业已证实，GLP-1和FGF21均可改善胰岛β细胞功能和存活，但两者之间是否存在相互调控尚未见报道。课题组前期研究显示，GLP-1受体激动剂（GLP-1RA）可改善db/db小鼠胰岛功能，抑制棕榈酸诱导的β细胞凋亡。预实验结果显示，GLP-1RA升高db/db小鼠胰岛FGF21荧光强度，促进小鼠β细胞系FGF21产生。本项目拟在db/db小鼠及棕榈酸诱导的原代胰岛和β细胞系中探讨GLP-1RA对FGF21表达和分泌及对β细胞功能和存活的影响，利用FGF21中和抗体或敲减技术验证FGF21是否参与GLP-1RA改善β细胞功能和存活。检测GLP-1受体、FGF21受体及下游信号通路的变化，通过添加拮抗剂或联合基因敲减技术验证特异信号分子在GLP-1RA调控FGF21产生进而改善β细胞功能和存活中的介导作用。本项目的开展有助于阐明GLP-1保护β细胞的新机制，为糖尿病治疗新策略研发提供科学依据。

It has been confirmed that both GLP-1 and FGF21 improve pancreatic β cell function and survival. However, the mutual regulation between them has not been validated. Our previous studies showed that GLP-1 receptor agonist (GLP-1RA) improved pancreatic islet function in db/db mice and inhibited palmitate-induced β cell apoptosis. Our preliminary studies showed that the fluorescence intensity of islet FGF21 was enhanced in db/db mice with GLP-1RA administration and the production of FGF21 was increased in GLP-1RA treated mouse β cell line. The aim of this project is to investigate the effect of GLP-1RA on the expression and secretion of FGF21 and the function and survival of β cells in db/db mice and palmitate-induced primary islets and β cell lines. The role of FGF21 in GLP-1RA improving β cell function and survival will be examined using FGF21 neutralizing antibodies or gene knockdown techniques. The differential expression of GLP-1 receptor, FGF21 receptor and their downstream signaling pathways will be characterized. And the role of regulated molecules mediated by GLP-1RA in regulating FGF21 production and the β cell function and survival will be identified by antagonists or gene knockdown techniques. The project will elucidate the new mechanism of GLP-1 in protecting β cells and provide a scientific basis for improving the development of diabetes treatment strategies.