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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：
10426639
负责人：
Brigid Ellen Gregg
金额：
$ 7.89万
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 2022-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10426639
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 Structure of beta Cell of islet Testing Time TimeLine blood glucose regulation design diabetes risk endocrine pancreas development 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 islet stem cells modifiable risk mother nutrition nutrition offspring pancreas development postnatal prenatal exposure prevent progenitor programs public health relevance response sensor stem cells 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.