Familial hyperinsulinemia complicated by extreme insulin resistance during pregnancy: a probable postreceptor defect

Detailed studies of a family with hyperinsulinemia are reported. The index patient, a 30-yr-old woman with polycystic ovary syndrome, presented with gestational diabetes which was completely resistant to insulin in the presence of severe endogenous hyperinsulinemia. Sensitivity to insulin was regained after delivery. Therapy with cyproterone acetate and ethinyl estradiol for hirsutism exacerbated the hyperinsulinemia toward the levels occurring in pregnancy, with a concomitant deterioration of glucose tolerance. Five other members of her family also were found to have hyperinsulinemia together with high concentrations of circulating C-peptide. Antibodies to insulin and to insulin receptors were not detected, insulin antagonists were not increased, and insulin degradation in the circulation was normal. Insulin extracted from the patient's serum was identical to normal insulin by the criteria of Sephadex chromatography, placental membrane insulin receptor binding, and stimulation of 2-deoxyglucose uptake in isolated rat adipocytes. Although [125I]insulin binding to erythrocytes of all family members and to the patient's placental membranes was markedly reduced, binding to fibroblast cultures from the patient was normal. Insulin-stimulated glucose transport in these fibroblasts also was normal, but there was a mild (20%) reduction in the concentration of cytochalasin B-binding sites in erythrocyte ghosts. Insulin resistance in this family may be due to a partial defect distal to the insulin receptor. This is asymptomatic unless metabolic stresses (pregnancy or steroid administration) are superimposed.