Section of Periodontology, Faculty of Dental Science, Kyushu University, Fukuoka, Japan.
Section of Vascular Cell Biology, Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA.
J Dent Res. 2023 Sep;102(10):1152-1161. doi: 10.1177/00220345231181539. Epub 2023 Jul 14.
Epidemiological studies suggest that the severity of periodontitis is higher in people with diabetes than in healthy individuals. Insulin resistance might play a crucial role in the pathogenesis of multiple diabetic complications and is reportedly induced in the gingiva of rodents with type 2 diabetes; however, the molecular mechanisms underlying the pathogenesis of diabetes-related periodontitis remain unclear. Therefore, we aimed to investigate whether endothelial insulin resistance in the gingiva may contribute to the pathogenesis of periodontitis as well as elucidate its underlying molecular mechanisms. We demonstrated that insulin treatment downregulated lipopolysaccharide (LPS)-induced or tumor necrosis factor α (TNFα)-induced VCAM1 expression in endothelial cells (ECs) via the PI3K/Akt activating pathway, resulting in reduced cellular adhesion between ECs and leukocytes. Hyperglycemia-induced selective insulin resistance in ECs diminished the effect of insulin on LPS- or TNFα-stimulated VCAM1 expression. Vascular endothelial cell-specific insulin receptor knockout (VEIRKO) mice exhibited selective inhibition of the PI3K/Akt pathway in the gingiva and advanced experimental periodontitis-induced alveolar bone loss via upregulation of , α, , , and neutrophil migration into the gingiva compared with that in the wild-type (WT) mice despite being free from diabetes. We also observed that insulin-mediated activation of FoxO1, a downstream target of Akt, was suppressed in the gingiva of VEIRKO and high-fat diet (HFD)-fed mice, hyperglycemia-treated ECs, and primary ECs from VEIRKO. Further analysis using ECs transfected with intact and mutated FoxO1, with mutations at 3 insulin-mediated phosphorylation sites (T24A, S256D, S316A), suggested that insulin-mediated regulation of VCAM1 expression and cellular adhesion of ECs with leukocytes was attenuated by mutated FoxO1 overexpression. These results suggest that insulin resistance in ECs may contribute to the progression of periodontitis via dysregulated VCAM1 expression and cellular adhesion with leukocytes, resulting from reduced activation of the PI3K/Akt/FoxO1 axis.
流行病学研究表明，与健康个体相比，糖尿病患者的牙周炎严重程度更高。胰岛素抵抗可能在多种糖尿病并发症的发病机制中起关键作用，据报道，在 2 型糖尿病啮齿动物的牙龈中会诱导产生胰岛素抵抗；然而，糖尿病相关牙周炎发病机制的分子机制尚不清楚。因此，我们旨在研究牙龈内皮细胞胰岛素抵抗是否有助于牙周炎的发病机制，并阐明其潜在的分子机制。我们证明，胰岛素通过 PI3K/Akt 激活途径下调内皮细胞（ECs）中脂多糖（LPS）诱导或肿瘤坏死因子 α（TNFα）诱导的 VCAM1 表达，从而减少 ECs 与白细胞之间的细胞黏附。高血糖诱导的内皮细胞选择性胰岛素抵抗会减弱胰岛素对 LPS 或 TNFα 刺激的 VCAM1 表达的作用。血管内皮细胞特异性胰岛素受体敲除（VEIRKO）小鼠在牙龈中表现出 PI3K/Akt 途径的选择性抑制，以及通过上调 和 、 和中性粒细胞向牙龈迁移，与野生型（WT）小鼠相比，实验性牙周炎诱导的牙槽骨丢失进展更快，尽管它们没有糖尿病。我们还观察到，VEIRKO 和高脂肪饮食（HFD）喂养小鼠、高血糖处理的 ECs 和 VEIRKO 原代 ECs 中，胰岛素介导的 Akt 下游靶标 FoxO1 的激活被抑制。使用转染完整和突变 FoxO1 的 ECs（在 3 个胰岛素介导的磷酸化位点处具有突变：T24A、S256D、S316A）进行进一步分析表明，FoxO1 过表达减弱了胰岛素对 ECs 与白细胞之间 VCAM1 表达和细胞黏附的调节作用。这些结果表明，ECs 中的胰岛素抵抗可能通过下调 PI3K/Akt/FoxO1 轴的激活，导致 VCAM1 表达和白细胞与 ECs 的细胞黏附失调，从而促进牙周炎的进展。
