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.
Highlights
Worldwide there is an increasing prevalence of diabetes and its complications
Serum CML correlated positively with soluble receptors for receptor for AGEs (RAGE) (sRAGE), peripheral mononuclear (PMNC) RAGE, HOMA-IR, Intercellular Adhesion Molecule-1 (ICAM-1), Vascular cell adhesion molecule-1 (VCAM-1) and MDA, but inversely with PMNC AGER1. sRAGE and RAGE was positively correlated with AGER; intima-media thickness (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; flow-mediated vasodilation (FMD) with sRAGE, CML and HbA1c; IMT with sRAGE, and arterial stiffness with sRAGE, sCML and AGER1
Summary
Elevated levels of circulating advanced glycation end products (AGEs) are believed to play a major role in the pathogenesis of macrovascular and microvascular disease in diabetes mellitus [1]. Endogenous formation of AGEs is increased in diabetes as the result of hyperglycemia and increased oxidative stress in this condition. AGEs interact with the receptor for AGEs (RAGE) on the cell membrane and induce deleterious effects via activation of nuclear factor κ-B, and increased oxidative stress and inflammatory mediators [3]. AGEs combine with circulating soluble receptors for RAGE (sRAGE), C-truncated isoforms lacking cytosolic and transmembrane domains. Decreased levels of AGER1 have been described in chronic diabetes and other conditions of sustained oxidative stress [7]. To date no study has simultaneously assessed these different components of the AGE-RAGE axis, namely serum AGEs, sRAGE, cellular RAGE and AGER1, in the same individual
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