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

妊娠期二甲双胍：对胎儿的影响

• 批准号: 10683230
• 负责人: Kjersti Marie Aagaard
• 金额: $ 142.14万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-17 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10683230
• 关键词: 4 year old; Acceleration; Adolescent; American; Animal Feed; Animals; Automobile Driving; Biogenesis; Birth Weight; Clinical; Clinical Research; Clinical Trials; Conceptions; Data; Development; Diabetes Mellitus; Diet; Epidemic; Epidemiology; Event; Exposure to; Future; Gestational Diabetes; Growth; High Fat Diet; Insulin Resistance; Islet Cell; Lactation; Life; Liver; Low Birth Weight Infant; Macaca mulatta; Measures; Metabolic; Metabolic Pathway; Metabolic syndrome; Metabolism; Metagenomics; Metformin; Mitochondria; Modeling; Molecular; Muscle; Muscle Fibers; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Obesity; Organ; Outcome; Pancreas; Pathway interactions; Perinatal; Pharmacodynamics; Phenotype; Physiological; Physiology; Placebos; Polycystic Ovary Syndrome; Prediabetes syndrome; Predisposition; Pregnancy; Primates; Puberty; Risk; Series; Specimen; Testing; Weaning; Woman; clinical implementation; cohort; dietary control; early adolescence; early life exposure; epigenomics; experimental study; feeding; fetal; juvenile animal; mRNA Translation; metabolomics; microbial; mother nutrition; next generation; nonhuman primate; obesity development; offspring; postnatal; prenatal exposure; prepregnancy; prevent; primary outcome; secondary outcome; transcriptomics; western diet

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.

二甲双胍为每年5000万美国人处方，目前处于围产期（怀孕前， 怀孕期间和产后）临床用途。在过去的十年中，临床适应症和务实使用二甲双胍 超越了怀孕以外的明显糖尿病的静静扩展，现在包括糖尿病和 肥胖，多囊卵巢综合征，2型糖尿病和妊娠糖尿病。随着其扩大的使用，问题 出现了意外的长期伤害。在这些关注二甲双胍暴露期间的基本原理 由于孕产妇使用的扩展而发展，其基本药效学和机制 行动，我们和其他人认为，在胎儿生活中，这是破坏重要代谢途径的行动 建立正常出生体重和适当的早期产后生长轨迹所必需的。当与 孕产妇西方饮食（WSD），胎儿二甲双胍的暴露导致糖尿病前的早期发展， 早期青少年（青春期发作）中肥胖和胰岛素抵抗的证据。 我们受到初步数据的启发，以购买非人类私人模型的开发 二甲双胍的使用。作为一项基于三臂机械的临床研究，我们将确定二甲双胍的影响 或安慰剂暴露于孕妇，直到哺乳期会发展出肥胖和胰岛素抵抗的发展。这 研究足以检验以下假设：材料二甲双胍孤立或与A结合使用 产妇高脂饮食使低出生体重和异常追赶增长，肥胖和胰岛素抵抗 青春期开始时的后代（大约3-4岁）。在AIM 1中，我们将确定早期生命二甲双胍是否 控制和/或WSD喂养的大坝中的暴露会导致低出生体重和异常追赶增长，导致肥胖症 和青春期后代的胰岛素抵抗。在AIM 2中，我们将确定二甲双胍暴露的影响 在WSD喂养的大坝中，胎儿（G145）和青少年（青春期发作）代谢生理学。这将包括核心 母体和胎儿器官代谢的度量（肝脏，肌肉，肠道和胰腺）。在AIM 3中，我们将确定 断奶后代是否可以改善或减轻Mater二甲双胍在 WSD喂养的大坝。最后，在AIM 4中，我们将确定早期二甲双胍暴露对控制的分子影响 WSD引起的肝脏，肠道，肌肉和胰腺中母体和胎儿代谢的核心测量的改变。 考虑到最近出现的流行病学证据和二甲双胍作用的已知机制， 一个理性的关注，而不是预防发育节目，怀孕期间使用二甲双胍可能 在下一代有加速肥胖和代谢综合征的后果。 当前提案中生成的动物，标本和均匀生成的多粒数据将集体 告知正在进行的临床试验和未来的临床实施。