2型糖尿病已成为严重威胁人们健康和生命的非传染性疾病，对新的分子实体和治疗策略的需求仍然紧迫。本项目前期研究发现傣药光叶子花中单体ZYM01具有显著降糖和胰岛保护作用，机制研究发现ZYM01能够直接刺激肠道GLP-1分泌，是具有全新作用机制的原创候选新药。靶标验证工作中我们发现ZYM01对离子通道TRPV6有激动作用。TRPV6是一类高选择性Ca2 +通道并在肠道广泛表达，但其与肠道GLP-1分泌相关性研究暂无，可能是参与GLP-1分泌调节的新颖靶标。申请项目将论证ZYM01降糖药效、促GLP-1分泌以及TRPV6激动活性之间的依赖关系，明确ZYM01靶向肠道TRPV6离子通道促进GLP-1分泌进而改善高血糖的药理机制和作用靶标蛋白，同时也首次建立TRPV6通道与GLP-1分泌和血糖调节之间的相关性，为完善GLP-1分泌机制、发现降糖新策略、新靶标提供线索。

Over the last few years, incretin-based therapies have emerged as important agents in the treatment of type 2 diabetes (T2D). These agents exert their effect via the incretin system, specifically targeting the receptor for the incretin hormone glucagon-like peptide 1 (GLP-1). Two classes of incretin-based therapies are available: GLP-1 receptor agonists and dipeptidyl peptidase-4 inhibitors. There are currently no clinical drugs that directly promote GLP-1 secretion..Transient receptor potential vanilloid subfamily member 6 (TRPV6) is a highly selective Ca2+ channel that exerts its normal physiological function via Ca2+ absorption in the intestine and kidney. The secretion of GLP-1 is a process of vesicle exocytosis, elevated intracellular calcium is the ultimate trigger for exocytosis. Although TRPV6 is highly calcium-permeable and widely expressed in the intestine, its association with GLP-1 secretion and hypoglycemic studies has hardly been reported. .Our study found that the compound ZYM01 in the Bougainvillea glabraChoisy (which was used for hypoglycemic by the Dai ethnic group in China) had a good hypoglycemic effect and a significant islet protection function. Our studies found ZYM01 concentrated in the intestine directly stimulated the secretion of GLP-1 and exerted the hypoglycemic effects in vivo. Also in cultured STC-1 cells, ZYM01 promoted GLP-1 secretion in a dose- dependent manner. In the overexpressed - TRPV6 HEK293T cells, we used the patch-clamp techniques to confirmed that ZYM01 is an agonist for TRPV6, and in the STC-1, knockdown the expression of TRPV6 by siRNA blocks the increase of the secretion of GLP-1 stimulated by ZYM01..Based on this, the project will further clarify the hypoglycemic mechanism of the candidate ZYM01, and demonstrate the correlation between TRPV6 and ZYM01 to promote GLP-1 secretion and blood glucose regulation. Our work may provide first-in-class hypoglycemic candidates and original drug targets for diabetes treatment.