从SIRT1/FoxO1通路介导的胰岛β细胞去分化角度部分阐明开郁清热方治疗2型糖尿病的作用机制

Type2 diabetes mellitus(T2DM) has been a critical illness that threatens human health. Recent studies indicate that the dedifferentiation of pancreatic β cells may be the key problem for the continuous islet dysfunction. FoxO1 has the function of inhibiting β cells dedifferentiation, while SIRT1 can enhance FoxO1 transcriptional activity through deacetylation. Our studies have shown that the main pathogenesis of T2DM is abdominal fullness and interior heat on the perspective of traditional Chinese medicine and Kaiyuqingre Formula is an effective prescription for the treatment of T2DM. Based on what has been reported that Kaiyuqingre Formula upregulated the level of SIRT1, we take the Ins2/GFP transgenic animal and β cell models of T2DM and the models with SIRT1interved by chemicals as objects , take cell lineage tracer as key technology to verify that whether Kaiyuqingre Formula may inhibit β cells dedifferentiation by upregulating the level of SIRT1 which may induce the deacetylation of FoxO1. Through the above research, we are looking forward to test the hypothesis that the down- regulation of SIRT1 reduces the activity of FoxO1 may be an important mechanism for the dedifferentiation of induced β cells in high glucose environment , while Kaiyuqingre Formula may inhibit the dedifferentiation of β cells by regulating the SIRT1/FoxO1 signaling pathway to protect the islet function. This research is expected to provide a new scientific basis for the prevention and treatment of T2DM with traditional Chinese medicine.

2型糖尿病（T2DM）是危害人类健康的重大疾病。新近研究表明胰岛β细胞去分化可能是T2DM胰岛功能持续减退的关键原因，FoxO1具有抑制β细胞去分化的作用，而SIRT1可通过去乙酰化增强FoxO1的转录活性。团队研究发现“中满内热”是T2DM的核心病机，开郁清热方是针对该病机治疗T2DM的有效方剂。本研究在前期证实开郁清热方可上调SIRT1表达的基础上，分别以Ins2/GFP转基因和化学试剂干预SIRT1表达的T2DM动物及β细胞模型为研究对象，运用细胞谱系示踪技术探讨开郁清热方是否通过上调SIRT1使FoxO1去乙酰化从而抑制β细胞去分化。通过上述研究，拟验证假说:SIRT1下调使FoxO1活性降低是高糖诱发β细胞去分化的重要机制，而开郁清热方可能通过调控SIRT1/FoxO1信号通路抑制β细胞去分化从而保护胰岛功能。本项目有望为中医药防治T2DM提供新的科学依据。