SummaryPrevious studies have suggested that fetal hyperinsulinemia which occurs in offspring of diabetic mothers is responsible for diminished surfactant production and respiratory distress syndrome. Recognition of specific insulin effects on fetal lung tissue prompted us to characterize insulin receptors on plasma membranes of fetal rabbit lung tissue and to investigate the effects of maternal diabetes on such receptors. Six pairs of pregnant New Zealand rabbits were studied. One of each pair received alloxan (60 mg/kg) intravenously on day 14 of pregnancy, whereas the controls received saline. Animals were sacrificed on day 28 of gestation, and for each experiment, crude plasma membranes were prepared from maternal and pooled fetal lung tissue for125I-insulin binding studies. Plasma glucose values were elevated for both maternal diabetic (246 ± 81versus98.5 ± 7.1 mg/dl;P< 0.001) and fetal diabetic offspring (160 ± 69versus55 ± 12 mg/dl;P< 0.02) in comparison to controls. Fetal diabetic offspring had plasma insulin values significantly higher than control fetuses (84.8 ± 25versus23.2 ± 3.7 μU/ml), (mean ± S.D.);P< 0.05). Insulin was undetectable in diabetic mothers.Lung membranes from fetuses of diabetic animals bound significantly more insulin than did those of control fetuses. Scatchard analysis yielded curvilinear plots of bound fractionsversustotal amount of insulin bound suggesting the presence of more than one class of receptors or negative cooperativity. Assuming two classes of receptors, one of high affinity and low capacity and another of low affinity and high capacity, we found that fetal membranes had a five-fold increase in binding capacity of high-affinity receptors as compared to adult membranes. In spite of marked hyperinsulinemia in the offspring of the diabetic animal, the fetal lung, far from experiencing a down-regulation of insulin receptor binding, showed increased insulin binding. This finding is consistent with observations made previously on circulating monocytes of infants of diabetic mothers.