Menin调控β细胞再生改善2型糖尿病的分子机制

Inadequate or damaged pancreatic β cells are the leading cause of diabetes. Hence, enhancing β cell proliferation or regeneration is highly desirable for treating diabetes. However, the key molecular network that is crucial for β cell regeneration is poorly understood. Our previous results found that Men1 excision not only renders mice resistant to streptozotocin (STZ)-induced hyperglycemia, but also ameliorates hyperglycemia in mice with pre-existing STZ-induced diabetes. These findings strongly suggest that repressing menin can be a novel means to enhance β cell regeneration and ameliorate diabetes. However, how menin regulates β cell regeneration remains unclear. Thus, in this proposal, we will investigate how menin epigenetically regulates transcription of cyclin A and β cell proliferation, in concert with an histone modification regulator, PRMT5. Second, we will explore the mechanisms underlying the interplay between menin/PRMT5 and GLP-1/CREB in controlling cyclin A transcription and β cell proliferation. Third, the synergistic impact of Men1 excision and GLP-1 on ameliorating type 2 diabetes will be examined in transgenic and various diabetic mouse models. These studies will likely unravel a novel mechanism in controlling β cell proliferation via the interplay between menin and GLP-1 through epigenetic regulation of gene transcription, paving the way to develop novel and menin pathway-based strategies to treat diabetes.

胰岛β细胞数量缺乏与受损是导致糖尿病的主要因素，刺激β细胞增殖和再生将成为一种改善糖尿病的重要手段。然而，β细胞再生进程中起关键作用的特异性分子及其调控网络目前知之甚少。我们发现，menin被敲除后明显改善高脂饮食及链脲霉素streptozotocin诱导的葡萄糖耐受性损伤，显著降低小鼠血糖含量，但menin如何调控β细胞增殖及其关键的分子网络尚未阐明。本项目拟明确menin与PRMT5在调控β细胞再生过程中的协同作用；阐明menin与PRMT5通过组蛋白修饰调控细胞周期因子的表观遗传学机制；深入鉴定menin/PRMT5与GLP-1/CREB在调控cyclin A及β细胞增殖进程中的拮抗作用；利用转基因及糖尿病小鼠模型，评估敲除menin与GLP-1联合改善糖尿病的关键生物学作用。这将有助于对研究通过靶向联合干预促进β细胞再生及提高胰岛素水平，最终开发新型2型糖尿病治疗药物具有积极的指导

促进细胞增殖增加胰岛β细胞数量对2型糖尿病的治疗具有重要意义。已证明menin可以调节β细胞增殖，但相关机制尚未完全阐明。本项目研究发现：1. menin表观遗传调节β细胞细胞周期因子E2F3和cyclin A2表达，机制研究发现menin抑制组蛋白乙酰转移酶SRC1结合，从而减少E2F3启动子H3乙酰化，抑制其转录表达。2. GLP-1通过PKA磷酸化menin第487位丝氨酸，menin磷酸化失去抑制β细胞Ins1和cyclin D2基因表达作用，从而促进β胰岛素合成和分泌及增殖。3. menin可以调节E2泛素连接酶Skp2与FOXO1结合，从而减少FOXO1泛素化，抑制其降解，从而增加FOXO1蛋白水平。因此，这些研究结果将为阐明menin调节β细胞增殖和GLP-1治疗糖尿病的机制提供新的科学依据，也将为开发新的治疗2型糖尿病的药物奠定基础。