二甲双胍通过上调胰高糖素样肽-1受体表达而与胰高糖素样肽-1类似物在抗动脉粥样硬化中发挥协同作用

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.

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。

项目背景：近年来，基于胰高糖素样肽-1（ glucagon-like peptide 1, GLP-1）的新型降糖药成为糖尿病治疗领域的热点。既往研究证实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。GLP-1类似物的上述血管保护作用是通过内皮细胞表达的GLP-1受体而实现。近期研究显示二甲双胍可通过上调胰岛β细胞的GLP-1受体表达而增强GLP-1的促胰岛素分泌效应。..研究内容：本项重点在人脐静脉内皮细胞损伤模型和ApoE -/-小鼠动脉粥样硬化动物模型中，研究二甲双胍和GLP-1类似物利拉鲁肽在内皮保护和抗动脉粥样硬化中的保护效应及二者的协同作用，探讨该协同效应的分子机制。此外，本项目也关注了GLP-1类似物对血管内皮的直接保护效应。同时，探讨长期应用肠促胰素药物在胰腺方面的安全性。..重要结果：在棕榈酸诱导的内皮细胞损伤模型以及高脂喂养的ApoE-/-小鼠动脉粥样硬化模型中，二甲双胍和利拉鲁肽可以单独地、剂量依赖性地发挥血管内皮保护作用。两药极低剂量的单独干预均不能产生保护效应，但极低剂量的二者联合则能显著抑制高脂诱导的血管内皮细胞功能异常。进一步，二甲双胍能够依赖AMPK通路，上调血管内皮细胞GLP-1受体表达和PKA的磷酸化水平。该机制可能解释了上述二甲双胍与利拉鲁肽在血管内皮保护中的协同作用。 此外，我们在新诊断的2型糖尿病患者中发现，生活方式干预的基础上联合GLP-1类似物艾塞那肽干预12周，能够显著增加患者冠状动脉血流储备、降低sICAM-1和sVCAM-1的水平。上述血管内皮的保护效应可能通过GLP-1受体依赖性地激活AMPK/PI3K-Akt/eNOS通路而实现。同时，我们关注了GLP-1类似物的胰腺安全性：系统综述高质量大型随机对照研究显示，在2型糖尿病患者中长期应用肠促胰素药物（GLP-1类似物和DPP-4抑制剂）不增加胰腺癌和胰腺炎风险；应用2年以上还可能降低胰腺癌的发病风险。