Research Centre for Early Origins of Health and Disease, Robinson Institute, and School of Paediatrics and Reproductive Health, University of Adelaide, SA 5005, Australia.
Placenta. 2010 Mar;31 Suppl(0):S60-5. doi: 10.1016/j.placenta.2009.12.015. Epub 2010 Jan 22.
Being born small due to poor growth before birth increases the risk of developing metabolic disease, including type 2 diabetes, in later life. Inadequate insulin secretion and decreasing insulin sensitivity contribute to this increased diabetes risk. Impaired placental growth, development and function are major causes of impaired fetal growth and development and therefore of IUGR. Restricted placental growth (PR) and function in non-human animals induces similar changes in insulin secretion and sensitivity as in human IUGR, making these valuable tools to investigate the underlying mechanisms and to test interventions to prevent or ameliorate the risk of disease after IUGR. Epigenetic changes induced by an adverse fetal environment are strongly implicated as causes of later impaired insulin action. These have been well-characterised in the PR rat, where impaired insulin secretion is linked to epigenetic changes at the Pdx-1 promotor and reduced expression of this transcription factor. Present research is particularly focussed on developing intervention strategies to prevent or reverse epigenetic changes, and normalise gene expression and insulin action after PR, in order to translate this to treatments to improve outcomes in human IUGR.
由于出生前生长不良导致出生时体重较轻，会增加日后患代谢性疾病（包括 2 型糖尿病）的风险。胰岛素分泌不足和胰岛素敏感性下降导致糖尿病风险增加。胎盘生长、发育和功能受损是胎儿生长和发育不良（即 IUGR）的主要原因。非人类动物的胎盘生长受限（PR）和功能受限会引起类似于人类 IUGR 的胰岛素分泌和敏感性变化，这使其成为研究潜在机制和测试预防或改善 IUGR 后疾病风险的干预措施的有价值工具。不良胎儿环境引起的表观遗传变化被强烈认为是导致胰岛素作用受损的原因。在 PR 大鼠中，这些变化已经得到了很好的描述，其中胰岛素分泌受损与 Pdx-1 启动子的表观遗传变化以及该转录因子表达减少有关。目前的研究特别侧重于开发干预策略，以预防或逆转 PR 后的表观遗传变化，并使基因表达和胰岛素作用正常化，以便将其转化为改善人类 IUGR 治疗结果的治疗方法。
