PRENATAL GLUCOCORTICOID EXPOSURE LEADS TO OFFSPRING HYPERGLYCEMIA IN THE RAT - STUDIES WITH THE 11-BETA-HYDROXYSTEROID DEHYDROGENASE INHIBITOR CARBENOXOLONE

Recent human epidemiological studies have linked low birth weight with a substantially increased risk of non-insulin-dependent diabetes mell itus in later life. These data suggest that the intrauterine environme nt plays a crucial role in determining later glucose homeostasis, but the mechanism is unknown. We have proposed that exposure of the fetus to excess maternal glucocorticoids may underpin the epidemiological fi ndings. Normally placental 11 beta-hydroxysteroid dehydrogenase type 2 (11 beta-HSD-2) protects the fetus from the normally higher maternal levels of glucocorticoids by inactivating corticosterone and cortisol to inert Il-keto products. Here we show that administration of carbeno xolone, an inhibitor of placental 11 beta-HSD 2, to pregnant rats, lea ds to a significant reduction in average birth weight (20 % fall). At 6 months of age, the male offspring of carbenoxolone-treated pregnanci es had similar weights to controls, but showed significantly higher fa sting plasma glucose (6.0 +/- 0.3 vs 4.8 +/- 0.2 mmol/l; p < 0.01) and exhibited significantly greater plasma glucose (10 % higher) and insu lin (38 % higher) responses to an oral glucose load. These effects of carbenoxolone require intact maternal adrenal glands suggesting that i nhibition of fete-placental 11 beta-HSD 2 is key. These data support t he notion that defiency of placental 11 beta-HSD, by exposing the fetu s to excess maternal glucocorticoids, reduces growth and predisposes t o hyperglycaemia in later life.