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The aim of this study was to determine the distribution of sRAGE isoforms and whether sRAGE isoforms are associated with risk of T2DM development in subjects spanning the glucose tolerance continuum. In this retrospective analysis, circulating total sRAGE and endogenous secretory RAGE (esRAGE) were quantified via ELISA, and cleaved RAGE (cRAGE) was calculated in 274 individuals stratified by glucose tolerance status (GTS) and obesity. Group differences were probed by ANOVA, and multivariate ordinal logistic regression was used to test the association between sRAGE isoform concentrations and the proportional odds of developing diabetes, vs. normal glucose tolerance (NGT) or impaired glucose tolerance (IGT). When stratified by GTS, total sRAGE, cRAGE, and esRAGE were all lower with IGT and T2DM, while the ratio of cRAGE to esRAGE (cRAGE:esRAGE) was only lower ( P &lt; 0.01) with T2DM compared with NGT. When stratified by GTS and obesity, cRAGE:esRAGE was higher with obesity and lower with IGT ( P &lt; 0.0001) compared with lean, NGT. In ordinal logistic regression models, greater total sRAGE (odds ratio, 0.91; P &lt; 0.01) and cRAGE (odds ratio, 0.84; P &lt; 0.01) were associated with lower proportional odds of developing T2DM. Reduced values of sRAGE isoforms observed with both obesity and IGT are independently associated with greater proportional odds of developing T2DM. The mechanisms by which each respective isoform contributes to obesity and insulin resistance may reveal novel treatment strategies for diabetes. <\/jats:p>","DOI":"10.1152\/ajpendo.00146.2017","type":"journal-article","created":{"date-parts":[[2017,8,15]],"date-time":"2017-08-15T20:50:16Z","timestamp":1502830216000},"page":"E631-E640","source":"Crossref","is-referenced-by-count":58,"title":["Circulating soluble RAGE isoforms are attenuated in obese, impaired-glucose-tolerant individuals and are associated with the development of type 2 diabetes"],"prefix":"10.1152","volume":"313","author":[{"given":"Edwin R.","family":"Miranda","sequence":"first","affiliation":[{"name":"Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, Illinois"},{"name":"Integrative Physiology Laboratory, University of Illinois at Chicago, Chicago, Illinois"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vikram S.","family":"Somal","sequence":"additional","affiliation":[{"name":"Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, Illinois"},{"name":"Integrative Physiology Laboratory, University of Illinois at Chicago, Chicago, Illinois"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacob T.","family":"Mey","sequence":"additional","affiliation":[{"name":"Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, Illinois"},{"name":"Integrative Physiology Laboratory, University of Illinois at Chicago, Chicago, Illinois"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian K.","family":"Blackburn","sequence":"additional","affiliation":[{"name":"Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, Illinois"},{"name":"Integrative Physiology Laboratory, University of Illinois at Chicago, Chicago, Illinois"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward","family":"Wang","sequence":"additional","affiliation":[{"name":"College of Applied Health Sciences, University of Illinois at Chicago, Chicago, Illinois"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Farabi","sequence":"additional","affiliation":[{"name":"Department of Biobehavioral Health Science, University of Illinois at Chicago, Chicago, Illinois"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6596-4199","authenticated-orcid":false,"given":"Kristian","family":"Karstoft","sequence":"additional","affiliation":[{"name":"Centre of Inflammation and Metabolism and Centre for Physical Activity Research, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ciaran E.","family":"Fealy","sequence":"additional","affiliation":[{"name":"Metabolic Translational Research Center, Endocrinology &amp; Metabolism Institute, Cleveland, Ohio"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sangeeta","family":"Kashyap","sequence":"additional","affiliation":[{"name":"Metabolic Translational Research Center, Endocrinology &amp; Metabolism Institute, Cleveland, Ohio"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7321-9917","authenticated-orcid":false,"given":"John P.","family":"Kirwan","sequence":"additional","affiliation":[{"name":"Metabolic Translational Research Center, Endocrinology &amp; Metabolism Institute, Cleveland, Ohio"},{"name":"Department of Pathobiology, Cleveland Clinic, Cleveland, Ohio"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurie","family":"Quinn","sequence":"additional","affiliation":[{"name":"Department of Biobehavioral Health Science, University of Illinois at Chicago, Chicago, Illinois"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas P. 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