Abstract
Summary: Previous 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 for 125I-insulin binding studies. Plasma glucose values were elevated for both maternal diabetic (246 ± 81 versus 98.5 ± 7.1 mg/dl; P < 0.001) and fetal diabetic offspring (160 ± 69 versus 55 ± 12 mg/dl; P < 0.02) in comparison to controls. Fetal diabetic offspring had plasma insulin values significantly higher than control fetuses (84.8 ± 25 versus 23.2 ± 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 fractions versus total 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.
Speculation: Hyperinsulinemia occurring postnatally appears to lead to down-regulation of insulin binding. Although the mechanisms of down-regulation are not clearly understood, from a teleological standpoint the phenomenon may be viewed as partially protecting the organism from the effects of hyperinsdinism because less binding sites are available for insulin to exert its effects on target tissues. In the fetus, this protective mechanism does not appear to exist in at least two tissues examined thus far, circulating monocytes of the human and lung tissue of the rabbit. The fetus with hyperinsulinemia may therefore be subject to the double jeopardy of higher concentrations of insulin and higher binding of insulin to its target tissues.
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Neufeld, N., Corbo, L. & Kaplan, S. Plasma Membrane Insulin Receptors in Fetal Rabbit Lung. Pediatr Res 15, 1058–1062 (1981). https://doi.org/10.1203/00006450-198107000-00017
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DOI: https://doi.org/10.1203/00006450-198107000-00017