The role of Nrf2 in beta cell expansion during pregnancy

总结 哺乳动物妊娠的后期阶段伴随着增加的胰岛素抵抗， 增加胎儿对葡萄糖的需求。因此，作为一种补偿性反应，为了维持 当母体血糖水平正常时，β细胞群扩大，导致胰岛素释放增加。 β细胞增殖、β细胞新生和β细胞凋亡减少被认为是主要的 妊娠期间β细胞适应性反应的贡献者和这种适应性反应的缺陷可能导致 妊娠期糖尿病（GDM）。我的初步结果表明，Nrf2是适应性β细胞所必需的。 在营养过剩的成年小鼠中，Nrf2水平在妊娠小鼠的β细胞中上调， 小鼠尽管多项研究描述了Nrf2对2型和1型糖尿病患者β细胞的保护作用， 尽管在这些模型中，没有研究发现Nrf2在妊娠期间β细胞群扩增中的作用。 体内Nrf2功能的丧失或获得是否影响妊娠小鼠的β细胞增殖、存活和质量？ 这种潜在的改变在产后早期是否持续存在？体内Nrf2功能丧失或获得 会影响怀孕小鼠的胰岛素分泌吗体内Nrf2功能的丧失或获得是否影响葡萄糖稳态 在怀孕的老鼠身上在妊娠期间，哪些基因在胰岛中上调和下调， 体内Nrf2功能的丧失或获得？怀孕期间胰岛中的Nrf2靶基因有哪些？进行人体 β细胞也需要Nrf2用于妊娠驱动的增殖？这些重要的问题 Nrf2在妊娠期间β细胞中的生理作用需要得到回答，以推进我们的知识， 找到治疗GDM的方法。我们假设Nrf2是β细胞扩增所必需的， 妊娠和Nrf2表达或功能破坏导致GDM。我们相信NRF2可以作为一个 潜在的治疗靶点。我们将通过完成以下具体步骤来验证我们的假设 目的：1）探讨Nrf2在妊娠期β细胞团扩增中的作用。2)将查清 Nrf2在妊娠期间调节β细胞群扩增的机制。3)测试Nrf2是否为 妊娠介导的适应性人β细胞体内增殖所必需的。这些研究将提供 深入了解Nrf2如何促进怀孕期间功能性β细胞群的扩增，并将提供 设计和测试治疗GDM的新治疗策略的关键基础平台。

Summary The late stages of the mammalian pregnancy are accompanied with increased insulin resistance due to the increased glucose demand of the growing fetus. Therefore, as a compensatory response, in order to maintain the maternal normal blood glucose levels, the beta cells mass expands leading to increased insulin release. Beta cell proliferation, beta cell neogenesis, and decreased beta cell apoptosis, are believed to be major contributors for beta cell adaptive response during pregnancy and defects in this adaptive response can lead to gestational diabetes mellitus (GDM). My preliminary results indicate that Nrf2 is required for adaptive beta cell expansion in adult mice during overnutrition, and that Nrf2 levels are upregulated in beta cells of pregnant mice. Despite multiple studies describing Nrf2 protective effects on beta cells in Type 2 and Type 1 diabetic models, no study has ever uncovered the role of Nrf2 in the expansion of beta cell mass during pregnancy. Does in vivo loss- or gain-of-Nrf2 function affect beta cell proliferation, survival and mass in pregnant mice? Does this potential alteration persist in the early post-partum period? Does in vivo loss- or gain-of-Nrf2 function affect insulin secretion in pregnant mice? Does in vivo loss- or gain-of-Nrf2 function affect glucose homeostasis in pregnant mice? Which genes are upregulated and downregulated in islets during pregnancy in response to in vivo loss or gain of Nrf2 function? Which are the Nrf2 target genes in islets during pregnancy? Do human beta cells also require Nrf2 for pregnancy-driven proliferation? These important questions about the physiological role of Nrf2 in beta cells during pregnancy need to be answered to advance our knowledge and find therapeutic means to treat GDM. We hypothesize that Nrf2 is necessary for beta cell expansion during pregnancy and that disruption of Nrf2 expression or function leads to GDM. We believe Nrf2 can serve as a potential therapeutic target for treating GDM. We will test our hypothesis by completing the following specific aims: 1) To determine the role of Nrf2 on the expansion of beta-cell mass during pregnancy. 2) To uncover the mechanisms by which Nrf2 regulates beta-cell mass expansion during pregnancy. 3) To test if Nrf2 is necessary for pregnancy-mediated adaptive human beta cell proliferation in vivo. These studies will provide insight into how Nrf2 promotes expansion of functional beta-cell mass during pregnancy and will provide a crucial basic platform for designing and testing novel therapeutic strategies for the treatment of GDM.