title: Synergistic effects of metformin with liraglutide against endothelial dysfunction through GLP-1 receptor and PKA signalling pathway.
abstract: 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.
authors.affiliation: Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Ke
authors.affiliation: Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing, China.
authors.forename: Ye
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing, China.
authors.forename: Ran
authors.initials: R
authors.lastname: Lu
authors.affiliation: Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Tian
authors.affiliation: Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing, China.
authors.forename: Wenfang
authors.initials: W
authors.lastname: Hou
authors.affiliation: Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing, China.|Department of Endocrinology and Metabolism, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China.
authors.forename: Guang
authors.initials: G
authors.lastname: Wang
authors.affiliation: Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Wei
authors.affiliation: Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing, China.
authors.forename: Tianpei
authors.initials: T
authors.lastname: Hong
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D059305:Diet, High-Fat; D004357:Drug Synergism; D000067757:Glucagon-Like Peptide-1 Receptor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D000069450:Liraglutide / Q000494:pharmacology*; D008297:Male; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D019308:Palmitic Acid / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D001057:Apolipoproteins E; D000067757:Glucagon-Like Peptide-1 Receptor; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D019308:Palmitic Acid; D000069450:Liraglutide; D008687:Metformin; D052250:Nitric Oxide Synthase Type III; D017868:Cyclic AMP-Dependent Protein Kinases; D055372:AMP-Activated Protein Kinases