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

低出生体重与成年后患糖尿病的风险增加有关。胎儿在子宫中暴露于过量的“压力”类固醇激素（称为糖皮质激素）被认为是一个潜在的原因。在动物和人类中，产前糖皮质激素治疗降低了出生体重，并永久性地升高了血糖（高血糖）和血压。这些影响传递给后代，而无需进一步的糖皮质激素治疗。怀孕期间的压力事件/疾病会增加糖皮质激素水平，并可能产生类似的长期影响。我们在大鼠肝脏中发现，这些作用可能是由两种称为GR和HNF 4a的基因表达的变化介导的。我们现在要证明这个概念。此外，由于这些基因也存在于胰腺中，它们控制胰岛素分泌，我们将确定它们的表达是否也在这个器官中紊乱，以及这是否会导致胰岛素分泌紊乱。我们还希望阐明这些基因的变化在几代人之间遗传的机制。这些研究可能为糖尿病的病因及其与低出生体重的联系提供新的见解。它们还可能表明预防或改善糖尿病的方法，以及告知糖皮质激素在孕妇和婴儿中的治疗用途。

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.