The GLP-1 analogue lixisenatide decreases atherosclerosis in insulin-resistant mice by modulating macrophage phenotype
Open accessAbstract
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.
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In atherosclerosis-prone ApoE−/− and insulin-resistant mice, lixisenatide increases plaque stability.
“Vinué et al. showed in atherosclerosis-prone apolipoprotein E-deficient (ApoE−/−) and insulin-resistant mice that lixisenatide can diminish the atherosclerosis burden by reducing the size of atheroma plaques, increasing plaque stability, and reprogramming macrophages to the anti-inflammatory M2 phenotype by enhanced activation of signal transducer and activator of transcription (STAT)3, which is a”
From Protection against stroke with glucagon-like peptide-1 receptor agonists: a comprehensive review of potential mechanisms (2022) · cites this paper as [44]
In atherosclerosis-prone ApoE−/− and insulin-resistant mice, lixisenatide reduces the size of atheroma plaques.
“Vinué et al. showed in atherosclerosis-prone apolipoprotein E-deficient (ApoE−/−) and insulin-resistant mice that lixisenatide can diminish the atherosclerosis burden by reducing the size of atheroma plaques, increasing plaque stability, and reprogramming macrophages to the anti-inflammatory M2 phenotype by enhanced activation of signal transducer and activator of transcription (STAT)3, which is a”
From Protection against stroke with glucagon-like peptide-1 receptor agonists: a comprehensive review of potential mechanisms (2022) · cites this paper as [44]
In atherosclerosis-prone ApoE−/− and insulin-resistant mice, lixisenatide reprograms macrophages to the anti-inflammatory M2 phenotype by enhanced activation of STAT3.
“Vinué et al. showed in atherosclerosis-prone apolipoprotein E-deficient (ApoE−/−) and insulin-resistant mice that lixisenatide can diminish the atherosclerosis burden by reducing the size of atheroma plaques, increasing plaque stability, and reprogramming macrophages to the anti-inflammatory M2 phenotype by enhanced activation of signal transducer and activator of transcription (STAT)3, which is a”
From Protection against stroke with glucagon-like peptide-1 receptor agonists: a comprehensive review of potential mechanisms (2022) · cites this paper as [44]
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- Authors
- Vinué, Á., Navarro, J., Herrero-Cervera, A., García-Cubas, M., Andrés-Blasco, I., Martínez-Hervás, S., Real, J. T., Ascaso, J. F., & González-Navarro, H.
- Affiliations
- INCLIVA Health Research Institute (ES)
- Universitat de València (ES)
- Venue
- Diabetologia
- Published
- 2017-06-12
- Volume
- 60
- Issue
- 9
- Pages
- 1801-1812
- ISSN
- 0012-186X (ISSN-L)
- 1432-0428
- OpenAlex
- W2626992208
- Cited by
- 137
- References
- 40
- Citations by year
- 2026: 18 · 2025: 21 · 2024: 20 · 2023: 9 · 2022: 17 · 2021: 20 · 2020: 10 · 2019: 10 · 2018: 10 · 2017: 2
- FWCI
- 6.91
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Diabetologia (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Sanofi
- European Foundation for the Study of Diabetes
- Universitat de València
- Centro de Investigación Biomédica en Red Diabetes y Enfermedades Metabólicas Asociadas (CB07/08/0043, CP16/00013)
- INCLIVA Instituto de Investigación Sanitaria
- Instituto de Salud Carlos III (PI16/, CP10/00555, CP16/00013, PI16/00091, PI13/00834, CB07/08/0043)
- European Regional Development Fund (CB07/08/0043, CP10/00555, CP16/00013)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- lixisenatide, GLP-1 analogues, atherosclerosis, insulin resistance, macrophage polarization, M2 macrophages, STAT3, STAT1, interleukin-6, arginase-1, inducible nitric oxide synthase, liraglutide, type 2 diabetes, cardiovascular risk
- MeSH terms
- Glucagon-Like Peptide-2 Receptor, Animals, Diabetes Mellitus, Type 2, Inflammation, Insulin Resistance, Macrophages, Peptides, Atherosclerosis, STAT3 Transcription Factor, Mice, Glucagon-Like Peptide 1
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