Hypothyroidism and glucocorticoids modulate the development of hepatic insulin receptors

We investigated the influence of hypothyroidism and of gluco-corticoid treatment on the in utero and postnatal maturation of insulin receptors on partially purified liver plasma membranes of the rabbit. Treatment of pregnant does with propylthiouracil (PTU) 200 mg/day plus thyroxine (T4) 20 µg on alternate days resulted in fetal but not maternal hypothyroidism because PTU crosses the placenta whereas T4 does not (fetal free T4 undetect-able compared to control of 0.21 ± 0.012 ng/dl; mean ± S.E.). At 28 days of gestation (term ~31 days), insulin binding and receptor number of hypothyroid animals was only 50% of that found in controls (P < 0.01). Intramuscular injection of betamethasone (0.085 mg/kg) to mothers on days 25 and 26 of gestation sup-pressed fetal corticosterone concentration at day 28 of gestation from 10.5 ± 1.5 ng/ml (mean ± S.E.) in controls to 2.1 ± 0.28 ng/ ml (P < 0.01); insulin binding and receptor number was ~50% of controls (P < 0.01). Using the two-site receptor model, the decrease in receptor number induced by hypothyroidism and glucocorticoids was due solely to reduction in the number of low-affinity sites without any change in the high affinity sites or affinity constants of either receptor class. Ongoing treatment with PTU for 6 postnatal days produced persistant hypothyroidism (free T4 0.15 ± 0.1 ng/dl versus control 0.73 ± 0.1 ng/dl, P < 0.01) physical signs of immaturity, and prevented the normal postnatal maturation of insulin receptor characteristics. Insulin binding was reduced (P < 0.02) and the proportion of high and low affinity receptor sites remained similar to those of 28-day-old fetuses. In contrast, normal maturational changes in insulin receptor characteristics were evident on day 6 in the liver membranes of animals simultaneously receiving PTU and replacement T4 (free T4 0.63 ± 0.17 versus control 0.73 ±0.1 ng/dl). Thus, the normal pattern of hepatic insulin receptor development can be modulated by hypothyroidism and glucocorticoid exposure.