胰高糖素样肽-1（GLP-1）类似物和二甲双胍均具有独立于降糖之外的内皮保护和抗动脉粥样硬化作用。此外，二甲双胍可通过上调胰岛GLP-1受体表达而增强GLP-1的促胰岛素分泌效应。我们的预实验显示，低剂量GLP-1类似物或二甲双胍对棕榈酸诱导的内皮细胞氧化损伤未见保护作用，但两者联合则可显著阻止棕榈酸诱导的内皮细胞氧化损伤。我们假设：二甲双胍通过上调内皮细胞GLP-1受体表达，与GLP-1类似物在抗动脉粥样硬化中发挥协同作用。本课题拟在棕榈酸诱导的内皮细胞损伤模型和小鼠动脉粥样硬化模型中，明确二甲双胍与GLP-1类似物在改善内皮功能和抗动脉粥样硬化中的协同作用；探索二甲双胍对内皮细胞GLP-1受体表达的调节及相关信号通路；明确GLP-1受体在该协同效应中的作用。本课题有助于阐明GLP-1类似物和二甲双胍联合治疗在血管保护中的协同作用及机制，为优化糖尿病大血管病变防治策略提供理论基础。

Previous studies showed that either glucagon-like peptide 1 (GLP-1) analogue or metformin had a protective action on the endothelial function, independently of their glucose lowering effects. Moreover, it has been recently reported that metformin upregulated the expression of GLP-1 receptor in pancreatic beta-cells and promoted the insulinotropic effect of GLP-1 in beta-cells. Our preliminary data have shown that low dose of metformin or liraglutide, a GLP-1 analogue, alone had no significant protective effect on oxidative stress and endothelial dysfunction induced by palmitic acid in endothelial cells. However, combination treatment with the low doses of the two agents dramatically prevented the endothelial damage induced by palmitic acid. Therefore, we hypothesize that metformin may have a synergistic effect with GLP-1 analogues in endothelial function protection and anti-atherosclerosis, via upregulation of GLP-1 receptor expression in endothelial cells. In this project, we aim to further confirm the synergistic effect of GLP-1 analogues (such as liraglutide and dulagutide) and metformin combination treatment in endothelial function protection and anti-atherosclerosis, in the cultured cell model of palmitic acid-induced endothelial damage and in ApoE-/- mouse model of atherosclerosis; to explore the effects of metformin on GLP-1 receptor expression in endothelial cells and the possible signaling pathway involved in this process; and to investigate whether the regulation of GLP-1 receptor expression is essential in this synergistically protective effect. This project will extend the understanding of the combination therapy with GLP-1 analogues and metformin in cardiovascular protection, and will help to refine the prevention and treatment strategies of macrovascular complications in patients with diabetes.