Nrf2 and the adaptive expansion of beta cell mass

摘要 据估计，3000万至6000万患有I型或II型糖尿病的美国人将受益于 促进功能性β细胞团的扩增和增强保护。然而，人类的贝塔细胞 顽固地抵制那些可以安全地扩大糖尿病患者的β细胞团的治疗。因此，有一种 迫切需要确定和开发新的途径，以安全地扩大β细胞团。β细胞作为一种 对胰岛素需求增加的自然适应性反应，而葡萄糖本身就是一种有效的β细胞有丝分裂原。 在这里，我们将探索β细胞中一种令人兴奋的新途径，即抗氧化剂Nrf2途径，我们最近 FOUND是葡萄糖刺激的β细胞增殖所必需的，并能促进其增殖。我们一直在研究 葡萄糖刺激基因表达近20年，并发现碳水化合物反应 元件结合蛋白(ChREBP)是一种葡萄糖敏感转录因子，是葡萄糖刺激所必需的 β细胞增殖。令人惊讶的是，我们还发现全长ChREBPα亚型的过度表达 将啮齿动物和人类葡萄糖刺激的β细胞增殖放大2到3倍，而不会导致细胞死亡。我们的 初步数据表明，ChREBPα过表达重新编程新陈代谢，以提供合成代谢 核扩散的基石。值得注意的是，ChREBPα增加了线粒体的生物合成，氧气 消费率和三磷酸腺苷产量。从功能上讲，用ChREBPα预处理可促进移植 人类胰岛在STZ治疗的NOD.SCID小鼠中的结果。因为基因治疗增加了 ChREBPα的丰度是不现实的，我们关注的是负责显著的途径 ChREBPα介导的合成代谢作用。我们发现ChREBPα介导的β细胞增殖增加 需要抗氧化剂Nrf2途径的激活。NRF2还提高了线粒体的含量和活性， 并促进合成代谢。此外，Nrf2的激活是正常葡萄糖刺激所必需的。 或适应性的β细胞增殖，在体外和体内。值得注意的是，Nrf2的表达增加足以 在体内用标准食物促进啮齿动物β细胞的增殖，在体外促进人β细胞的增殖， 即使在低浓度的葡萄糖中也是如此。重要的是，几种药理上的NRF2激活剂要么是 已批准或正在进行各种病理学的临床试验，但没有一种涉及β细胞生物学。因此， NRF2在β细胞的适应性扩张中发挥着以前未被认识到的关键作用，这可能是 在治疗上被剥削。目前的提议将检验令人兴奋的假设，即Nrf2增加 β细胞的线粒体和合成代谢功能，既增加了增殖能力，又增加了 防止氧化应激。我们将：1)阐明Nrf2在β细胞适应性扩增中的作用 质量；2)确定Nrf2的增加或减少是否会改变人类胰岛移植的结果。3) 探讨Nrf2促进葡萄糖刺激的增殖的机制。 好了！

Summary It is estimated that 30-60 million Americans with Type I or Type 2 diabetes would benefit from therapies that promote expansion and enhance protection of functional beta cell mass. However, human beta cells are stubbornly resistant to therapies that would safely expand beta cell mass in diabetic patients. Thus there is an urgent need to identify and exploit new pathways to safely expand beta cell mass. Beta cells proliferate as a natural adaptive response to increased demand for insulin, and glucose itself is an effective beta cell mitogen. Here, we will explore an exciting new pathway in beta cells, the antioxidant Nrf2 pathway, that we recently found is necessary for and augments glucose-stimulated beta cell proliferation. We have been studying glucose-stimulated gene expression for nearly two decades and have found that carbohydrate response element binding protein (ChREBP), a glucose-sensing transcription factor, is required for glucose-stimulated beta cell proliferation. Surprisingly, we also found that overexpression of the full length ChREBPα isoform amplifies, by 2 to 3-fold, rodent and human glucose-stimulated beta cell proliferation, without cell death. Our preliminary data demonstrate that ChREBPα overexpression reprograms metabolism to provide anabolic building blocks for proliferation. Remarkably, ChREBPα increases mitochondrial biogenesis, oxygen consumption rates, and ATP production. Functionally, pretreatment with ChREBPα enhances transplantation outcomes of human islets in STZ-treated NOD.SCID mice. Since gene therapy maneuvers that increase ChREBPα abundance are not practical, we focused on the pathways responsible for the remarkable ChREBPα-mediated anabolic effect. We found that the ChREBPα-mediated increase in beta cell proliferation requires the activation of the antioxidant Nrf2 pathway. Nrf2 also enhances mitochondrial content and activity, and increases anabolic metabolism. Furthermore, activation of Nrf2 is necessary for normal glucose-stimulated or adaptive beta cell proliferation, in vitro and in vivo. Strikingly, increased expression of Nrf2 is sufficient to drive rodent beta cell proliferation on a standard chow diet in vivo, and human beta cell proliferation in vitro, even in low concentrations of glucose. Importantly, several pharmacological Nrf2 activators are either approved or being tested in clinical trials for a variety of pathologies, but none address beta cell biology. Thus, Nrf2 performs a previously unrecognized critical role in the adaptive expansion of beta cells that may be exploited therapeutically. The current proposal will test the exciting hypothesis that Nrf2 increases mitochondrial and anabolic function in beta cells providing both increased capacity to proliferate and increased protection from oxidative stress. We will: 1) Elucidate the role of Nrf2 in the adaptive expansion of beta cell mass; 2) Establish whether increasing or decreasing Nrf2 alters human islet transplantation outcomes. 3) Explore the mechanisms by which Nrf2 promotes glucose-stimulated proliferation. !