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

Abstract

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 11 ␤ -hydroxysteroid dehydrogenase type-2 (11 ␤ -HSD2) which inactivates glucocorticoids. We have shown previously that inhibiting 11 ␤ -HSD2 throughout pregnancy in rats reduces birth weight and causes hyperglycemia in the adult offspring. We now show that dexamethasone (a poor substrate for 11 ␤ -HSD2) administered to pregnant rats selectively in the last week of pregnancy reduces birth weight by 10% ( P Ͻ 0.05), and produces adult fasting hyperglycemia (treated 5.3 Ϯ 0.3; control 4.3 Ϯ 0.2 mmol/ liter, P ϭ 0.04), reactive hyperglycemia (treated 8.7 Ϯ 0.4; control 7.5 Ϯ 0.2 mmol/liter, P ϭ 0.03), and hyperinsulinemia (treated 6.1 Ϯ 0.4; control 3.8 Ϯ 0.5 ng/ml, P ϭ 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 ϭ 0.01) and 60% ( P Ͻ 0.01), respectively, while other liver enzymes (glucose-6-phosphatase, glucokinase, and 11 ␤ -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.

The Intrauterine Environment as Reflected by Birth Size and Twin and Zygosity Status Influences Insulin Action and Intracellular Glucose Metabolism in an Age- or Time-Dependent Manner

“…Vuguin et al (31) reported an elevated basal hepatic glucose production in normoglycemic intrauterine growth-retarded rats compared with control rats, indicating that uteroplacental insufficiency causes a primary defect in hepatic metabolism before the onset of overt hyperglycemia. Another study in animals demonstrated that an adverse intrauterine environment induced by dexamethasone resulted in overexpression of hepatic PEPCK and increased gluconeogenesis (32). Furthermore, maternal hypoxia (33) and protein deprivation (34) during pregnancy resulted in overexpression of PEPCK and downregulation of glucokinase, with the net effect of inappropriately elevated hepatic glucose production.…”

Glucocorticoid signalling affects pancreatic development through both direct and indirect effects

“…In humans it is known that prenatal exposure to prednisone or maternal Cushing's syndrome is associated with intrauterine growth retardation (IUGR) [11,12]. In rodents, fetal exposure to glucocorticoids induces IUGR at birth, and impaired glucose tolerance [13][14][15] and hypertension [16,17] at adult age. Numerous studies have investigated the deleterious effects of glucocorticoids on pancreatic beta cell function, showing altered glucosestimulated insulin release, both in vitro in islets treated with dexamethasone [18][19][20] and in vivo in mice overexpressing GR in the beta cells [21,22].…”

Efeito da administração pré-natal da dexametasona em ratas sobre os perfis glicídicos e hematológicos materno e da prole

“…Porém, aos 10 dias de idade, apenas os filhotes nascidos das fêmeas tratadas por 14 dias apresentaram aumento significativo da concentração sérica de carboidratos totais em relação aos das ratas do grupo-controle. Isto pode estar relacionado ao potencial da dexametasona em induzir o desenvolvimento da resistência insulina em ratos jovens (Nyirenda et al, 1998), pois, nos primeios dias de vida, a glicemia em ratos sofre grandes variações, em parte atribuídas a alterações abruptas no teor de enzimas responsáveis pela disponibilização da glicose hepática para o sangue, sendo a resistência à insulina um fator intensificador desse efeito (Carvalheira, 2002).…”

“…Durante a gestação, o transporte transplacentário de glicocorticoides é regulado pelas enzimas 11β-hidroxiesteroide desidrogenase (11β-HSD) tipo 1 e 2, que atuam na reativação e inativação de glicocorticoides, respectivamente, regulando a exposição do feto a esses fármacos (Diederich et al, 2002). Devido à progressiva redução da bioatividade da enzima 11β-HSD2 ao longo da gestação (Waddell et al, 1998), o terço final é o período de gestação em que ocorre maior permissibilidade do tráfego de glicocorticoides, levando a alterações fisiológicas, como a elevação do nível glicêmico pós-natal, a redução da síntese de receptores para insulina e a mobilização de glicogênio para a corrente sanguínea (Nyirenda et al, 1998).…”