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

 描述(申请人提供)：二甲双胍是为5000万美国人开的处方，正在接受怀孕期间的临床使用测试，但尽管如此，对怀孕期间接触二甲双胍对胰岛β细胞发育和后代新陈代谢健康的长期后果仍未完全了解。二甲双胍被发现可以抑制线粒体呼吸链，线粒体呼吸链改变细胞的能量状态，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。二甲双胍对mTORC1信号转导也有影响。动物模型的实验已经证实，胰腺发育过程中的代谢应激可能会永久性地损害β细胞的质量和功能(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细胞的不利影响。这项提议的目标是 目的：确定宫内接触二甲双胍对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。我们假设，在胚胎发育过程中，当面临妊娠蛋白限制或出生后高脂饮食(HFD)的代谢应激源时，二甲双胍对β细胞进行编程，以增加β细胞质量，降低对T2D的易感性。通过一系列精心设计的实验，我们的目标是确定妊娠期间接触二甲双胍增加新生儿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儿β细胞质量的影响来研究mTORC1信号的作用。我们还将使用药理学和遗传操作来检查AMPK通路对β细胞质量增强的贡献。我们的第二个目标是确定怀孕期间服用二甲双胍的能力，以保护后代免受 T2D对β细胞应激源的反应。为了验证这一假设，我们将描述Met后代的代谢和β细胞表型。我们还将使分离的蛋氨酸后代胰岛暴露于应激源，以寻找对细胞凋亡的抵抗，以及在妊娠期低蛋白饮食或出生后HFD的情况下，检查妊娠期二甲双胍对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细胞编程和整体新陈代谢的影响提供基本观察。这些研究意义重大，因为它们可能是设计干预措施的第一步，以克服因子宫营养条件异常而启动的异常β细胞发育程序。这项拟议的研究提供了一个概念创新，因为它将采用体外和体内的方法来确定二甲双胍对代谢性疾病规划的准确贡献。对于糖尿病、癌症和长寿等领域，我们对二甲双胍疗效的了解是非常重要的。

 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.