Link of beta cell proliferation and type 2 diabetes to epigenetic regulation.

需要足够数量的β细胞来产生足够量的胰岛素，以维持 正常增强β细胞增殖或再生可能是治疗2型糖尿病的有效手段 糖尿病（T2 D）。多发性内分泌腺瘤1型基因（Men 1）突变，该基因编码核内分泌腺瘤。 menin蛋白通常导致几种内分泌器官的良性增生，如胰岛，但 不影响其他器官，如肝脏。我们的长期目标之一是了解menin如何调节 β细胞增殖虽然利用抑制menin来增强β细胞再生是有吸引力的， 改善糖尿病，这曾经被认为是有问题的或不可行的，因为担心潜在的致瘤作用 是因为抑制了脑膜炎然而，最近快速的研究进展改变了这一观点。梅宁群岛 生理抑制，以增加β细胞增殖和预防妊娠糖尿病。我们最近 研究结果表明，menin与胰高血糖素样肽1（GLP-1）信号通路相互作用， β细胞再生，调节基因转录。例如，menin抑制，但GLP-1增加， 细胞周期蛋白A表达，将menin与GLP-1信号传导联系起来。Menin与组蛋白精氨酸PRMT 5相互作用 抑制基因转录的甲基转移酶。值得注意的是，Men 1切除不仅使小鼠对抗肿瘤药物具有抗性， 链脲佐菌素（STZ）诱导的高血糖症，但也改善了STZ诱导的预先存在的高血糖症 糖尿病小鼠我们自上次提交以来的新结果也表明，急性Men 1切除 正常化高脂肪饮食喂养的小鼠中预先存在的葡萄糖耐受不良。这些发现有力地表明， 抑制menin可以是增强β细胞再生和改善糖尿病的新方法。是 假设menin通常通过抑制细胞转录来抑制β细胞增殖 周期调节因子，如GLP-1诱导的细胞周期蛋白A，与表观遗传调节因子PRMT 5一致，Men 1 抑制导致β细胞再生和2型糖尿病的改善。因此，在本提案中，如何 menin抑制细胞周期调节基因的转录，如GLP-1诱导的细胞周期蛋白A， 研究了第二，menin和GLP-1通路之间相互作用的潜在机制， 控制细胞周期蛋白A转录和β细胞增殖的方法。第三，影响男性1 将在T2 D小鼠模型中检查对改善T2 D的抑制作用。这些研究可能会揭开新的 通过menin和GLP-1通路之间的相互作用控制β细胞增殖的机制 通过基因转录的表观遗传调控。拟议的研究可能为发展 治疗T2 D的新的和基于menin途径的策略。

An adequate number of beta cells are required for production of a sufficient amount of insulin to maintain normoglycemia. Enhancing beta cell proliferation or regeneration can be an effective means to treat type 2 diabetes (T2D). Mutations in the multiple endocrine neoplasia type 1 gene (Men1), which encodes the nuclear protein menin, usually result in benign hyperplasia in several endocrine organs, such as pancreatic islets, but do not affect other organs, such as the liver. One of our long-term goals is to understand how menin regulates beta cell proliferation. Though it is attractive to tap into repressing menin to enhance beta cell regeneration and ameliorate diabetes, this was once thought problematic or unfeasible for fear of the potential tumorigenic effect from menin inhibition. However, recent and rapid research progress has altered this view. Menin is physiologically repressed to increase beta cell proliferation and prevent gestational diabetes. Our recent findings suggest that menin interplays with glucagon-like peptide 1 (GLP-1) signaling pathway, which promotes beta cell regeneration, to regulate gene transcription. For instance, menin suppresses, but GLP-1 increases cyclin A expression, linking menin to GLP-1 signaling. Menin interacts with PRMT5, a histone arginine methytransferase that represses gene transcription. Notably, Men1 excision not only renders mice resistant to streptozotocin (STZ)-induced hyperglycemia, but also ameliorates pre-existing hyperglycemia in STZ-induced diabetic mice. Our new results since the last submission also demonstrate that acute Men1 excision normalized pre-existing glucose intolerance in high-fat diet-fed mice. These findings strongly suggest that repressing menin can be a novel means to enhance beta cell regeneration and ameliorate diabetes. It is hypothesized that menin normally suppresses beta cell proliferation through repressing transcription of cell cycle regulators, such as GLP-1-induced cyclin A, in concert with epigenetic regulator PRMT5, and that Men1 inhibition leads to beta cell regeneration and amelioration of type 2 diabetes. Thus, in this proposal, how menin represses transcription of cell cycle-regulating genes, such as GLP-1-induced cyclin A, will be investigated. Second, the mechanisms underlying the interplay between menin and the GLP-1 pathway in controlling cyclin A transcription and beta cell proliferation will be elucidated. Third, the impact of Men1 inhibition on ameliorating T2D will be examined in T2D mouse models. These studies will likely unravel novel mechanisms in control of beta cell proliferation by the interplay between menin and the GLP-1 pathway through epigenetic regulation of gene transcription. The proposed studies may pave the way to developing novel and menin pathway-based strategies to treat T2D.