Journal
AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM
Volume 313, Issue 6, Pages E631-E640Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpendo.00146.2017
Keywords
receptor for advanced glycation end products; type 2 diabetes; obesity; insulin resistance; glucose tolerance
Categories
Funding
- American Diabetes Association-Junior Faculty Award [1-14-JF-32]
- National Center for Advancing Translational Sciences Clinical and Translational Science Award [24989, 29879]
- Central Society for Clinical and Translational Research, University of Chicago Diabetes Research Training Center (National Institute of Diabetes and Digestive and Kidney Diseases) [20595]
- National Institutes of Health [R01-AG-12834, R01-NR-007760, R01-DK-109948]
- European Foundation
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The soluble receptor for advanced glycation end products (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 sRAGK 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 strati lied 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 with NGT. When stratified by GTS and obesity, cRAGE:esRAGE was higher with obesity and lower with IGT (p < 0.0001) compared with 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.
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