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

糖皮质激素和成人高血糖的胎儿编程：剖析基本分子机制

• 批准号: G0501934/1
• 负责人: Moffat Nyirenda
• 金额: $ 95.77万
• 依托单位: University of Edinburgh
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2006
• 资助国家: 英国
• 起止时间: 2006 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=G0501934%2F1
• 关键词: Glucocorticoids; foetal; programming; adult; hyperglycaemia

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.

低出生体重与成年后患糖尿病的风险增加有关。有人认为，子宫内的胎儿接触过量的“应激”类固醇激素（称为糖皮质激素）是一个潜在原因。在动物和人类中，产前糖皮质激素治疗可降低出生体重并永久升高血糖（高血糖）和血压。这些影响会遗传给后代，无需进一步糖皮质激素治疗。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。我们在大鼠肝脏中证明，这些效应可能是由 GR 和 HNF4a 两种基因的表达变化介导的。我们现在希望证明这个想法。此外，由于这些基因也存在于控制胰岛素分泌的胰腺中，因此我们将确定它们的表达是否也在该器官中紊乱，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代代相传的机制。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。它们还可能指出预防或改善糖尿病的方法，并告知糖皮质激素在孕妇和幼儿中的治疗用途。