Glipizide alleviates periodontitis pathogenicity via inhibition of angiogenesis, osteoclastogenesis, and M1/M2 macrophage ratio in periodontal tissue

Abstract

AbstractNew consensus indicates type 2 diabetes mellitus (T2DM) and periodontitis as comorbidity and may share common pathways of disease progression. Sulfonylureas have been reported to improve the periodontal status in periodontitis patients. Glipizide, a sulfonylurea widely used in the treatment of T2DM, has also been reported to inhibit inflammation and angiogenesis. However, the effect of Glipizide on periodontitis pathogenicity has not been investigated yet. We developed ligature-induced periodontitis in mice and treated with different concentrations of glipizide. Periodontal tissue status, alveolar bone loss, and osteoclast numbers were analyzed. Immunohistochemistry, RT-qPCR, and ELISA analyzed the inflammatory cells' infiltration and angiogenesis. Transwell assay and Western bolt analyzed macrophage migration and polarization. 16S rRNA sequencing analyzed the effect of glipizide on the oral microbial flora. mRNA sequencing of bone marrow-derived macrophages (BMMs) stimulated byP. gingivalislipopolysaccharide (Pg-LPS) after treatment with glipizide was analyzed. Glipizide reduced alveolar bone resorption, periodontal tissue degeneration, and the number of osteoclasts in periodontitis-affected periodontal tissue (PAPT). Glipizide-treated periodontitis mice showed reduced micro-vessel density and leukocyte/macrophage infiltration in PAPT. Glipizide significantly inhibited osteoclast differentiation in vitro experiments. Glipizide treatment did not affect the oral microbiome of periodontitis mice. mRNA sequencing and KEGG analysis showed that glipizide activated PI3K/AKT signaling in LPS-stimulated BMMs. Glipizide inhibited the LPS-induced migration of BMMs but promoted M2/M1 macrophage ratio in LPS-induced BMMs via activation of PI3K/AKT signaling. In conclusion, glipizide inhibits angiogenesis, macrophage inflammatory phenotype, and osteoclastogenesis to alleviate periodontitis pathogenicity suggesting its’ possible application in the treatment of periodontitis and diabetes comorbidity.