Context. The interaction of advanced glycation end-products (AGEs), including N-(carboxymethyl)lysine-protein adducts (CML) and S100A12 protein, with their cellular receptor (RAGE) is implicated in the pathogenesis of diabetic vascular complications. RAGE has a circulating secretory receptor form, soluble RAGE (sRAGE), which, by neutralizing the action of AGEs, might exert a protective role against the development of cardiovascular disease (CVD).

Objective. To investigate whether plasma sRAGE levels are associated with glycemic control, proinflammatory factors or circulating ligands of RAGE such as plasma CML and S100A12 protein.

Study design. We studied 160 subjects, 84 subjects with type 2 diabetes (age 60 ± 7 yr) and 76 nondiabetic controls (age 45 ± 10 yr).

Results. Plasma sRAGE was lower in diabetic patients than in controls (141[53-345] vs. 735[519-1001] pg/mL, median [interquartile range], P < 0.0001), while CML levels were higher in diabetic patients than in controls (67.9[46.0-84.7] vs. 43.4[28.0-65.0] µg/mL, P < 0.0001). In stepwise regression analysis of the whole dataset, HbA_1c, insulin resistance (as HOMA), and C-reactive protein (CRP) were independently associated with plasma sRAGE, whereas age was not. In a subgroup of 26 diabetic and 24 nondiabetic subjects of similar age (54 ± 3), plasma S100A12 levels were higher in diabetic subjects (49[39-126] vs. 28[21-39] ng/mL). Moreover, low sRAGE and high S100A12 were strongly associated with increased risk for CVD (Framingham score). In this subgroup, plasma S100A12 level was the only determinant of plasma sRAGE concentration.

Conclusion. Plasma level of sRAGE is downregulated in chronic hyperglycemia; among its ligands, S100A12 protein, but not CML, appears to be associated with this effect.