{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T16:17:47Z","timestamp":1791389867677,"version":"4.3.3"},"reference-count":23,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2020,5,10]],"date-time":"2020-05-10T00:00:00Z","timestamp":1589068800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100010414","name":"Health Research Board","doi-asserted-by":"publisher","award":["HRB\u2010POR\u20102014\u2010619"],"award-info":[{"award-number":["HRB\u2010POR\u20102014\u2010619"]}],"id":[{"id":"10.13039\/100010414","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["acrjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Arthritis & Rheumatology"],"published-print":{"date-parts":[[2020,6]]},"abstract":"\n Objective<\/jats:title>\n \n To investigate a role for insulin\u2010resistant pathways in inflammation and therapeutic targeting for disease modification in rheumatoid arthritis (\n RA<\/jats:styled-content>\n ).\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n RA<\/jats:styled-content>\n disease activity and cardiovascular risk factors, including insulin resistance and body mass index (\n BMI<\/jats:styled-content>\n ), were assessed in an Irish\n RA<\/jats:styled-content>\n cohort. Glucose transporter 1 (\n GLUT<\/jats:styled-content>\n \u20101) and\n GLUT<\/jats:styled-content>\n \u20104 activity in\n RA<\/jats:styled-content>\n and osteoarthritis (\n OA<\/jats:styled-content>\n ) synovial tissue was examined using immunohistochemistry. Spontaneous release of proinflammatory mediators from ex vivo\n RA<\/jats:styled-content>\n synovial explants and primary synovial fibroblast (\n SF<\/jats:styled-content>\n ) cell culture supernatants was quantified by enzyme\u2010linked immunosorbent assay. Phosphorylated\n AMP<\/jats:styled-content>\n \u2010activated protein kinase (p\u2010\n AMPK<\/jats:styled-content>\n ) and\n GLUT<\/jats:styled-content>\n \u20101 protein expression was analyzed by Western blotting. Cellular glycolytic and oxidative phosphorylation was assessed using extracellular flux analysis.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Insulin resistance was independently associated with both\n BMI<\/jats:styled-content>\n (unstandardized coefficient B 0.113 [95% confidence interval (95%\n CI<\/jats:styled-content>\n ) 0.059\u20130.167];\n P<\/jats:italic>\n < 0.001) (n = 61) and swollen joint count in 28 joints (\n SJC<\/jats:styled-content>\n 28) (B 0.114 [95%\n CI<\/jats:styled-content>\n 0.032\u20130.197];\n P<\/jats:italic>\n = 0.008) (n = 61). Increased\n GLUT<\/jats:styled-content>\n \u20101 expression in\n RA<\/jats:styled-content>\n synovium (n = 26) versus\n OA<\/jats:styled-content>\n synovium (n = 16) was demonstrated (\n P<\/jats:italic>\n = 0.0003), with increased expression in the lining, sublining, and vascular regions. In contrast, decreased\n GLUT<\/jats:styled-content>\n \u20104 expression in the\n RA<\/jats:styled-content>\n lining layer (n = 21) versus the\n OA<\/jats:styled-content>\n lining layer (n = 8) was observed (\n P<\/jats:italic>\n = 0.0358). Decreased\n GLUT<\/jats:styled-content>\n \u20101 protein expression was observed in parallel with increased p\u2010\n AMPK<\/jats:styled-content>\n protein expression in\n SF<\/jats:styled-content>\n s in the presence of metformin (n = 4). Metformin increased glycolytic activity and decreased oxidative phosphorylation in\n RASF<\/jats:styled-content>\n s (n = 7) (\n P<\/jats:italic>\n < 0.05 for both). Metformin or aminoimidazole carboxamide ribonucleotide presence decreased spontaneous production of interleukin\u20106 (\n IL<\/jats:styled-content>\n \u20106),\n IL<\/jats:styled-content>\n \u20108, and monocyte chemotactic protein 1 in\n RA<\/jats:styled-content>\n synovial explants and\n SF<\/jats:styled-content>\n s (n = 5\u20137).\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n \n Insulin resistance is significantly associated with\n BMI<\/jats:styled-content>\n and synovitis in\n RA<\/jats:styled-content>\n , suggesting distinct interplay between glucose availability and inflammation in\n RA<\/jats:styled-content>\n . Furthermore, the effect of metformin on proinflammatory mechanisms suggests a role for\n AMPK<\/jats:styled-content>\n \u2010modifying compounds in the treatment of\n RA<\/jats:styled-content>\n .\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/art.41190","type":"journal-article","created":{"date-parts":[[2019,12,16]],"date-time":"2019-12-16T08:26:31Z","timestamp":1576484791000},"page":"896-902","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":40,"title":["Insulin\u2010Resistant Pathways Are Associated With Disease Activity in Rheumatoid Arthritis and Are Subject to Disease Modification Through Metabolic Reprogramming: A Potential Novel Therapeutic Approach"],"prefix":"10.1002","volume":"72","author":[{"given":"Lorna","family":"Gallagher","sequence":"first","affiliation":[{"name":"Trinity College Dublin and Tallaght Hospital Dublin Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sian","family":"Cregan","sequence":"additional","affiliation":[{"name":"Trinity College Dublin and Tallaght Hospital Dublin Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monika","family":"Biniecka","sequence":"additional","affiliation":[{"name":"St. Vincent's University Hospital University College Dublin Dublin Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clare","family":"Cunningham","sequence":"additional","affiliation":[{"name":"Trinity College Dublin Dublin Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Douglas J.","family":"Veale","sequence":"additional","affiliation":[{"name":"St. Vincent's University Hospital University College Dublin Dublin Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David J.","family":"Kane","sequence":"additional","affiliation":[{"name":"Trinity College Dublin and Tallaght Hospital Dublin Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8084-0429","authenticated-orcid":false,"given":"Ursula","family":"Fearon","sequence":"additional","affiliation":[{"name":"Trinity College Dublin Dublin Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5979-3680","authenticated-orcid":false,"given":"Ronan H.","family":"Mullan","sequence":"additional","affiliation":[{"name":"Trinity College Dublin and Tallaght Hospital Dublin Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,5,10]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.509"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/1529-0131(200112)44:12<2737::AID-ART460>3.0.CO;2-#"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1093\/rheumatology\/kew306"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2015-208476"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI13505"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.2337\/db16-0915"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2013.03.020"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.23937\/2469-5726\/1510005"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.1186\/ar4290"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2014-205216"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF01375656"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.27584"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.1780380107"},{"key":"e_1_2_6_15_1","doi-asserted-by":"publisher","DOI":"10.1136\/ard.2010.142240"},{"key":"e_1_2_6_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.38986"},{"key":"e_1_2_6_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clinbiochem.2010.01.012"},{"key":"e_1_2_6_18_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.22053"},{"key":"e_1_2_6_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm782"},{"key":"e_1_2_6_20_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.00284.2006"},{"key":"e_1_2_6_21_1","first-page":"241","article-title":"AMPK 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