Circulating Soluble RAGE Isoforms are Attenuated in Obese, Impaired Glucose Tolerant Individuals and are Associated with the Development of Type 2 Diabetes

The soluble receptor for advanced glycation endproducts (sRAGE) may be protective against inflammation associated with obesity and type 2 diabetes (T2DM). 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, versus 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<0.01) with T2DM compared to NGT. When stratified by GTS and obesity, cRAGE:esRAGE was higher with obesity and lower with IGT (p<0.0001) compared to lean, NGT. In ordinal logistic regression models, greater total sRAGE (odds ratio: 0.91; p<0.01) and cRAGE (odds ratio: 0.84; p<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.