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: 10364417
• 负责人: Kjersti Marie Aagaard
• 金额: $ 154.59万
• 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/10364417
• 关键词: 4 year old; Adolescent; American; Animals; Automobile Driving; Biogenesis; Birth Weight; Clinical; Clinical Research; Clinical Trials; Conceptions; Data; Development; Diabetes Mellitus; Diet; Epidemic; Epidemiology; Event; Exposure to; Future; Genetic Translation; 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; Pregnancy; Primates; Puberty; Risk; Series; Specimen; Testing; Weaning; Woman; base; clinical implementation; cohort; dietary control; early adolescence; early life exposure; epigenomics; experimental study; feeding; fetal; juvenile animal; 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5000万美国人开二甲双胍，目前在围产期（孕前）、