转录因子E2F3调节的细胞增殖在胃旁路手术增进2型糖尿病胰岛beta细胞数量中的作用与机制

胰岛β细胞数量减少及其所致的胰岛素水平降低是2型糖尿病发生发展的关键环节，胃旁路手术增多糖尿病β细胞数量但机理不清楚。β细胞增殖是维持β细胞数量和血糖稳态的重要细胞机制。我们发现糖尿病GK大鼠行胃旁路手术后，胰岛β细胞增殖显著增强，β细胞E2F3表达升高。E2F是调控细胞周期的重要转录调节因子，沉默E2F3导致β细胞增殖抑制，细胞数量减少。此外，激活胆汁酸核受体FXR导致β细胞数量增多，E2F3表达增高。以此为基础，我们将采用分子生物学、细胞生物学及免疫细胞化学等方法探讨①E2F3是否通过cyclin A2促进β细胞增殖；②E2F3是否为FXR调节的靶分子；③FXR调节E2F3表达的表观遗传机制；④CDCA/FXR-E2F3轴在介导胃旁路手术促β细胞增殖中的作用。研究结果将为揭示胃旁路手术治疗糖尿病的分子机制提供新理论，为以增加胰岛β细胞数量为目标的糖尿病治疗和药物研发提供新靶点。

Decreased β-cell mass with resultant diminished insulin levels plays a key role in progression in type 2 diabetes mellitus (T2DM). It has been found that Roux-en-Y gastric bypass (RYGB) signifcantly improves β-cell mass, which results in remission of T2DM. However, the mechanisms underlying remain largely unknown. β-cell proliferation is essential for maintaining β-cell mass. Our data show that enhanced β-cell proliferation and insulin level in diabetic GK rats after RYGB. This is associated with improved expression of E2F3 in β-cells in GK rats. E2F3 is a transcription factor that plays an important role in regulation of cell cycle.We found that E2F3 KD resulted in reduced β-cell proliferation and β-cell mass. Moreover, we found that activation of FXR (farsenoid-X receptor) leads to enhanced β-cell proliferation and β-cell mass. Based on these findings, we would employ RYGB rat or mouse models to determine ⑴ whether or not the effect of E2F3-enhanced β-cell proliferation is mediated by cyclin A2; ⑵ is E2F3 the target molecular of FXR,and involved in FXR-enhanced β-cell proliferation? ⑶ how dose FXR epigenetically regulate E2F3 expression; ⑷ Is CDCA/FXR-E2F3 axis implicated in RYGB-improved β-cell proliferation in T2DM? The results of this study will shed light on revealing the cellular mechanisms underlying the beneficial effect of RYGB on β-cell mass in T2DM.