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

基本信息

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
项目类别：
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

项目摘要

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、在过去的十年中，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随着其广泛使用，肥胖、多囊卵巢综合征、2 型糖尿病和妊娠糖尿病等问题也随之而来。出现了这些对二甲双胍暴露的担忧的根本原因。其基本药效学和作用机制是由于扩大母体使用而产生的。我们和其他人共同努力破坏胎儿生命期间重要的代谢途径，这些途径是与建立正常出生体重和适当的产后早期生长轨迹相结合是必要的。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。从怀孕前到哺乳期接触安慰剂或暴露于肥胖和胰岛素抵抗的影响。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在目标 1 中，我们将确定是否在生命早期使用二甲双胍。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，从而导致肥胖在目标 2 中，我们将确定二甲双胍暴露的影响。 WSD 喂养的母鼠的研究重点是母体、胎儿 (G145) 和幼体（至青春期开始）的代谢生理学，这将包括核心。在目标 3 中，我们将确定母体和胎儿器官代谢（肝脏、肌肉、肠道和胰腺）的测量。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。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Western diet-induced shifts in the maternal microbiome are associated with altered microRNA expression in baboon placenta and fetal liver.

西方饮食引起的母体微生物组变化与狒狒胎盘和胎儿肝脏中 microRNA 表达的改变有关。

DOI：
发表时间：
2022
期刊：
影响因子：
0
作者：
Sugino, Kameron Y;Mandala, Ashok;Janssen, Rachel C;Gurung, Sunam;Trammell, MaJoi;Day, Michael W;Brush, Richard S;Papin, James F;Dyer, David W;Agbaga, Martin;Friedman, Jacob E;Castillo;Jonscher, Karen R;Myers, Dean A
通讯作者：
Myers, Dean A