Stxbp6调控胰岛素产生及其敏感性在糖稳态中的机制探究

糖尿病已成为重大卫生健康问题，主要病因是胰岛素不足或胰岛素抵抗导致的糖稳态失衡。Syntaxin结合蛋白6（STXBP6）C端是卷曲螺旋的SNARE结构域，可通过调控SNARE蛋白复合体的组装与稳定性来负调控胰岛素的胞吐分泌，参与糖稳态调节及糖尿病的发生发展。然而，敲除STXBP6是否可以在体内促进胰岛素的产出，对胰岛素的胞吐分泌及糖稳态调控有何影响仍不清楚。我们构建了Stxbp6缺失小鼠模型并发现其体重减轻，GTT和GIIS受损，伴胰岛异常、G6PC上调和IRS1下调，提示Stxbp6缺失降低了胰岛素生产能力并促进胰岛素抵抗。本项目拟运用免疫组化、流式、电生理、转录组学和代谢组学等方法，从H9-β细胞、min6细胞系模型和Stxbp6缺失小鼠模型两个层面，探索STXBP6在胰岛素产生及其敏感性中的作用机制。本项目有望提高对糖稳态调控机制的认识，对开发血糖控制的新方法也具有一定的指导意义。

Diabetes has become a major public health problem, the main cause is the imbalance of glucose homeostasis caused by insulin deficiency or insulin resistance. Syntaxin binding protein 6 (STXBP6) with a the coiled-coil SNARE domain, can negatively regulate insulin exocytosis and secretion by regulating the assembly and stability of the SNARE protein complex, and participate in the regulation of glucose homeostasis and the onset and development of diabetes. However, it is still unclear whether knocking out STXBP6 can promote insulin production in the body, and how it affects insulin exocytosis and regulation of glucose homeostasis. We constructed a Stxbp6 deletion mouse model and found that its weight loss, GTT and GIIS damage, with islet abnormalities, G6PC up-regulation and IRS1 down-regulation, suggesting that Stxbp6 deletion reduces insulin production capacity and promotes insulin resistance. This project intends to synthetically use methods such as immunohistochemistry, flow cytometry, electrophysiology, transcriptomics and metabolomics, from H9-β cells and min6 cell line models to Stxbp6 deletion mouse models, to explore the effects and mechanisms of STXBP6 on insulin production and its sensitivity. This project would improve the understanding of the underlying regulation mechanism of glucose homeostasis, and also provide potential guiding significance for the development of new methods of blood glucose control.