GLUCOCORTICOID EXPOSURE IN LATE-GESTATION PERMANENTLY PROGRAMS RAT HEPATIC PHOSPHOENOLPYRUVATE CARBOXYKINASE AND GLUCOCORTICOID RECEPTOR EXPRESSION AND CAUSES GLUCOSE-INTOLERANCE IN ADULT OFFSPRING

Low birth weight in humans is predictive of insulin resistance and dia betes in adult life. The molecular mechanisms underlying this link are unknown but fetal exposure to excess glucocorticoids has been implica ted, The fetus is normally protected from the higher maternal levels o f glucocorticoids by fete-placental 11 beta-hydroxysteroid dehydrogena se type-2 (11 beta-HSD2) which inactivates glucocorticoids. We have sh own previously that inhibiting 11 beta-HSD2 throughout pregnancy in ra ts reduces birth weight and causes hyperglycemia in the adult offsprin g. We now show that dexamethasone (a poor substrate for 11 beta-HSD2) administered to pregnant rats selectively in the last week of pregnanc y reduces birth weight by 10% (P < 0.05), and produces adult fasting h yperglycemia (treated 5.3 +/- 0.3; control 4.3 +/- 0.2 mmol/liter, P = 0.04), reactive hyperglycemia (treated 8.7 +/- 0.4; control 7.5 +/- 0 .2 mmol/liter, P = 0.03), and hyperinsulinemia (treated 6.1 +/- 0.4; c ontrol 3.8 +/- 0.5 ng/ml, P = 0.01) on oral glucose loading, In the ad ult offspring of rats exposed to dexamethasone in late pregnancy, hepa tic expression of glucocorticoid receptor (GR) mRNA and phosphoenolpyr uvate carboxykinase (PEPCK) mRNA land activity) are increased by 25% ( P = 0.01) and 60% (P < 0.01), respectively, while other liver enzymes (glucose-6-phosphatase, glucokinase, and 11 beta-hydroxysteroid dehydr ogenase type-1) are unaltered. Tn contrast dexamethasone, when given i n the first or second week of gestation, has no effect on offspring in sulin/glucose responses or hepatic PEPCK and GR expression, The increa sed hepatic GR expression may be crucial, since rats exposed to dexame thasone in utero showed potentiated glucose responses to exogenous cor ticosterone. These observations suggest that excessive glucocorticoid exposure late in pregnancy predisposes the offspring to glucose intole rance in adulthood, Programmed hepatic PEPCK overexpression, perhaps m ediated by increased GR, may promote this process by increasing glucon eogenesis.