Circulating soluble RAGE isoforms are attenuated in obese, impaired-glucose-tolerant individuals and are associated with the development of type 2 diabetes

Abstract

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 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 ( < 0.01) with T2DM compared with NGT. When stratified by GTS and obesity, cRAGE:esRAGE was higher with obesity and lower with IGT ( < 0.0001) compared with lean, NGT. In ordinal logistic regression models, greater total sRAGE (odds ratio, 0.91; < 0.01) and cRAGE (odds ratio, 0.84; < 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.

Metabolic Derangements Contribute to Reduced sRAGE Isoforms in Subjects with Alzheimer’s Disease

“…The above factors were selected for investigation due to their independent importance in disease pathophysiology and sRAGE biology. For example, we have previously found that glucose tolerance and obesity have a strong influence on sRAGE [ 29 ] and that adiposity (fat mass) is associated with attenuated sRAGE pools [ 35 ]. Further, this project aimed to characterize sRAGE profiles by cognitive status and commonly used markers of metabolic health to serve as a foundation for future work.…”

“…Insulin (Genway), amylin (Millipore), S100B (Millipore), sRAGE (R&D), and esRAGE (As One International) were quantified using ELISA per the manufacturer's protocol. Serum cRAGE was computed by subtracting esRAGE from the total plasma sRAGE pool as previously described [ 33 ], and the cRAGE : esRAGE ratio was subsequently calculated [ 29 ].…”

“…Both isoforms of sRAGE lack the transmembrane and cytosolic domains necessary for signal transduction and act as a ligand decoy, thus attenuating intracellular RAGE signaling and subsequent inflammation [ 25 ]. Individuals with obesity, diabetes, or CI alone present with reduced circulating sRAGE profiles compared to lean healthy controls [ 26 – 29 ]. This evidence has led to the emergence of sRAGE as a suggested biological marker of both glucose tolerance status [ 29 ] and cognitive decline [ 30 , 31 ].…”

Can advanced glycation end‐products and their receptors be affected by weight loss? A systematic review

“…Previous studies have shown that esRAGE has the strongest correlation with BMI and body fat percentage, where changes in esRAGE negatively correlate with fat mass changes . Conversely, a significant increase in total sRAGE as a result of weight‐loss 24 and 36 months after bariatric surgery was verified .…”

“…Thus, future mechanistic work is necessary to determine if changes in adiponectin secretion and the proportion of circulating sRAGE isoforms are in fact causally linked . Although not many studies have investigated the sRAGE isoforms changes after weight loss, it was shown that improvements in body composition are related to increased sRAGE isoforms …”