Programming hyperglycaemia in the rat through prenatal exposure to glucocorticoids-fetal effect or maternal influence?

Abstract

In a previous study, we showed that exposure of rats to dexamethasone (Dex) selectively in late pregnancy produces permanent induction of hepatic phosphoenolpyruvate carboxykinase (PEPCK) expression and hyperglycaemia in the adult offspring. The mechanisms by which glucocorticoids cause this programming are unclear but may involve direct actions on the fetus/neonate, or glucocorticoids may act indirectly by affecting maternal postnatal nursing behaviour. Using a cross-fostering paradigm, the present data demonstrate that switching the offspring at birth from Dex-treated dams to control dams does not prevent induction of PEPCK or hyperglycaemia. Similarly, offspring born to control dams but reared by Dex-treated dams from birth maintain normal glycaemic control. During the neonatal period, injection of saline per se was sufficient to cause exaggeration in adult offspring responses to an oral glucose load, with no additional effect from Dex. However, postnatal treatment with either saline or Dex did not alter hepatic PEPCK activity. Prenatal Dex permanently raised basal plasma corticosterone levels, but under stress conditions there were no differences in circulating corticosterone levels. Likewise, Dex-exposed rats had similar plasma catecholamine concentrations to control animals. These findings show that glucocorticoids programme hyperglycaemia through mechanisms that operate on the fetus or directly on the neonate, rather than via effects that alter maternal postnatal behaviour during the suckling period. The hyperglycaemic response does not appear to result from abnormal sympathoadrenal activity or hypothalamic-pituitary-adrenal response during stress.

Is programming of glucocorticoid receptor expression by prenatal dexamethasone in the rat secondary to metabolic derangement in adulthood?

“…Trunk blood plasma corticosterone levels were similar in SHAM and CORT rats ( Fig. 1), and elevated relative to the normal circadian mean (26,27).…”

The Size and Distribution of Midbrain Dopaminergic Populations are Permanently Altered by Perinatal Glucocorticoid Exposure in a Sex- Region- and Time-Specific Manner

“…It would also appear that cross-fostering per se may not be without significant effects on maternal behaviors (Maccari et al, 1995) and has been reported to reduce baseline and nicotine-stimulated DA secretion in the nucleus accumbens (Kane et al, 2004). On the other hand, certain programming effects of prenatal dexamethasone treatment were unaffected by cross-fostering to control dams, suggesting that the GC effects operate directly in the fetus (Nyirenda et al, 2001). On balance, the foregoing considerations illustrate the value of selecting a minimally intrusive treatment protocol, along with exposure to modest doses of dexamethasone, as a valid approach to investigating neurobiological programming by GCs.…”

Prenatal Programming of Hypertension

“…Hyperglycemia, impaired insulin secretion, insulin resistance, and even frank diabetes in the offspring have been induced by some prenatal maneuvers with or without IUGR (55,60 -66). Underlying mechanisms may include decreased number of pancreatic ␤ cells (67)(68)(69), upregulation of hepatic enzymes that may convey insulin resistance (55,60), and upregulation of the glucocorticoid receptor (60,70,71). In contrast, Gatford et al (72) reported that 5-yr-old sheep made that were hypertensive by prenatal administration of dexamethasone exhibited unchanged insulin sensitivity.…”