The Influence of Developmental Exposure to Maternal Overnutrition and Metformin on Offspring Mitochondrial Health and Beta Cell Function

发育期暴露于母亲营养过剩和二甲双胍对后代线粒体健康和 β 细胞功能的影响

• 批准号: 10601500
• 负责人: Darian Thomas Carroll
• 金额: $ 3.3万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10601500
• 关键词: 1 year old; Adenosine Monophosphate; Adipose tissue; Adult; Alpha Cell; Architecture; Attenuated; Automobile Driving; Beta Cell; Biological Assay; Birth Weight; Body mass index; Cell Count; Cell Fraction; Cell Proliferation; Cell Respiration; Cell physiology; Cells; Circulation; Classification; Clinical; Collaborations; Consumption; Data; Development; Disease; Dose; Drug Prescriptions; Endocrine; Environment; Exhibits; Exposure to; Failure; Female; Female of child bearing age; Fetal Growth; Fetal Growth Retardation; Fetus; Gene Expression; Genus Hippocampus; Gestational Diabetes; Glucose; Goals; Growth; Health; Human; Individual; Insulin; Intake; Islets of Langerhans; Knowledge; Life; Lighting; Link; Liver; Macaca mulatta; Maintenance; Metabolic; Metabolic Diseases; Metabolism; Metformin; Microscopy; Mitochondria; Mitochondrial Electron Transport Complex I; Modeling; Morphology; Mothers; Muscle; NADH dehydrogenase (ubiquinone); Non-Insulin-Dependent Diabetes Mellitus; Obesity; Outcome; Overnutrition; Overweight; Pancreas; Pathway interactions; Phenotype; Phosphotransferases; Physiological; Placenta; Polycystic Ovary Syndrome; Pre-Eclampsia; Pregnancy; Pregnant Women; Prevalence; Production; Proliferating; Protein Synthesis Inhibition; Regulation; Resolution; Respiration; Risk; Structure; Structure of beta Cell of islet; Therapeutic; Time; Tissues; Transmission Electron Microscopy; United States; Woman; cell growth; clinical practice; density; detection of nutrient; early childhood; endocrine pancreas development; epigenetic regulation; experience; fetal; fetal programming; glucose uptake; insulin granule; insulin secretion; interest; islet; maternal obesity; mother nutrition; next generation; nonhuman primate; nutrient metabolism; offspring; pancreas development; post pregnancy; prenatal exposure; response; single nucleus RNA-sequencing; western diet

Project Summary/Abstract In collaboration with a non-human primate (NHP) consortium with over a decade of experience studying the developmental origins of health and disease in response to maternal overnutrition, this proposal will evaluate the effect that intrauterine exposure to metformin and overnutrition has on the development of pancreatic beta cells and islet mitochondrial health in fetal Rhesus macaques. In the United States, 31% of women of childbearing age are classified as overweight or obese. As global rates of obesity rise, the influence of developmental exposure to maternal overnutrition and the drugs prescribed to treat maternal metabolic disease on offspring metabolic outcomes is of critical interest. Metformin is typically prescribed for the treatment of Type 2 Diabetes; however, use of metformin has been expanded over the past decade to treatment for gestational diabetes, polycystic ovarian syndrome, and preeclampsia. Data suggests that metformin crosses the placental barrier and equilibrates in fetal circulation, raising concerns for unintended fetal harm. While the target of metformin is unknown, a proposed mechanism of metformin is activation of 5’ adenosine monophosphate kinase (AMPK), a nutrient sensing kinase that is central to regulation of pathways associated with cellular growth, proliferation, metabolism, and epigenetic regulation. Metformin has also been shown to inhibit complex I of the mitochondrial electron transport chain, reducing the production of ATP, which is important for glucose-stimulated insulin secretion from beta cells. The goal of the studies outlined in this proposal is to elucidate the influence that maternal consumption of a western style diet and metformin has on beta-cell mass, identity, and function at the fetal stage of development in a highly relevant NHP model. Additionally, this proposal includes studies investigating the individual and combined effects of maternal overnutrition and metformin on islet mitochondrial morphology and function in offspring. To accomplish these goals, I will use high resolution microscopy, real time metabolic analyses, and single nucleus RNA sequencing to identify programmed mechanisms that may correlate to increased propensity for beta cell failure later in the offspring’s life.

项目摘要/摘要 与非人类灵长类动物（NHP）合作，并具有十多年的研究经验 健康和疾病的发育起源响应孕产妇的营养，该提议将评估 内部暴露于二甲双胍和营养不良的影响对胰腺β的发展产生的影响 胎儿猕猴中的细胞和胰岛线粒体健康。在美国，有31％的妇女 生育年龄被归类为超重或肥胖。随着肥胖的全球速度上升， 发育性暴露于产妇营养和用于治疗母体代谢的药物 后代代谢结局的疾病是关键的。通常针对 2型糖尿病的治疗；但是，在过去的十年中，二甲双胍的使用已扩大到 治疗妊娠糖尿病，多囊卵巢综合征和先兆子痫的治疗方法。数据表明这一点 二甲双胍横穿胎儿循环中的位置屏障和等效物，引起了对意外的担忧 胎儿伤害。虽然二甲双胍的靶点尚不清楚，但提出的二甲双胍机制是激活5' 腺苷一磷酸激酶（AMPK），一种营养感应激酶，是调节途径的核心 与细胞生长，增殖，代谢和表观遗传调节有关。二甲双胍也是 证明可以抑制线粒体电子传输链的复合物I，从而减少了ATP的产生， 对于β细胞中葡萄糖刺激的胰岛素分泌很重要。研究中概述的研究目的 建议是阐明西方风格饮食和二甲双胍对物质消耗的影响 在高度相关的NHP模型中，在发育的胎儿阶段的β细胞质量，身份和功能。 此外，该建议包括研究孕产妇的个体和综合效应的研究 胰岛线粒体形态和后代功能上的二甲双胍。完成这些 目标，我将使用高分辨率显微镜，实时代谢分析和单核RNA测序 确定可能与贝塔细胞失败的前景相关的编程机制，以后 后代的生活。