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。子宫内胎儿暴露于过量的名为糖皮质激素的“应激”类固醇激素被认为是潜在的原因。在动物和人类中，产前糖皮质激素治疗可降低新生儿体重，并永久性地升高血糖(高血糖)和血压。这些影响会在没有进一步糖皮质激素治疗的情况下遗传给后代。怀孕期间的应激事件/疾病会增加糖皮质激素水平，并可能产生类似的长期影响。我们已经在大鼠肝脏中表明，这些效应可能是通过两个基因GR和HNF4a表达的变化来调节的。我们现在希望证明这一观点。此外，由于这些基因也存在于控制胰岛素分泌的胰腺中，我们将确定它们的表达是否也在这个器官中错乱，以及这是否会导致胰岛素分泌障碍。我们还希望阐明这些基因的变化是通过什么机制代代相传的。这些研究可能会为糖尿病的病因及其与低出生体重的联系提供新的见解。它们还可以指出预防或改善糖尿病的方法，以及在孕妇和婴儿中使用糖皮质激素的治疗方法。

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.