The AGE-RAGE Axis and Its Relationship to Markers of Cardiovascular Disease in Newly Diagnosed Diabetic Patients

Abstract

AimThe purpose of the study was the simultaneous measurement of all the different components of the AGE-RAGE axis as well as several non-invasive markers of cardiovascular disease (CVD) in a cohort of newly diagnosed diabetic patients.Materials and MethodsIn 80 newly diagnosed diabetic patients we measured serum carboxymethyllysine (CML), soluble RAGE (sRAGE) and peripheral mononuclear (PMNC) RAGE and AGER1 mRNA together with ICAM-1, VCAM-1, and malondialdehyde (MDA). We also assessed cardiovascular function by measurement of flow-mediated vasodilation (FMD), intima-media thickness (IMT) and arterial stiffness. Univariant correlation analysis was used to determine correlation between the variables in the study and multiple regression analysis was used to examine the association between the AGE-RAGE axis components and FMD, IMT and arterial stiffness.ResultsSerum CML correlated positively with sRAGE, PMNC RAGE, HOMA-IR, ICAM-1, VCAM-1 and MDA, but inversely with PMNC AGER1. sRAGE and RAGE was positively correlated with AGER; IMT was positively correlated with HOMA-IR, ICAM-1, VCAM-1, MDA, and sRAGE and arterial stiffness had correlation with HOMA-IR, ICAM-1, VCAM-1, MDA, CML, sRAGE, AGER1 and RAGE. In multivariate analysis we found a significant relationship between CML with PMNC RAGE, HOMA-IR; sRAGE with VCAM-1 and MDA; PMNC RAGE with PMNC AGER1and CML; PMNC AGER1 with PMNC RAGE; FMD with sRAGE, CML and HbA1c; IMT with sRAGE, and arterial stiffness with sRAGE, sCML and AGER1ConclusionsWe found significant and strong associations between the different components of the AGE-RAGE axis and also found significant association between AGE-RAGE axis markers, especially sRAGE with several noninvasive markers of cardiovascular disease risk. sRAGE, an easily measured parameter in blood, may potentially be used as a surrogate marker of AGEs-RAGE in patients with diabetes.

Advanced glycation end products and their receptors did not show any association with body mass parameters in metabolically healthy adolescents

“…Of interest, serum CML levels in the current cohort were significantly higher than those of obese male adults in another study who had an average age of 43 years (p < 0.001) . They were also only slightly lower than patients newly diagnosed with diabetes, reported by our group, who had an average age of 48.5 years (p < 0.036) . That study used the same methodology for measuring CML as this study and comprised participants of the same region and country.…”

Critical Appraisal of Advanced Glycation End Products (AGEs) and Circulating Soluble Receptors for Advanced Glycation End Products (sRAGE) as a Predictive Biomarkers for Cardiovascular Disease in Hemodialysis Patients

“…Lately, some studies on chronic kidney disease (CKD) patients that were undergoing dialysis revealed that sRAGE was not related to CVD [ 24 , 48 ]. However, Villegas-Rodríguez et al (2016) found a significant association between the AGE–RAGE axis markers, especially the sRAGE, with several non-invasive markers of cardiovascular-disease risk in the population of patients with newly diagnosed diabetes type 2 [ 49 ]. It was also suggested that sRAGE could be a biomarker for a RAGE-mediated disease, especially vascular-disease [ 12 ].…”

The role of advanced glycation end-products in the development of coronary artery disease in patients with and without diabetes mellitus: a review

“…Those involved in the endocytosis, breakdown, and removal of AGEs from the circulation; and those that activate a pro-inflammatory cellular response. AGER1, the prototype for the former class, has an additional role in inhibiting the production of reactive oxygen species and cellular defense mechanisms (Lu et al, 2004 ; Villegas-Rodriguez et al, 2016 ; Vlassara & Striker, 2011 ). AGER1 expression is upregulated on acute exposure to increased AGE concentrations, but is suppressed with chronic exposure to oxidative stress and high extracellular AGE levels, consistent with the finding of reduced AGER1 levels in patients with diabetes and chronic inflammatory disease (Vlassara & Uribarri, 2014 ).…”