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.

每年有 5000 万美国人服用二甲双胍，目前在围产期（怀孕前、 怀孕期间和产后）临床使用。过去十年，二甲双胍的临床适应症和实际使用 已稳步扩展到妊娠期以外的明显糖尿病的治疗，现在包括糖尿病前期和糖尿病前期 肥胖、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，以下问题 出现了意想不到的长期伤害。这些对二甲双胍暴露的担忧背后的理由 其基本药效学和机制是由于扩大母体使用而产生的发展 我们和其他人假设这些行为会破坏胎儿生命中重要的代谢途径，这些途径是 建立正常出生体重和适当的产后早期生长轨迹是必要的。当与 母亲西式饮食（WSD）、胎儿二甲双胍暴露会加速糖尿病前期的早期发展， 肥胖前期表型，有青春期早期（青春期开始）肥胖和胰岛素抵抗的证据。 我们受到初步数据的启发，致力于开发非人类灵长类动物母婴模型 二甲双胍的使用。作为一项基于三组机制的临床研究，我们将确定二甲双胍的影响 从怀孕前到哺乳期暴露于安慰剂或安慰剂对肥胖和胰岛素抵抗的发展的影响。这 研究有足够的能力来检验母亲单独使用二甲双胍或与其他药物联合使用的假设 产妇高脂肪饮食导致低出生体重和异常追赶性生长，导致肥胖和胰岛素抵抗 后代进入青春期（大约3-4岁）。在目标 1 中，我们将确定生命早期二甲双胍是否 对照和/或 WSD 喂养的母猪接触该物质会导致低出生体重和异常追赶性生长，从而导致肥胖 和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 WSD 喂养的母鼠中，研究的是母体、胎儿 (G145) 和幼体 (至青春期开始) 的代谢生理学。这将包括核心 母体和胎儿器官代谢（肝脏、肌肉、肠道和胰腺）的测量。在目标 3 中，我们将确定 断奶后代采用对照饮食是否可以改善或减轻母体二甲双胍暴露的影响 水务署供水的水坝。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 WSD 引起的母体和胎儿肝脏、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，有 一个合理的担忧是，怀孕期间使用二甲双胍不仅不会阻止发育规划，反而可能会 会产生意想不到的后果，加速下一代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。