Metformin in Pregnancy: Fetal Consequences & Long-term Offspring Outcomes in a NHP Model

每年向5000万美国人开处方，并且目前广泛用于围产期（怀孕前， 妊娠期间和产后）临床使用。在过去的十年中，二甲双胍的临床适应症和实际应用 已经稳步扩展到妊娠外显性糖尿病的治疗，现在包括糖尿病前期和 肥胖症、多囊卵巢综合征、2型糖尿病和妊娠糖尿病。随着其使用范围的扩大， 产生了意想不到的长期危害。这些二甲双胍暴露问题的基本原理是 由于扩大母体使用而导致的发展源于其基本药效学和 行动，我们和其他人假设收敛到破坏重要的代谢途径，在胎儿的生活，这是 因此，有必要建立正常的出生体重和适当的出生后早期生长轨迹。当结合 母体西式饮食（WSD），胎儿二甲双胍暴露导致糖尿病前期的早期发展加速， 在青春期早期（青春期开始）具有肥胖和胰岛素抵抗证据的肥胖前期表型。 我们受到我们的初步数据的启发，寻求开发一种非人灵长类动物的孕产妇模型。 使用二甲双胍。作为一项基于三臂机制的临床研究，我们将确定二甲双胍的影响 或从孕前到哺乳期的安慰剂暴露对肥胖和胰岛素抵抗发展的影响。这 研究有足够的把握度来检验母体二甲双胍单独使用或与 母亲的高脂肪饮食会导致低出生体重和异常的追赶性生长，导致肥胖和胰岛素抵抗， 青春期开始时的后代（大约3-4岁）。在目标1中，我们将确定早期生活二甲双胍 对照组和/或WSD喂养的母鼠暴露导致低出生体重和异常追赶生长，导致肥胖 和青春期少年后代的胰岛素抵抗。在目标2中，我们将确定二甲双胍暴露的影响 在WSD喂养的母鼠中，对母体、胎儿（G145）和幼年（至青春期开始）代谢生理学的影响。这将包括核心 测量母体和胎儿器官代谢（肝脏、肌肉、肠道和胰腺）。在目标3中，我们将确定 是否断奶后代到对照饮食可以改善或减轻母亲二甲双胍暴露的影响， WSD喂养的大坝。最后，在目标4中，我们将确定早期二甲双胍暴露如何对控制产生分子影响 和WSD诱导的母体和胎儿肝脏、肠道、肌肉和胰腺代谢核心指标的改变。 考虑到最近出现的流行病学证据和二甲双胍的已知作用机制， 合理的担忧是，妊娠期间使用二甲双胍可能 会产生意想不到的后果，加速下一代的肥胖和代谢综合征的流行。 当前提案中生成的动物、标本和统一生成的多组学数据将共同 为正在进行的临床试验和未来的临床实施提供信息。

Metformin is prescribed to 50 million Americans annually, and is currently in widespread perinatal (pre-pregnancy, during pregnancy, and post-natal) clinical use. Over the past decade, clinical indications and pragmatic use of metformin have steadily expanded beyond the treatment of overt diabetes outside of pregnancy, and now include prediabetes and obesity, polycystic ovary syndrome, type 2 diabetes, and gestational diabetes. With its expanded use, questions of unintended long-term harm have arisen. The rationale underlying these concerns for metformin exposure during development as a consequence of expanded maternal use arises from its basic pharmacodynamics and mechanisms of action, which we and others hypothesize converge to disrupt important metabolic pathways during fetal life, which are necessary to establish normal birth weight and appropriate early post-natal growth trajectory. When combined with a maternal Western-style diet (WSD), fetal metformin exposure leads to accelerated early development of a pre-diabetic, pre-obese phenotype with evidence of obesity and insulin resistance in early adolescence (puberty onset). We are inspired by our preliminary data to pursue development of a non-human primate model of maternal metformin use. Powered as a three-armed mechanistic-based clinical study, we will determine the impact of metformin or placebo exposure from pre-pregnancy through lactation on the development of obesity and insulin resistance. This study is adequately powered to test the hypothesis that maternal metformin use in isolation or in conjunction with a maternal high fat diet renders low birthweight and aberrant catch-up growth, driving obesity and insulin resistance in the offspring by onset of puberty (approximately 3-4 years of age). In Aim 1, we will determine if early life metformin exposure in control and/or WSD-fed dams leads to low birthweight and aberrant catch-up growth, resulting in obesity and insulin resistance in pubertal juvenile offspring. In Aim 2, we will determine what the impact of metformin exposure in WSD-fed dams is on maternal, fetal (G145) and juvenile (to puberty onset) metabolic physiology. This will include core measures of maternal and fetal organ metabolism (liver, muscle, gut and pancreas). In Aim 3, we will determine whether weaning offspring onto a control diet can ameliorate or mitigate the effects of maternal metformin exposure in WSD-fed dams. Finally, in Aim 4 we will determine how early metformin exposure wields its molecular impact on control and WSD-induced alterations of core measures of maternal and fetal metabolism in the liver, gut, muscle, and pancreas. Considering the recently emerged epidemiologic evidence and known mechanisms of actions of metformin, there is a rational concern that rather than preventing developmental programming, metformin use during pregnancy may have unintended consequences of accelerating obesity and the metabolic syndrome epidemic in the next generation. The animal, specimen, and uniformly generated multi’omic data generated in the current proposal will collectively inform ongoing clinical trials and future clinical implementation.