Endothelial Insulin Resistance Exacerbates Experimental Periodontitis
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 diabet...
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Veröffentlicht in: | Journal of dental research 2023-09, Vol.102 (10), p.1152-1161 |
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creator | Zeze, T. Shinjo, T. Sato, K. Nishimura, Y. Imagawa, M. Chen, S. Ahmed, A.-k. Iwashita, M. Yamashita, A. Fukuda, T. Sanui, T. Park, K. King, G.L. Nishimura, F. |
description | 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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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.</description><identifier>ISSN: 0022-0345</identifier><identifier>EISSN: 1544-0591</identifier><identifier>DOI: 10.1177/00220345231181539</identifier><identifier>PMID: 37448347</identifier><language>eng</language><publisher>Los Angeles, CA: SAGE Publications</publisher><subject>1-Phosphatidylinositol 3-kinase ; AKT protein ; Alveolar bone ; Bone loss ; Diabetes ; Diabetes mellitus (non-insulin dependent) ; Down-regulation ; Endothelial cells ; Epidemiology ; FOXO1 protein ; Gingiva ; Gum disease ; High fat diet ; Hyperglycemia ; Insulin resistance ; Leukocyte migration ; Leukocytes ; Leukocytes (neutrophilic) ; Lipopolysaccharides ; Molecular modelling ; Monocyte chemoattractant protein 1 ; Pathogenesis ; Periodontitis ; Phosphorylation ; Tumor necrosis factor-α</subject><ispartof>Journal of dental research, 2023-09, Vol.102 (10), p.1152-1161</ispartof><rights>International Association for Dental, Oral, and Craniofacial Research and American Association for Dental, Oral, and Craniofacial Research 2023</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c477t-f0c8b53027bf3713142f3cd372b477be40227e789e8d7315fb768506307cd4f03</citedby><cites>FETCH-LOGICAL-c477t-f0c8b53027bf3713142f3cd372b477be40227e789e8d7315fb768506307cd4f03</cites><orcidid>0000-0002-8269-2826</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://journals.sagepub.com/doi/pdf/10.1177/00220345231181539$$EPDF$$P50$$Gsage$$H</linktopdf><linktohtml>$$Uhttps://journals.sagepub.com/doi/10.1177/00220345231181539$$EHTML$$P50$$Gsage$$H</linktohtml><link.rule.ids>314,780,784,21819,27924,27925,43621,43622</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/37448347$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Zeze, T.</creatorcontrib><creatorcontrib>Shinjo, T.</creatorcontrib><creatorcontrib>Sato, K.</creatorcontrib><creatorcontrib>Nishimura, Y.</creatorcontrib><creatorcontrib>Imagawa, M.</creatorcontrib><creatorcontrib>Chen, S.</creatorcontrib><creatorcontrib>Ahmed, A.-k.</creatorcontrib><creatorcontrib>Iwashita, M.</creatorcontrib><creatorcontrib>Yamashita, A.</creatorcontrib><creatorcontrib>Fukuda, T.</creatorcontrib><creatorcontrib>Sanui, T.</creatorcontrib><creatorcontrib>Park, K.</creatorcontrib><creatorcontrib>King, G.L.</creatorcontrib><creatorcontrib>Nishimura, F.</creatorcontrib><title>Endothelial Insulin Resistance Exacerbates Experimental Periodontitis</title><title>Journal of dental research</title><addtitle>J Dent Res</addtitle><description>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.</description><subject>1-Phosphatidylinositol 3-kinase</subject><subject>AKT protein</subject><subject>Alveolar bone</subject><subject>Bone loss</subject><subject>Diabetes</subject><subject>Diabetes mellitus (non-insulin dependent)</subject><subject>Down-regulation</subject><subject>Endothelial cells</subject><subject>Epidemiology</subject><subject>FOXO1 protein</subject><subject>Gingiva</subject><subject>Gum disease</subject><subject>High fat diet</subject><subject>Hyperglycemia</subject><subject>Insulin resistance</subject><subject>Leukocyte migration</subject><subject>Leukocytes</subject><subject>Leukocytes (neutrophilic)</subject><subject>Lipopolysaccharides</subject><subject>Molecular modelling</subject><subject>Monocyte chemoattractant protein 1</subject><subject>Pathogenesis</subject><subject>Periodontitis</subject><subject>Phosphorylation</subject><subject>Tumor necrosis factor-α</subject><issn>0022-0345</issn><issn>1544-0591</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2023</creationdate><recordtype>article</recordtype><recordid>eNp1kE9Lw0AQxRdRbK1-AC9S8OIldf9mNkcpUQuCInoOm81EU9JNzW5Av71bWhUUTzMwv3nz5hFyyuiMMYBLSjmnQiouGNNMiWyPjJmSMqEqY_tkvJknG2BEjrxfUsoyrsUhGQmQUgsJY5LnrurCK7aNaacL54e2cdNH9I0Pxlmc5u_GYl-agD72a-ybFboQ2YfYdlXnQhMaf0wOatN6PNnVCXm-zp_mt8nd_c1ifnWXWAkQkppaXSpBOZS1ACaY5LWwlQBexnmJMvoFBJ2hrkAwVZeQakVTQcFWsqZiQi62uuu-exvQh2LVeIttaxx2gy_id5qrmEQa0fNf6LIbehfdRUrpjNNUQ6TYlrJ9532PdbGOH5r-o2C02GRc_Mk47pztlIdyhdX3xleoEZhtAW9e8Ofs_4qfB_WB8A</recordid><startdate>20230901</startdate><enddate>20230901</enddate><creator>Zeze, T.</creator><creator>Shinjo, T.</creator><creator>Sato, K.</creator><creator>Nishimura, Y.</creator><creator>Imagawa, M.</creator><creator>Chen, S.</creator><creator>Ahmed, A.-k.</creator><creator>Iwashita, M.</creator><creator>Yamashita, A.</creator><creator>Fukuda, T.</creator><creator>Sanui, T.</creator><creator>Park, K.</creator><creator>King, G.L.</creator><creator>Nishimura, F.</creator><general>SAGE Publications</general><general>SAGE PUBLICATIONS, INC</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>K9.</scope><scope>NAPCQ</scope><scope>U9A</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0002-8269-2826</orcidid></search><sort><creationdate>20230901</creationdate><title>Endothelial Insulin Resistance Exacerbates Experimental Periodontitis</title><author>Zeze, T. ; Shinjo, T. ; Sato, K. ; Nishimura, Y. ; Imagawa, M. ; Chen, S. ; Ahmed, A.-k. ; Iwashita, M. ; Yamashita, A. ; Fukuda, T. ; Sanui, T. ; Park, K. ; King, G.L. ; Nishimura, F.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c477t-f0c8b53027bf3713142f3cd372b477be40227e789e8d7315fb768506307cd4f03</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2023</creationdate><topic>1-Phosphatidylinositol 3-kinase</topic><topic>AKT protein</topic><topic>Alveolar bone</topic><topic>Bone loss</topic><topic>Diabetes</topic><topic>Diabetes mellitus (non-insulin dependent)</topic><topic>Down-regulation</topic><topic>Endothelial cells</topic><topic>Epidemiology</topic><topic>FOXO1 protein</topic><topic>Gingiva</topic><topic>Gum disease</topic><topic>High fat diet</topic><topic>Hyperglycemia</topic><topic>Insulin resistance</topic><topic>Leukocyte migration</topic><topic>Leukocytes</topic><topic>Leukocytes (neutrophilic)</topic><topic>Lipopolysaccharides</topic><topic>Molecular modelling</topic><topic>Monocyte chemoattractant protein 1</topic><topic>Pathogenesis</topic><topic>Periodontitis</topic><topic>Phosphorylation</topic><topic>Tumor necrosis factor-α</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Zeze, T.</creatorcontrib><creatorcontrib>Shinjo, T.</creatorcontrib><creatorcontrib>Sato, K.</creatorcontrib><creatorcontrib>Nishimura, Y.</creatorcontrib><creatorcontrib>Imagawa, M.</creatorcontrib><creatorcontrib>Chen, S.</creatorcontrib><creatorcontrib>Ahmed, A.-k.</creatorcontrib><creatorcontrib>Iwashita, M.</creatorcontrib><creatorcontrib>Yamashita, A.</creatorcontrib><creatorcontrib>Fukuda, T.</creatorcontrib><creatorcontrib>Sanui, T.</creatorcontrib><creatorcontrib>Park, K.</creatorcontrib><creatorcontrib>King, G.L.</creatorcontrib><creatorcontrib>Nishimura, F.</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Premium</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of dental research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Zeze, T.</au><au>Shinjo, T.</au><au>Sato, K.</au><au>Nishimura, Y.</au><au>Imagawa, M.</au><au>Chen, S.</au><au>Ahmed, A.-k.</au><au>Iwashita, M.</au><au>Yamashita, A.</au><au>Fukuda, T.</au><au>Sanui, T.</au><au>Park, K.</au><au>King, G.L.</au><au>Nishimura, F.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Endothelial Insulin Resistance Exacerbates Experimental Periodontitis</atitle><jtitle>Journal of dental research</jtitle><addtitle>J Dent Res</addtitle><date>2023-09-01</date><risdate>2023</risdate><volume>102</volume><issue>10</issue><spage>1152</spage><epage>1161</epage><pages>1152-1161</pages><issn>0022-0345</issn><eissn>1544-0591</eissn><abstract>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.</abstract><cop>Los Angeles, CA</cop><pub>SAGE Publications</pub><pmid>37448347</pmid><doi>10.1177/00220345231181539</doi><tpages>10</tpages><orcidid>https://orcid.org/0000-0002-8269-2826</orcidid><oa>free_for_read</oa></addata></record> |
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subjects | 1-Phosphatidylinositol 3-kinase AKT protein Alveolar bone Bone loss Diabetes Diabetes mellitus (non-insulin dependent) Down-regulation Endothelial cells Epidemiology FOXO1 protein Gingiva Gum disease High fat diet Hyperglycemia Insulin resistance Leukocyte migration Leukocytes Leukocytes (neutrophilic) Lipopolysaccharides Molecular modelling Monocyte chemoattractant protein 1 Pathogenesis Periodontitis Phosphorylation Tumor necrosis factor-α |
title | Endothelial Insulin Resistance Exacerbates Experimental Periodontitis |
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