Metformin accelerates wound healing by Akt phosphorylation of gingival fibroblasts in insulin-resistant prediabetes mice
Metformin accelerates wound healing by Akt phosphorylation of gingival fibroblasts in insulin-resistant prediabetes mice
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DOI：
10.1002/jper.21-0362
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发表时间：
2021-09-23
影响因子：
4.3
通讯作者：
Iwata, Takanori
中科院分区：
文献类型：
--
作者：
Kominato, Hiromi;Takeda, Kohei;Iwata, Takanori
背景：本研究旨在探讨二甲双胍对胰岛素抵抗糖尿病前期患者牙周创面愈合的影响。方法C57BL/6J小鼠分别饲喂普通饲料(ND)和高脂饲料(HFD)10周，其中半数HFD小鼠给予二甲双胍(HFD+Met)治疗2周。进行胰岛素和糖耐量试验。手术切除上颌磨牙附近的腭部牙龈(2.0x0.5 mm)。术后1周进行组织形态计量学评价。用实时定量聚合酶链式反应检测组织中血管内皮生长因子(VEGF)和内皮型一氧化氮合酶(ENOS)的mRNA表达。体外培养的人牙龈成纤维细胞(HGFs)在高糖和对照条件下，分别加入或不加入二甲双胍，观察细胞的增殖和迁移情况。在高糖和对照条件下，分别检测AKT的磷酸化和胰岛素刺激后血管内皮生长因子的表达。结果HFD小鼠的血糖水平和胰岛素抵抗程度明显高于ND小鼠。与ND组相比，HFD组牙周创面愈合明显延迟，而HFD+MET组明显改善。HFD组VEGF和eNOS表达下降在HFD+MET组明显升高。与对照组相比，高糖条件下HGFs的增殖和迁移明显受损；二甲双胍治疗部分减弱了这些影响。二甲双胍可明显恢复高糖条件下下调的Akt磷酸化和VEGF的表达。结论二甲双胍通过促进胰岛素信号转导通路中Akt的磷酸化，促进HGFs的增殖和迁移，从而改善胰岛素抵抗前期糖尿病患者牙周伤口的延迟愈合。
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 x 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.