Link of Beta Cell Proliferation and Type 2 Diabetes to Epigenetic Regulation

描述（由申请人提供）：需要足够数量的β细胞来产生足够数量的胰岛素以维持正常血糖。增强β细胞增殖或再生可能是治疗2型糖尿病（T2D）的有效手段。编码核蛋白menin的多发性内分泌瘤1型基因（Men1）的突变通常会导致几个内分泌器官（如胰岛）的良性增生，但不会影响其他器官，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。尽管利用抑制menin来增强β细胞再生和改善糖尿病是有吸引力的，但由于担心menin抑制可能产生致瘤作用，这一度被认为是有问题的或不可行的。然而，最近快速的研究进展改变了这一观点。Menin在生理上被抑制以增加β细胞增殖和预防妊娠糖尿病。我们最近的研究结果表明，menin与胰高血糖素样肽1 （GLP-1）信号通路相互作用，促进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的表达，将menin与GLP-1信号传导联系起来。Menin与PRMT5相互作用，PRMT5是一种抑制基因转录的组蛋白精氨酸甲基转移酶。值得注意的是，Men1切除不仅使小鼠对STZ诱导的高血糖产生抗性，而且还改善了STZ诱导的糖尿病小鼠原有的高血糖。自上次提交以来，我们的新结果还表明，急性Men1切除使高脂肪饮食喂养的小鼠先前存在的葡萄糖不耐受正常化。这些发现强烈表明，抑制menin可能是一种促进β细胞再生和改善糖尿病的新方法。据推测，menin通常通过抑制细胞周期调节因子的转录来抑制β细胞增殖

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: There are over 20 million patients with diagnosed or undiagnosed type 2 diabetes in the United States of America; in these patients there is an inadequate number of beta cells to control blood glucose. Our proposed studies likely unravel a new pathway, the menin pathway, in controlling beta cell proliferation, and this pathway could be modulated to ameliorate type 2 diabetes. These studies will likely pave the way to develop the next generation of new drugs to treat this widespread disease.