systemic lupus erythematosus: description of antiinsulin receptor antibodies that enhance insulin binding and inhibit insulin action.

We studied a patient with systemic lupus erythematosus and type B insulin resistance, who progressed from extreme insulin resistance to fasting hypoglycemia. The plasma insulin level was 63.3 +/- 20.9 pmol/L in the fasting state and rose above 1440 pmol/L postprandially. Intravenous administration of human insulin caused almost no decline in plasma glucose. Therefore, it was concluded that the patient was still resistant to insulin and that plasma insulin did not play a crucial role in the development of hypoglycemia. Immunoglobulin G from this patient did not inhibit insulin binding to the insulin receptor; rather, it enhanced [125I]insulin binding in both the immunoprecipitate and the in vitro binding assay to intact cells. Antiinsulin receptor antibodies strongly inhibited insulin internalization in human adipocytes, slowed down the dissociation of [125I]insulin from receptors and failed to induce down-regulation of surface insulin receptors in both the presence and absence of insulin. Finally, autoantibodies mimicked the insulin stimulatory effect on human fat cell lipogenesis even after long term exposure, but inhibited the metabolic potency of insulin when added simultaneously with the natural ligand. We conclude that antiinsulin receptor antibodies induce fasting hypoglycemia, through their continuous receptor stimulatory action, and insulin resistance, possibly by a conformational perturbation of the receptor protein, which, in turn, uncouples insulin receptor binding from receptor function.