Maternal exposure to dexamethasone or cortisol in early pregnancy differentially alters insulin secretion and glucose homeostasis in adult male sheep offspring

Miles J De Blasio, Miodrag Dodic, Andrew John Jefferies, Karen Margaret Moritz, Marelyn Wintour-Coghlan, Julie A Owens

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Abstract

An adverse intra-uterine environment increases the risk of developing various adult-onset diseases, whose nature varies with the timing of exposure. Maternal undernutrition in humans can increase adiposity, and the risk of coronary heart disease and impaired glucose tolerance in adult life, which may be partly mediated by maternal or fetal endocrine stress responses. In sheep, dexamethasone in early pregnancy impairs cardiovascular function, but not glucose homeostasis in adult female offspring, however male offspring are often more susceptible to early life programming . Pregnant sheep were infused intravenously with saline (0.19 ml/hour), dexamethasone (0.48 mg/hour) or cortisol (5 mg/hour), for 2 days from 26 to 28 days gestation. In male offspring, size at birth and postnatal growth were measured, and glucose tolerance (intravenous glucose tolerance test (IVGTT)), insulin secretion and insulin sensitivity of glucose, alpha-amino nitrogen and free fatty acid metabolism were assessed at 4 years of age. We show that cortisol but not dexamethasone treatment of mothers causes fasting hyperglycaemia in adult male offspring. Maternal cortisol induced a 2nd phase hyperinsulinaemia during IVGTT, whereas maternal dexamethasone induced a 1st phase hyperinsulinaemia. Dexamethasone improved glucose tolerance, while cortisol had no impact, and neither affected insulin sensitivity. This suggests that maternal glucocorticoid exposure in early pregnancy alters glucose homeostasis and induces hyperinsulinaemia in adult male offspring, but in a glucocorticoid specific manner. These consequences of glucocorticoid exposure in early pregnancy may lead to pancreatic exhaustion and diabetes longer term and are consistent with stress during early pregnancy contributing to such outcomes in humans. Key words: glucocorticoids, early pregnancy, insulin secretion, sheep, glucose tolerance.
Original languageEnglish
Pages (from-to)E75 - E82
Number of pages8
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Volume293
Issue number1
Publication statusPublished - 2007

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