Glucocorticoids and foetal programming of adult hyperglycaemia: dissecting the fundamental molecular mechanisms

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Low birth weight is associated with increased risk of diabetes in adulthood. Exposure of the foetus in the womb to excess ‘stress‘ steroid hormones called glucocorticoids has been suggested as a potential cause. In animals and humans prenatal glucocorticoid treatment reduces birth weight and permanently elevates blood glucose (hyperglycaemia) and blood pressure. These effects are passed onto future generations without further glucocorticoid treatment. Stressful events/illnesses during pregnancy increase glucocorticoid levels, and may have similar long-term effects. We have shown in rat liver that these effects might be mediated by changes in expression of two genes called GR and HNF4a. We now wish to prove this notion. Additionally, because these genes are also present in the pancreas where they control insulin secretion, we will determine whether their expression is also deranged in this organ and whether this causes disturbed insulin secretion. We also wish to elucidate the mechanisms through which the changes in these genes are inherited across generations. These studies may provide new insights into causes of diabetes, and its link with low birth weight. They may also indicate ways of preventing or ameliorating diabetes, as well as inform the therapeutic use of glucocorticoids in pregnant mothers and young babies.