Programming of beta-cells and Glucose Homeostasis by Maternal Metformin Exposure

母体二甲双胍暴露对 β 细胞和血糖稳态的编程

• 批准号: 9324994
• 负责人: Brigid Ellen Gregg
• 金额: $ 15.78万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9324994
• 关键词: Adenosine Monophosphate; Adult Children; Affect; American; Animal Model; Animals; Apoptosis; Beta Cell; Cell physiology; Clinical; Clinical Trials; Complex; Cyclic AMP-Dependent Protein Kinases; Development; Diabetes Mellitus; Embryo; Embryonic Development; Energy Supply; Environmental Risk Factor; Epidemic; Exhibits; Exposure to; FRAP1 gene; Fetus; First Pregnancy Trimester; Genetic; Gestational Diabetes; Glucose; Goals; Health; High Fat Diet; Impairment; Incidence; Infant; Investigation; Life; Longevity; Malignant Neoplasms; Mediating; Metabolic; Metabolic Diseases; Metabolic stress; Metabolism; Metformin; Methods; Mitochondria; Molecular; Morphology; Mothers; Motion; Mus; Mutation; Neonatal; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Nutritional; Oral; Pancreas; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Phenotype; Predisposition; Pregnancy; Protein Kinase; Protein-Restricted Diet; Proteins; Public Health; Raptors; Research; Resistance; Respiratory Chain; Risk; Risk Factors; Role; Signal Pathway; Signal Transduction; Stem cells; Structure of beta Cell of islet; Testing; Time; TimeLine; blood glucose regulation; design; diabetes risk; endoplasmic reticulum stress; experimental study; fetal; genetic manipulation; glucose tolerance; high risk; impaired glucose tolerance; improved; improved functioning; in utero; in vivo; innovation; insight; insulin secretion; islet; modifiable risk; mother nutrition; nutrition; offspring; pancreas development; postnatal; prenatal exposure; prevent; progenitor; programs; public health relevance; response; sensor; stressor; therapy design

 DESCRIPTION (provided by applicant): Metformin is prescribed to 50 million Americans and is being tested for clinical use during pregnancy, but despite this there is an incomplete understanding of the long-term consequences of exposure during pregnancy on pancreatic beta-cell development the metabolic health of the offspring. Metformin has been found to inhibit the mitochondrial respiratory chain, which alters cellular energy status and triggers the activation of AMPK, a nutrient and energy sensor activated during times of energy depletion. Metformin also has an impact on mTORC1 signaling. Experiments in animal models have established that metabolic stress during pancreatic development can be permanently detrimental to beta-cell mass and function (beta-cell programming), but the mechanisms by which these energy supply-related changes occur are unclear. The long-term goal of this research is to identify targets in energy signaling pathways that could be manipulated to prevent adverse maternal nutritional effects on the developing beta-cell. The objective of this proposal is to determine the effect of in utero exposure to metformin on beta-cell programming and later type 2 diabetes (T2D) risk and to uncover the molecular mechanisms that underlie these metabolic and morphologic changes. We hypothesize that metformin programs beta-cells during embryogenesis to enhance beta-cell mass and decrease susceptibility to T2D when faced with the metabolic stressors of gestational protein restriction or postnatal high fat diet (HFD). Through a set of carefully designed experiments we aim to determine the mechanisms by which gestational exposure to metformin enhances neonatal beta-cell mass. We will investigate the role of mTORC1 signaling by assessing the effect of mutations in the mTORC1 pathway on neonatal beta-cell mass in mice. We will also use pharmacologic and genetic manipulations to examine the contribution of the AMPK pathway to the beta-cell mass enhancement. Our second aim is to establish the ability of metformin exposure during gestation to protect offspring against the development of T2D in response to beta-cell stressors. To test this hypothesis, we will characterize the metabolic and beta-cell phenotype of Met offspring. We will also expose isolated Met offspring islets to stressors to look for resistance to apoptosis as well as examine the ability of metformin exposure during gestation to prevent the development of diabetes in the setting of gestational low-protein diet or postnatal HFD. These studies will provide fundamental observations on the effect of metformin on programming of the developing beta-cell and of overall metabolism. These studies are significant because they may be the first step in designing interventions to overcome the aberrant beta-cell developmental program set into motion by abnormal in utero nutrient conditions. The proposed research provides a conceptual innovation because it will employ an ex-vivo and in vivo approach to identify the precise contribution of metformin to programming of metabolic disease. Contribution to our knowledge of the effects of metformin is fundamental for the fields of diabetes, cancer and longevity.

 描述（由申请人提供）：5000万美国人服用了二甲双胍，并且正在对妊娠期间的临床使用进行测试，但尽管如此，人们对妊娠期间暴露于二甲双胍对胰腺β细胞发育和代谢的长期后果的了解还不完全。后代的健康。已发现二甲双胍抑制线粒体呼吸链，这改变了细胞能量状态并触发AMPK的激活，AMPK是一种在能量耗尽时激活的营养和能量传感器。Metalloprotein也对mTORC1信号传导有影响。动物模型的实验已经确定，胰腺发育期间的代谢应激可能对β细胞的质量和功能（β细胞编程）造成永久性损害，但这些能量供应相关变化发生的机制尚不清楚。这项研究的长期目标是确定能量信号通路中的靶点，这些靶点可以被操纵，以防止母体营养对发育中的β细胞产生不良影响。本提案的目的是 确定宫内暴露于二甲双胍对β细胞编程和后来的2型糖尿病（T2D）风险的影响，并揭示这些代谢和形态学变化的分子机制。我们假设二甲双胍在胚胎发生过程中对β细胞进行编程，以增强β细胞质量，并在面临妊娠蛋白限制或出生后高脂饮食（HFD）的代谢应激时降低对T2D的易感性。通过一系列精心设计的实验，我们旨在确定妊娠期二甲双胍暴露增强新生儿β细胞质量的机制。我们将通过评估mTORC1通路突变对小鼠新生β细胞质量的影响来研究mTORC1信号传导的作用。我们还将使用药理学和遗传操作来检查AMPK途径对β细胞质量增强的贡献。我们的第二个目的是确定妊娠期二甲双胍暴露保护后代免受 2型糖尿病对β细胞应激的反应。为了检验这一假设，我们将表征Met后代的代谢和β细胞表型。我们还将使分离的Met后代胰岛暴露于应激源，以寻找对细胞凋亡的抗性，并检查妊娠期间二甲双胍暴露在妊娠期低蛋白饮食或产后HFD环境中预防糖尿病发展的能力。这些研究将提供二甲双胍对发育中β细胞编程和总体代谢影响的基本观察结果。这些研究意义重大，因为它们可能是设计干预措施以克服异常子宫内营养条件引起的异常β细胞发育程序的第一步。拟议的研究提供了一个概念上的创新，因为它将采用体外和体内方法来确定二甲双胍对代谢疾病编程的精确贡献。对二甲双胍作用的了解是糖尿病、癌症和长寿领域的基础。