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

每年有5000万美国人服用二甲双胍，目前正处于广泛的围产期(孕前， 孕期和产后)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 已稳步扩大到妊娠外显性糖尿病的治疗范围，现在包括糖尿病前期和 肥胖、多囊卵巢综合征、2型糖尿病和妊娠期糖尿病。随着它的广泛使用，问题是 意想不到的长期伤害已经出现。这些担忧背后的理由是二甲双胍在 作为扩大母体使用的结果的发展来自于其基本的药效学和 我们和其他人假设，这些行动会聚在一起，扰乱胎儿生命中重要的代谢途径，这些途径是 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。当与 母体西式饮食(WSD)，胎儿接触二甲双胍会加速糖尿病前期的早期发展， 在青春期早期(青春期开始)有肥胖和胰岛素抵抗证据的肥胖前期表型。 我们受到初步数据的启发，致力于开发非人类灵长类动物的母体模型 二甲双胍的使用。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的发展的影响。这 这项研究有足够的力量来检验这一假设，即母体二甲双胍单独使用或与 母亲高脂肪饮食导致低出生体重和异常追赶生长，导致肥胖和胰岛素抵抗 进入青春期(大约3-4岁)的后代。在目标1中，我们将确定早期生命二甲双胍 暴露在对照组和/或饮用WSD的水坝中会导致低出生体重和异常的追赶生长，从而导致肥胖。 以及青春期幼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 在饲喂WSD的母鼠中，母体、胎儿(G145)和幼体(到青春期开始)的代谢生理学。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 让子代断奶并接受对照饮食是否可以改善或减轻母体接触二甲双胍的影响 灌溉水源的水坝。最后，在目标4中，我们将确定二甲双胍早期应用如何在控制方面发挥其分子影响。 WSD导致肝脏、肠道、肌肉和胰腺中母体和胎儿新陈代谢的核心指标发生变化。 考虑到最近出现的流行病学证据和已知的二甲双胍的作用机制，有 一种理性的担忧是，怀孕期间使用二甲双胍可能不会阻止发育规划 在下一代加速肥胖和代谢综合征流行的意想不到的后果。 本提案中生成的动物、标本和统一生成的多组体数据将共同 告知正在进行的临床试验和未来的临床实施。

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.