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Effects of Tirzepatide on macrophage polarization, inflammatory factors and atherosclerotic genes in RAW264.7 cells under oxidative low-density lipoprotein

ABSTRACT: Tirzepatide (TZP) is a novel dual agonist of glucagon-like peptide -1/glucose-dependent insulinotropic polypeptide receptors. TZP represents a significant advance in the treatment of diabetes and obesity. Clinical trials have shown that TZP significantly reduces cardiovascular risk in patients with diabetes or obese patients who are at high CV risk. We report here that TZP exerts anti-atherosclerotic effects by altering macrophage polarization and inflammatory expression. Under oxLDL, the expression of inflammatory factors in RAW264.7 cells increased, and the phenotype of M1 macrophages increased. After TZP treatment, M2 macrophages increased and anti-inflammatory factor expression increased in RAW264.7 cells. In summary, our data provide a new mechanism for TZP in the treatment of oxLDL-induced foam cell formation.

ORGANISM(S): Mus musculus

PROVIDER: GSE287433 | GEO | 2025/08/01

REPOSITORIES: GEO

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Project description:Immune-mediated beta cell destruction and lack of alpha cell responsiveness to hypoglycaemia are hallmarks of type 1 diabetes pathology. The incretin hormone glucose-dependent insulinotropic polypeptide (GIP) may hold therapeutic potential for type 1 diabetes due to its insulinotropic and glucagonotropic effects as well as its beta cell protective effects shown in rodent islets. Here, we examined the functional and transcriptomic effects of GIP treatment upon diabetogenic cytokine exposure to interleukin (IL)-1β ± interferon (IFN)-γ in human EndoC-βH5 beta cells and isolated human islets, respectively. GIP dose-dependently augmented glucose-stimulated insulin secretion from EndoC-βH5 cells and increased insulin and glucagon secretion from human islets during high and low glucose concentrations, respectively. The insulinotropic effect of GIP in EndoC-βH5 cells was abrogated by KN-93, an inhibitor of calcium/calmodulin-dependent protein kinase 2 (CaMK2). GIP did not prevent cytokine-induced apoptosis or cytokine-induced functional impairment of human EndoC-βH5 cells. GIP also did not prevent cytokine-induced apoptosis in human islets. GIP treatment of human islets with or without cytokines for 24 hours did not significantly impact the transcriptome. GIP potentiated cytokine-induced secretion of IL-10 and c-c motif chemokine ligand (CCL)-2 from human islets while decreasing the secretion of c-x-c motif chemokine ligand (CXCL)-8. In EndoC-βH5 cells, GIP reduced IFN-γ-induced secretion of tumor necrosis factor (TNF)-α, IL-2, IL-6, and IL-10, but increased the secretion of CXCL8, CCL2, CCL4, and CCL11. In conclusion, our results suggest that the insulinotropic effect of GIP is CaMK2-dependent. Furthermore, our results indicate that GIP does not provide substantial cytoprotective effects against diabetogenic cytokine challenge or significantly modulate the transcriptome of human islets when applied at a supraphysiological level. GIP may, however, still exert selective inflammation-modulatory effects upon diabetogenic cytokine exposure.

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Effects of Tirzepatide on macrophage polarization, inflammatory factors and atherosclerotic genes in RAW264.7 cells under oxidative low-density lipoprotein

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