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

项目摘要/摘要 与一个具有十多年研究经验的非人灵长类(NHP)联盟合作 健康和疾病的发育起源针对产妇营养过剩，这项建议将评估 宫内应用二甲双胍和营养过剩对胰岛β细胞发育的影响 胚胎恒河猴细胞和胰岛线粒体健康状况。在美国，31%的女性 生育年龄被归类为超重或肥胖。随着全球肥胖率的上升， 母体营养过剩的发育暴露与治疗母体代谢的药物 疾病对后代代谢结果的影响是至关重要的。二甲双胍通常是开给 治疗2型糖尿病；然而，二甲双胍的使用在过去十年中已扩大到 治疗妊娠期糖尿病、多囊卵巢综合征和先兆子痫。数据表明， 二甲双胍跨越胎盘屏障，在胎儿循环中保持平衡，引发了人们对意外情况的担忧 对胎儿的伤害。虽然二甲双胍的靶点尚不清楚，但已提出的一种机制是激活5‘ 腺苷一磷酸激酶(AMPK)，一种对信号转导途径起核心调节作用的营养感应激酶 与细胞生长、增殖、新陈代谢和表观遗传调节有关。二甲双胍也一直在 抑制线粒体电子传输链的复合体I，减少ATP的产生，从而 对葡萄糖刺激的胰岛β细胞分泌胰岛素很重要。其中概述的研究目标是 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，这项建议还包括调查母婴的单独和综合影响的研究。 营养过剩和二甲双胍对子代胰岛线粒体形态和功能的影响。要实现这些目标 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 以确定可能与晚些时候β细胞衰竭倾向增加相关的编程机制 后代的生命。

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.