The impact of metformin exposure on placental ageing, metabolism, and mitochondrial function

二甲双胍是一种常见的处方药在怀孕在许多全球设置。在过去5年中，二甲双胍已被英国、美国和新西兰等国家的国家机构认可为治疗妊娠期糖尿病（GDM）的胰岛素的可接受和经济替代品。美托洛尔还用于妊娠期间的其他适应症，例如产妇肥胖和多囊卵巢。随着全球GDM风险因素（如肥胖和孕妇年龄）的增加，孕妇使用二甲双胍的比例可能会上升。此外，计划在低资源环境下进行妊娠期二甲双胍的新试验，特别是在亚洲和非洲。试验表明，二甲双胍可以限制孕妇在怀孕期间的体重增加，并稳定血糖。然而，目前尚不清楚二甲双胍如何影响胎盘功能或长期影响婴儿的生长。我们对二甲双胍治疗GDM试验的荟萃分析显示，与胰岛素治疗相比，二甲双胍治疗后婴儿出生时较小，但出生后生长追赶，这表明二甲双胍可能会限制妊娠期间胎儿的生长。在妊娠晚期，胎儿的生长高度依赖于胎盘。胎盘在营养感应、能量调节和代谢中起着关键作用，所有这些对胎儿的正常生长和发育都至关重要。在本项目中，我们将研究二甲双胍对人类妊娠胎盘功能的影响，这对长期胎儿生长和心脏代谢结局具有潜在的重要影响。我们将使用从先前两项具有里程碑意义的人类研究中捐赠的胎盘，这些研究中的母亲在怀孕期间接受二甲双胍治疗。我们将评估与对照组相比，二甲双胍治疗胎盘的细胞老化标志物（例如测量端粒长度、老化相关基因表达和氧化应激），以确定二甲双胍是否会导致正常胎盘老化过程加速。我们还将测量胎盘处理和关键营养素的转移。我们将寻找二甲双胍暴露胎盘与对照胎盘的代谢产物和脂质谱的差异，这可能对胎儿生长产生关键的长期影响。我们还将测试正常健康妊娠的胎盘细胞如何直接对生理相关浓度的二甲双胍作出反应。我们将研究与对照组相比，二甲双胍暴露的胎盘细胞如何有效地通过线粒体产生能量。我们还将测量胎盘氧利用率，并评估潜在破坏性自由基的泄漏。我们假设与未添加二甲双胍的相同细胞相比，暴露于二甲双胍的胎盘细胞将具有低效的能量产生。这项实验将测试二甲双胍是否对胎盘细胞本身有直接影响（而不是通过对母亲生理学的影响间接发挥作用），以及能量产生是否可能解释我们在怀孕期间接受二甲双胍治疗的母亲的婴儿生长模式中看到的差异。如果二甲双胍对人胎盘产生不良影响，则本研究将为孕妇及其医生提供关于妊娠期二甲双胍治疗决策的关键信息。这些结果也可能引起公共卫生政策制定者的兴趣，特别是英国NICE指南目前推荐二甲双胍作为GDM的一线药物治疗。二甲双胍对胎盘的影响也将引起生殖生物学家、胎盘生理学家和胎儿生长和发育规划领域其他科学家的兴趣和相关性。如果这些结果能够证明二甲双胍暴露对胎盘的影响，那么我们的研究将有助于增加妊娠期间二甲双胍安全性的证据。

Metformin is a commonly prescribed medication in pregnancy across many global settings. Over the past 5 years, metformin has been endorsed as an acceptable and economic alternative to insulin for treatment of gestational diabetes (GDM) by national bodies in countries including UK, US, and New Zealand. Metformin has also been trialled for other indications during pregnancy, for example maternal obesity and polycystic ovaries. With risk factors for GDM (for example obesity and maternal age) increasing globally, the proportion of pregnant women prescribed metformin is likely to rise. Moreover, new trials of metformin in pregnancy are planned in low-resource settings, particularly in Asia and Africa. Trials show that metformin limits maternal weight gain during pregnancy and stabilises blood sugar. However it is not known how metformin could affect placental function or impact on the baby's growth in the longer term. Our meta-analysis of trials of metformin treatment for GDM shows that babies are born smaller after metformin compared to insulin treatment but then catch-up in growth after birth, suggesting that metformin may restrict fetal growth during pregnancy. During late pregnancy, the growth of the fetus is highly dependent on the placenta. The placenta has key roles in nutrient-sensing, energy regulation, and metabolism, all of which are crucial for a normal pattern of fetal growth and development. In this project we will investigate the impact of metformin on placental function in human pregnancy, which has potential important consequences for long-term fetal growth and cardio-metabolic outcomes. We will use placentas donated from two previous landmark human studies where mothers were treated with metformin during pregnancy. We will assess markers of cellular ageing (for example measuring telomere length, ageing-associated gene expression, and oxidative stress) in placentas treated with metformin compared to controls to determine whether metformin causes the normal placental ageing process to accelerate. We will also measure placental processing and transfer of key nutrients. We will look for differences in the profiles of metabolic products and lipids in metformin-exposed compared to control placentas, which could have critical long-term effects on fetal growth.We will also test how placental cells from normal healthy pregnancies respond directly to physiologically-relevant concentrations of metformin. We will examine how efficiently metformin-exposed placental cells produce energy via mitochondria compared to controls. We will also measure placental oxygen utilisation and assess the leakage of potentially damaging free radicals. We hypothesise that placental cells exposed to metformin will have inefficient energy production compared to the same cells without added metformin. This experiment will test whether metformin has direct effects on the placental cells themselves (rather than acting indirectly via an effect on the mother's physiology) and also whether energy production might account for the differences that we see in the growth patterns of babies whose mothers are treated with metformin during pregnancy. If metformin adversely impacts on the human placenta, then this study will provide crucial information for pregnant women and their doctors in decision-making regarding metformin treatment in pregnancy. These results are also likely to be of interest to public health policy-makers, particularly as UK NICE guidelines currently recommend metformin as a first-line drug treatment for GDM. The impact of metformin on the placenta will also be of interest and relevance to reproductive biologists, placental physiologists, and other scientists in the field of fetal growth and developmental programming. If these results are reassuring regarding the impact of metformin-exposure on the placenta, then our study will be useful in adding to the body of evidence regarding metformin safety during pregnancy.