Metformin accelerates wound healing by Akt phosphorylation of gingival fibroblasts in insulin-resistant prediabetes mice

J Periodontol. 2021 Aug 24. doi: 10.1002/JPER.21-0362. Online ahead of print.

Abstract

Background: This study aimed to investigate the effects of metformin on gingival wound healing in insulin-resistant prediabetes.

Methods: C57BL/6J mice were fed normal diet (ND) or high-fat diet (HFD) for 10 weeks; half of the HFD mice were treated with metformin (HFD+ Met) for the last 2 weeks. Insulin and glucose tolerance tests were performed. The palatal gingiva (2.0 × 0.5 mm) was surgically removed adjacent to the maxillary molars. Post-surgical wound closure was histomorphometrically evaluated for 1 week. The mRNA expression of vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase (eNOS) in the tissue were quantified by real-time polymerase chain reaction. In vitro, the proliferation and migration of human gingival fibroblasts (HGFs) cultured under high-glucose or control conditions with/without metformin were analyzed. Akt phosphorylation and VEGF expression following the insulin stimulation were evaluated with/without metformin in high-glucose or control media.

Results: HFD mice showed significantly higher plasma glucose levels and insulin resistance than ND mice. Gingival wound healing was delayed in HFD group compared with ND group but significantly improved in HFD + MET group. The decreased expression of VEGF and eNOS in HFD group was significantly elevated in the HFD + MET group. The proliferation and migration of HGFs were significantly impaired in high-glucose conditions compared with control; metformin treatment partially attenuated these effects. Metformin treatment significantly recovered the downregulated Akt phosphorylation and VEGF expression in high-glucose conditions.

Conclusions: Metformin improved delayed gingival wound healing in insulin-resistant prediabetes by accelerating HGFs proliferation and migration via Akt phosphorylation in insulin signaling pathway.

Keywords: diabetes mellitus; fibroblasts; obesity; periodontitis; wound healing.