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

基本信息

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
项目类别：
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

项目摘要

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）：二甲双胍为 5000 万美国人开出处方，并且正在测试其在怀孕期间的临床使用，但尽管如此，人们对怀孕期间接触二甲双胍对胰腺 β 细胞发育和代谢的长期影响仍不完全了解。研究发现二甲双胍可以抑制线粒体呼吸链，从而改变细胞能量状态并触发 AMPK 的激活，而 AMPK 是一种在能量耗尽时激活的营养和能量传感器。动物模型实验表明，胰腺发育过程中的代谢应激可能会永久损害 β 细胞质量和功能（β 细胞编程），但这些与能量供应相关的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目标，这些目标可以被操纵以防止母体营养对发育中的β细胞产生不利影响。确定子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变化背后的分子机制。当面临妊娠蛋白限制或产后高脂肪饮食 (HFD) 的代谢应激源时，我们旨在确定其机制。妊娠期暴露于二甲双胍会增强新生儿 β 细胞质量，我们将通过评估 mTORC1 通路突变对小鼠新生儿 β 细胞质量的影响来研究 mTORC1 信号传导的作用。我们的第二个目标是确定妊娠期间暴露于二甲双胍以保护后代免受侵害的能力。为了验证这一假设，我们将表征 Met 后代的代谢和 β 细胞表型，我们还将分离的 Met 后代胰岛暴露于应激源，以寻找对细胞凋亡的抵抗力。检查妊娠期间暴露于二甲双胍在妊娠期低蛋白饮食或产后 HFD 的情况下预防糖尿病发展的能力。这些研究将为二甲双胍对发育中的 β 细胞编程和整体代谢的影响提供基本观察。。这些这项研究意义重大，因为它们可能是设计干预措施以克服因子宫内营养条件异常而启动的异常β细胞发育程序的第一步。拟议的研究提供了概念上的创新，因为它将采用体外和体内的方法。确定二甲双胍对代谢疾病规划的精确贡献的方法有助于我们了解二甲双胍的作用对于糖尿病、癌症和长寿领域至关重要。