| First Author | Vinué Á | Year | 2017 |
| Journal | Diabetologia | Volume | 60 |
| Issue | 9 | Pages | 1801-1812 |
| PubMed ID | 28608285 | Mgi Jnum | J:250466 |
| Mgi Id | MGI:5924111 | Doi | 10.1007/s00125-017-4330-3 |
| Citation | Vinue A, et al. (2017) The GLP-1 analogue lixisenatide decreases atherosclerosis in insulin-resistant mice by modulating macrophage phenotype. Diabetologia 60(9):1801-1812 |
| abstractText | AIMS/HYPOTHESIS: Recent clinical studies indicate that glucagon-like peptide-1 (GLP-1) analogues prevent acute cardiovascular events in type 2 diabetes mellitus but their mechanisms remain unknown. In the present study, the impact of GLP-1 analogues and their potential underlying molecular mechanisms in insulin resistance and atherosclerosis are investigated. METHODS: Atherosclerosis development was evaluated in Apoe (-/-) Irs2 (+/-) mice, a mouse model of insulin resistance, the metabolic syndrome and atherosclerosis, treated with the GLP-1 analogues lixisenatide or liraglutide. In addition, studies in Apoe (-/-) Irs2 (+/-) mice and mouse-derived macrophages treated with lixisenatide were performed to investigate the potential inflammatory intracellular pathways. RESULTS: Treatment of Apoe (-/-) Irs2 (+/-) mice with either lixisenatide or liraglutide improved glucose metabolism and blood pressure but this was independent of body weight loss. Both drugs significantly decreased atheroma plaque size. Compared with vehicle-treated control mice, lixisenatide treatment generated more stable atheromas, with fewer inflammatory infiltrates, reduced necrotic cores and thicker fibrous caps. Lixisenatide-treated mice also displayed diminished IL-6 levels, proinflammatory Ly6C(high) monocytes and activated T cells. In vitro analysis showed that, in macrophages from Apoe (-/-) Irs2 (+/-) mice, lixisenatide reduced the secretion of the proinflammatory cytokine IL-6 accompanied by enhanced activation of signal transducer and activator of transcription (STAT) 3, which is a determinant for M2 macrophage differentiation. STAT1 activation, which is essential for M1 phenotype, was also diminished. Furthermore, atheromas from lixisenatide-treated mice showed higher arginase I content and decreased expression of inducible nitric oxide synthase, indicating the prevalence of the M2 phenotype within plaques. CONCLUSIONS/INTERPRETATION: Lixisenatide decreases atheroma plaque size and instability in Apoe (-/-) Irs2 (+/-) mice by reprogramming macrophages towards an M2 phenotype, which leads to reduced inflammation. This study identifies a critical role for this drug in macrophage polarisation inside plaques and provides experimental evidence supporting a novel mechanism of action for GLP-1 analogues in the reduction of cardiovascular risk associated with insulin resistance. |
