Endothelial Insulin Resistance Exacerbates Experimental Periodontitis
Endothelial Insulin Resistance Exacerbates Experimental Periodontitis
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内皮胰岛素抵抗加剧实验性牙周炎
DOI：
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
F. Nishimura
中科院分区：
文献类型：
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作者：
T. Zeze;T. Shinjo;K. Sato;Y. Nishimura;M. Imagawa;S. Chen;A.;M. Iwashita;A. Yamashita;T. Fukuda;T. Sanui;K. Park;G. King;F. Nishimura
流行病学研究表明，糖尿病患者的牙周炎严重程度高于健康人。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，并且据报道在2型糖尿病啮齿类动物的牙龈中诱导，然而，糖尿病相关牙周炎发病的分子机制尚不清楚。因此，我们旨在探讨牙龈内皮胰岛素抵抗是否在牙周炎的发病机制中起作用，并阐明其潜在的分子机制。我们证实，胰岛素治疗通过PI3K/α激活途径下调脂多糖或肿瘤坏死因子α诱导的内皮细胞VCAM1的表达，从而减少内皮细胞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减弱了胰岛素对内毒素或肿瘤坏死因子α刺激的VCAM1表达的影响。与未患糖尿病的野生型(WT)小鼠相比，血管内皮细胞特异性胰岛素受体基因敲除(VEIRKO)小鼠表现出选择性地抑制牙龈中的PI3K/AKT通路，并通过上调Vcam1、肿瘤坏死因子α、单核细胞趋化蛋白-1、RANKL和中性粒细胞迁移到牙龈中来促进实验性牙周炎引起的牙槽骨丢失。我们还观察到，在VEIRKO和高脂饮食(HFD)喂养的小鼠、高血糖处理的ECs和VEIRKO的原代ECs中，Akt下游靶点FoxO1的胰岛素介导的激活受到抑制。进一步分析胰岛素介导的3个磷酸化位点(T24A、S256D、S316A)突变的完整和突变FoxO1的内皮细胞，发现突变的FoxO1过表达减弱了胰岛素对VCAM1表达的调节和内皮细胞与白细胞的黏附。这些结果表明，内皮细胞的胰岛素抵抗可能通过调节VCAM1的表达和细胞与白细胞的黏附而导致PI3K/Akt/FoxO1轴的激活减少，从而促进牙周炎的进展。
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 Vcam1, Tnfα, Mcp-1, Rankl, 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.
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影响因子：
4.3
作者：
King, George L.
通讯作者：
King, George L.
影响因子：
15.9
作者：
O'Neill, Brian T.;Lee, Kevin Y.;Kahn, C. Ronald
通讯作者：
Kahn, C. Ronald
影响因子：
16.8
作者：
Ouyang W;Li MO
通讯作者：
Li MO
影响因子：
29
作者：
Rask-Madsen C;Li Q;Freund B;Feather D;Abramov R;Wu IH;Chen K;Yamamoto-Hiraoka J;Goldenbogen J;Sotiropoulos KB;Clermont A;Geraldes P;Dall'Osso C;Wagers AJ;Huang PL;Rekhter M;Scalia R;Kahn CR;King GL
通讯作者：
King GL
影响因子：
4.1
作者：
Almeida, Maria
通讯作者：
Almeida, Maria