Glucocorticoid exposure in late gestation permanently programs rat hepatic phosphoenolpyruvate carboxykinase and glucocorticoid receptor expression and causes glucose intolerance in adult offspring.

May 29, 1998The Journal of clinical investigation

Late pregnancy stress hormone exposure permanently changes liver metabolism and causes glucose intolerance in adult rats

AI simplified

Circadian Biology on OpenScience ↗PubMed ↗DOI ↗

Abstract

Dexamethasone exposure in late pregnancy reduces birth weight by 10% and leads to significant metabolic changes in adult offspring.

Adult offspring exposed to dexamethasone show fasting hyperglycemia (5.3 +/- 0.3 mmol/liter) compared to controls (4.3 +/- 0.2 mmol/liter).
Reactive hyperglycemia is also increased in treated offspring (8.7 +/- 0.4 mmol/liter) versus controls (7.5 +/- 0.2 mmol/liter).
Hyperinsulinemia is observed in treated offspring at 6.1 +/- 0.4 ng/ml, while control levels are 3.8 +/- 0.5 ng/ml.
Hepatic expression of glucocorticoid receptor mRNA is increased by 25%, and phosphoenolpyruvate carboxykinase mRNA is increased by 60% in adult offspring exposed to dexamethasone.
No significant changes are noted in other liver enzymes like glucose-6-phosphatase and glucokinase in the treated group.
Dexamethasone exposure late in pregnancy may predispose offspring to glucose intolerance through enhanced gluconeogenesis.

AI simplified

Low birth weight in humans is predictive of insulin resistance and diabetes in adult life. The molecular mechanisms underlying this link are unknown but fetal exposure to excess glucocorticoids has been implicated. The fetus is normally protected from the higher maternal levels of glucocorticoids by feto-placental 11beta-hydroxysteroid dehydrogenase type-2 (11beta-HSD2) which inactivates glucocorticoids. We have shown previously that inhibiting 11beta-HSD2 throughout pregnancy in rats reduces birth weight and causes hyperglycemia in the adult offspring. We now show that dexamethasone (a poor substrate for 11beta-HSD2) administered to pregnant rats selectively in the last week of pregnancy reduces birth weight by 10% (P < 0.05), and produces adult fasting hyperglycemia (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; control 3.8+/-0.5 ng/ml, P = 0.01) on oral glucose loading. In the adult offspring of rats exposed to dexamethasone in late pregnancy, hepatic expression of glucocorticoid receptor (GR) mRNA and phosphoenolpyruvate carboxykinase (PEPCK) mRNA (and activity) are increased by 25% (P = 0.01) and 60% (P < 0.01), respectively, while other liver enzymes (glucose-6-phosphatase, glucokinase, and 11beta-hydroxysteroid dehydrogenase type-1) are unaltered. In contrast dexamethasone, when given in the first or second week of gestation, has no effect on offspring insulin/glucose responses or hepatic PEPCK and GR expression. The increased hepatic GR expression may be crucial, since rats exposed to dexamethasone in utero showed potentiated glucose responses to exogenous corticosterone. These observations suggest that excessive glucocorticoid exposure late in pregnancy predisposes the offspring to glucose intolerance in adulthood. Programmed hepatic PEPCK overexpression, perhaps mediated by increased GR, may promote this process by increasing gluconeogenesis.

Full Text

Full text is available at the source.

View full text ↗

Glucocorticoid exposure in late gestation permanently programs rat hepatic phosphoenolpyruvate carboxykinase and glucocorticoid receptor expression and causes glucose intolerance in adult offspring.

Abstract

Full Text

You found one interesting study. We’ll send the next 7.

what lands in your inbox each week:

Recent issues from the circadian biology brief