The GLP-1 analogue lixisenatide decreases atherosclerosis in insulin-resistant mice by modulating macrophage phenotype

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.

Atherosclerosis; GLP-1; Inflammation; Macrophage; STAT.