Synergistic effects of metformin with liraglutide against endothelial dysfunction through GLP-1 receptor and PKA signalling pathway.
Synergistic effects of metformin with liraglutide against endothelial dysfunction through GLP-1 receptor and PKA signalling pathway.
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二甲双胍联合利拉鲁肽通过GLP-1受体和PKA信号通路对抗内皮功能障碍的协同作用
DOI：
10.1038/srep41085
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发表时间：
2017-02-01
影响因子：
4.6
通讯作者：
Hong T
中科院分区：
文献类型：
--
作者：
Ke J;Liu Y;Yang J;Lu R;Tian Q;Hou W;Wang G;Wei R;Hong T
二甲双胍或胰高血糖素样肽-1 （GLP-1）类似物利拉鲁肽对心血管有益。然而，目前尚不清楚它们的联合治疗是否对血管系统有附加或协同作用。在本研究中，暴露于棕榈酸（PA）诱导内皮功能障碍的人脐静脉内皮细胞（HUVECs）与二甲双胍、利拉鲁肽或其联合孵育。高脂饲料（HFD）喂养的ApoE - / -小鼠随机分为对照组、二甲双胍组、利拉鲁肽组和联合治疗组。结果表明，在pa处理的huvec和hfd喂养的ApoE - / -小鼠中，较低剂量的二甲双胍和利拉鲁肽联合治疗可显著改善内皮功能障碍。二甲双胍上调GLP-1受体（GLP-1R）水平和蛋白激酶A （PKA）磷酸化。然而，PKA抑制而非GLP-1R阻断消除了二甲双胍对内皮功能的保护作用。此外，AMPK抑制剂化合物C消除二甲双胍介导的GLP-1R水平上调和PKA磷酸化。综上所述，二甲双胍与利拉鲁肽联用对内皮功能具有协同保护作用。此外，二甲双胍通过ampk依赖性途径刺激GLP-1R和PKA信号传导，这可能是其与利拉鲁肽协同保护作用的原因。我们的研究结果为二甲双胍与GLP-1的相互作用提供了新的见解，并为设计新的基于GLP-1的治疗2型糖尿病的治疗策略提供了重要信息。
Metformin or glucagon-like peptide-1 (GLP-1) analogue liraglutide has cardiovascular benefits. However, it is not clear whether their combined treatment have additive or synergistic effects on the vasculature. In this study, human umbilical vein endothelial cells (HUVECs), exposed to palmitic acid (PA) to induce endothelial dysfunction, were incubated with metformin, liraglutide or their combination. High fat diet (HFD)-fed ApoE−/−mice were randomized into control, metformin, liraglutide, and combination treatment groups. Results showed that in PA-treated HUVECs and HFD-fed ApoE−/−mice, combination of metformin and liraglutide at lower dose significantly improved endothelial dysfunction compared with the single treatment. Metformin upregulated GLP-1 receptor (GLP-1R) level and protein kinase A (PKA) phosphorylation. However, PKA inhibition but not GLP-1R blockade eliminated the protective effects of metformin on endothelial function. Furthermore, AMPK inhibitor compound C abolished the metformin-mediated upregulation of GLP-1R level and PKA phosphorylation. In conclusion, combination of metformin and liraglutide has synergistic protective effects on endothelial function. Moreover, metformin stimulates GLP-1R and PKA signalling via AMPK-dependent pathway, which may account for its synergistic protective effects with liraglutide. Our findings provide new insights on the interaction between metformin and GLP-1, and provide important information for designing new GLP-1-based therapy strategies in treating type 2 diabetes.