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.

项目总结/摘要 与一个具有十多年研究经验的非人灵长类动物（NHP）财团合作， 该提案将评估健康和疾病的发育起源，以应对孕产妇营养过剩， 宫内暴露于二甲双胍和营养过剩对胰腺β-淀粉样蛋白的影响 细胞和胰岛线粒体健康的恒河猴胎儿。在美国，31%的女性 育龄妇女被归类为超重或肥胖。随着全球肥胖率的上升， 发育过程中暴露于母体营养过剩和治疗母体代谢的药物 疾病对后代代谢结果的影响至关重要。二甲双胍通常用于 治疗2型糖尿病;然而，二甲双胍的使用在过去十年中已经扩大， 治疗妊娠糖尿病、多囊卵巢综合征和先兆子痫。数据表明 二甲双胍穿过胎盘屏障并在胎儿循环中平衡，引起了对非预期的 胎儿伤害虽然二甲双胍的靶点是未知的，但二甲双胍的一种提出的机制是激活5'-氨基-2-甲基-苯并[c]芘。 一磷酸腺苷激酶（AMPK），一种对调节途径至关重要的营养传感激酶 与细胞生长、增殖、代谢和表观遗传调节相关。梅托希亚也被 显示抑制线粒体电子传递链的复合物I，减少ATP的产生， 对于葡萄糖刺激的胰岛素从β细胞分泌是重要的。本报告概述的研究目标 建议阐明母亲食用西式饮食和二甲双胍对 在高度相关的NHP模型中，胎儿发育阶段的β细胞质量、身份和功能。 此外，该提案还包括调查孕产妇的个体和综合影响的研究 营养过剩和二甲双胍对后代胰岛线粒体形态和功能的影响。完成这些 我将使用高分辨率显微镜，真实的时间代谢分析，和单核RNA测序 为了识别可能与在治疗后期β细胞衰竭倾向增加相关的程序化机制， 后代的生活