Adrenocortical Imprint in the Fetus of a Diabetic Gestation

Abstract

Offspring of diabetics are at increased risk for diabetes as adults. As corticosteroids are intimately involved in glucose homeostasis, we investigated aspects of corticosteroid activity in the late gestation fetuses of control, moderately diabetic and insulin-controlled streptozotocin-induced diabetic rats. We found that moderate maternal diabetes had no effect upon litter size or fetal body weight. Uncontrolled maternal diabetes was accompanied by fetal hyperglycemia, hyperinsulinemia and elevated aldosterone. Maternal insulin treatment normalized fetal glucose and aldosterone; fetal insulin and corticosterone levels increased. Maternal diabetes had no effect upon fetal adrenal expression of P450scc mRNA; the abundance of P450c11β mRNA increased, and returned to that of the control gestation upon insulin treatment. P450c11AS mRNA was barely detectable, and decreased in the fetuses of insulin-treated diabetics. P450c11B3 mRNA was undetectable in all fetal groups. Our results implicate aspects of maternal diabetes in the expression of a fetal adrenocortical imprint, manifested as a greater abundance of P450c11β mRNA. Although not accompanied by elevated corticosterone in the fetus, this imprint could ultimately allow for greater potential corticosterone production in response to typical stimuli, and thus contribute to the tendency towards glucose dysregulation in these offspring of diabetic gestations.

Diabetic pregnancy in rats leads to impaired glucose metabolism in offspring involving tissue-specific dysregulation of 11β-hydroxysteroid dehydrogenase type 1 expression

“…Although it is well known that a maternal diabetic state provokes glucose intolerance and insulin resistance in the offspring, the cellular and molecular mechanisms for these phenomena remain unknown. Most previous studies of diabetic pregnant rats found that fetuses of diabetic mothers show hyperinsulinemia as a compensatory adaptation to maternal hyperglycemia (Pitkin and Van Orden, 1974;Malee and Wu, 1999). Otherwise, Kervan et al (1978) and we (Fujisawa et al, 2004) reported that severe hyperglycemia (20mmol/l b) in pregnant rats causes hypoinsulinemia in fetus due to speculated islet beta-cell exhaustion.…”

Streptozotocin-induced diabetes in the pregnant rat reduces 11 beta-hydroxysteroid dehydrogenase type 2 expression in placenta and fetal kidney

“…Most previous studies of diabetic pregnancy found that fetuses of diabetic mothers show hyperinsulinemia as a compensatory adaptation to maternal hyperglycemia (Pitkin and Van Orden, 1974;Conliffe and Mulay, 1988;Malee and Wu, 1999). Several studies showed that insulin levels in fetuses of diabetic mothers are not higher than control levels; rather they are low or normal (Holemans et al, 1991;Kervran et al, 1978).…”

Modulation of Cholesterol Transport by Insulin-Treated Gestational Diabetes Mellitus in Human Full-Term Placenta1

“…Utilization of CHOL by the fetal adrenal glands could also influence the levels of circulating lipoproteins. In diabetic animals, the adrenal function is impaired, which could result in a reduced utilization of circulating LDL [52,53]. However, the increased neonatal levels of FFA and indirectly the increased birth weight in normal-weight women with GDM could be due to the excessive internalization of lipoproteins into the placenta, the increased activity of LPL, and the increased expression of fatty acid carriers, such as CD36 in the case of obesity [54].…”