Insulin Resistance and Diabetes due to a Genetic Defect in Insulin Receptors*

A 14-yr-old woman presented with fasting hyperglycemia (269 mg/dl), fasting hyperinsulinemia (45 microU/ml), acanthosis nigricans, and insulin resistance. The patient's circulating insulin was normal by physical and biological criteria, and insulin receptor antibodies were not detected. Both the patient's in vivo dose-response curve for insulin-stimulated glucose transport in isolated adipocytes were shifted to the right and showed marked decreases in the maximal insulin response. Basal hepatic glucose output was significantly increased, and the in vivo dose-response curve for insulin-mediated suppression of basal hepatic glucose output was shifted to the right. Insulin binding to the patient's erythrocytes, monocytes, and adipocytes was markedly decreased. To confirm that the severe reduction in cellular insulin receptors was a primary rather than an acquired defect, similar studies were conducted using cultured fibroblasts. No detectable binding of insulin to these cells was observed. Further studies showed that the patient's mother and two sisters were hyperinsulinemic and insulin resistant, and had comparable, although less severe, changes in insulin binding. The patient was also demonstrated to have an insulin secretory defect both to both oral and iv glucose challenges. We thus conclude that this family demonstrates a genetic deficiency of insulin receptors, resulting in insulin resistance and, in this patient, severe diabetes mellitus.