Low Endogenous Secretory Receptor for Advanced Glycation End-Products Levels Are Associated With Inflammation and Carotid Atherosclerosis in Prediabetes

Objective:We investigated the correlation of endogenous secretory receptor for advanced glycation end-products (esRAGE), total soluble RAGE (sRAGE) and markers of inflammation, with early cardiovascular disease in subjects with prediabetes. We particularly focused on individuals with prediabetes identified only by glycated hemoglobin A1c (HbA1c) (5.7–6.4%) who had normal fasting glucose and were normotolerant after oral glucose tolerance test.Design:This was a cross-sectional study.Setting:The study was conducted in the Department of Clinical and Molecular Medicine, University of Catania, Italy.Main Outcome Measure:sRAGE, esRAGE, carboxymethyl-lysine, S100A12, HbA1c, fasting glycemia, oral glucose tolerance test, pulse wave velocity, and intima-media thickness were evaluated in subjects with prediabetes.Patients:Three hundred eighty subjects without previous history of diabetes were stratified into three groups: controls (n = 99), prediabetes (n = 220), and new-onset type 2 diabetes (n = 61).Results:Subjects with prediabetes exhibited the following: lower esRAGE (0.29 ± 0.18 vs 0.45 ± 0.26 ng/mL; P < .05) and higher S100A12 levels than controls. RT-PCR analysis in mononuclear cells revealed that the mRNA expression level of the esRAGE splice variant progressively decreased in patients with prediabetes and type 2 diabetes with respect to controls. No difference was observed in sRAGE and carboxymethyl-lysine plasma levels between the groups. After multiple regression analyses, only age, HbA1c, and hs-CRP were independently associated with esRAGE levels. Age, HbA1c, and esRAGE were the major determinants of intima-media thickness, whereas S100A12 and systolic blood pressure were the major determinants of pulse wave velocity. When we analyzed the subjects with HbA1c prediabetes (normal fasting glucose/normotolerant and HbA1c 5.7–6.4%), esRAGE and inflammatory markers plasma levels still remained significantly different in respect to controls.Conclusions:Subjects with HbA1c prediabetes exhibited significantly reduced esRAGE levels and increased levels of markers of inflammation. These alterations are associated with early markers of cardiovascular disease.Pre-diabetes is associated with advanced vascular damage. Our data shows that subjects with pre-diabetes exhibited low esRAGE plasma levels and gene expression, which are inversely related with markers of inflammation and atherosclerotic risk.