摘要糖尿病发病机制中的关键原因是功能性胰岛 β 细胞量(functionalβcell mass)的丢失,无法分泌足够的胰岛素以保持机体的血糖稳态.1型糖尿病主是免疫介导的 β 细胞凋亡导致的胰岛素绝对缺乏,而2型糖尿病在胰岛素抵抗同时,伴有不同程度的 β 细胞功能异常和凋亡.一系列最新研究示,2型糖尿病的 β 细胞功能受损与其无法维持正常的成熟功能状态有关,主可以归结为:(1)β 细胞身份的丢失(loss of cell identity),特别是那些成熟 β 细胞特异性转录因子及与功能密切相关蛋白的表达异常;(2)去分化(de-differentiation),定义为成熟 β 细胞退化到祖细胞或类干细胞状态.β 细胞功能性成熟的维持还与一群 β 细胞"不允许基因"(disallowed gene)的选择性低表达密切相关.本文将介绍胰岛 β 细胞成熟分化调控的最新进展,并融入本研究团队在此领域的研究成果,旨在为探索糖尿病临床干预供一些启示.

abstractsThe main etiology of diabetes mellitus is loss of functional β cell mass, which is responsible for the secretion of the insulin hormone to reduce elevated plasma glucose and to maintain glucose homeostasis. Type 1 diabetes has traditionally been characterized by autoimmune-mediated β-cell death leading to insulin dependence, whereas type 2 diabetes has hallmarks of peripheral insulin resistance, accompanied by β cell dysfunction, and cell death. However, a growing body of evidence suggests that β cell dysfunction and defects of functional maturation in type 2 diabetes involve: (1 ) loss of cell identity, specifically proteins associated with mature cell function and transcription factors like Pdx1,MafA,Nkx6. 1,Glut2,and GK,and (2) de-differentiation,defined by regression to a progenitor or stem cell-like state. Moreover, ectopic expression of genes that are disallowed in β cells is also crucial to maintain the mature phenotype of β cells. In this review, we will combine our preliminary data and summarize the recent literature describing how β cell functional maturation is regulated. We hope that this perspective could shed some lights on possible avenues of new therapeutic intervention for diabetes mellitus.