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Here, short-term administration of an antagonist to the receptor for advanced glycation end products (sRAGE) protected against murine diabetes at two independent research centers. Treatment with sRAGE increased regulatory T cells (Tregs) within the islets, pancreatic lymph nodes, and spleen, increasing islet insulin expression and function. Diabetes protection was abrogated by Treg depletion and shown to be dependent on antagonizing RAGE with use of knockout mice. Human Tregs treated with a RAGE ligand downregulated genes for suppression, migration, and Treg homeostasis (FOXP3, IL7R, TIGIT, JAK1, STAT3, STAT5b, CCR4). Loss of suppressive function was reversed by sRAGE, where Tregs increased proliferation and suppressed conventional T-cell division, confirming that sRAGE expands functional human Tregs. These results highlight sRAGE as an attractive treatment to prevent diabetes, showing efficacy and reproducibility at multiple research centers and in human T cells.<\/jats:p>","DOI":"10.2337\/db22-0177","type":"journal-article","created":{"date-parts":[[2022,6,17]],"date-time":"2022-06-17T11:32:07Z","timestamp":1655465527000},"page":"1994-2008","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":18,"title":["Soluble RAGE Prevents Type 1 Diabetes Expanding Functional Regulatory T Cells"],"prefix":"10.2337","volume":"71","author":[{"given":"Sherman S.","family":"Leung","sequence":"first","affiliation":[{"name":"1Glycation and Diabetes, Mater Research, The University of Queensland and Translational Research Institute, Brisbane, Australia"},{"name":"2School of Biomedical Sciences, The University of Queensland, Brisbane, 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Diabetes, Mater Research, The University of Queensland and Translational Research Institute, Brisbane, Australia"},{"name":"2School of Biomedical Sciences, The University of Queensland, Brisbane, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Watkins","sequence":"additional","affiliation":[{"name":"5Centre for Biodiscovery and Molecular Development of Therapeutics, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John J.","family":"Miles","sequence":"additional","affiliation":[{"name":"5Centre for Biodiscovery and Molecular Development of Therapeutics, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4055-6954","authenticated-orcid":false,"given":"Per-Henrik","family":"Groop","sequence":"additional","affiliation":[{"name":"6Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland"},{"name":"7Folkh\u00e4lsan Research Center, Helsinki, Finland"},{"name":"8Nephrology, Abdominal Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland"},{"name":"9Baker IDI Heart and Diabetes Institute, Melbourne, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean L.","family":"Scheijen","sequence":"additional","affiliation":[{"name":"10Laboratory for Metabolism and Vascular Medicine, Department of Internal Medicine, Maastricht University, Maastricht, the Netherlands"},{"name":"11Cardiovascular Research Institute Maastricht, Maastricht, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0190-2690","authenticated-orcid":false,"given":"Casper G.","family":"Schalkwijk","sequence":"additional","affiliation":[{"name":"10Laboratory for Metabolism and Vascular Medicine, Department of Internal Medicine, Maastricht University, Maastricht, the Netherlands"},{"name":"11Cardiovascular Research Institute Maastricht, Maastricht, the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6513-6406","authenticated-orcid":false,"given":"Raymond J.","family":"Steptoe","sequence":"additional","affiliation":[{"name":"12Diamantina Institute, The University of Queensland and Translational Research Institute, Brisbane, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristen J.","family":"Radford","sequence":"additional","affiliation":[{"name":"2School of Biomedical Sciences, The University of Queensland, 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