Circulating soluble receptor for advanced glycation end products is inversely associated with glycemic control and S100A12 protein.
BACKGROUND
The interaction of advanced glycation end products, including Nepsilon-(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 advanced glycation end products, might exert a protective role against the development of cardiovascular disease.


OBJECTIVE
The objective of the study was 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.


METHODS
We studied 160 subjects, 84 subjects with type 2 diabetes (aged 60 +/- 7 yr) and 76 nondiabetic controls (aged 45 +/- 10 yr).


RESULTS
Plasma sRAGE was lower in diabetic patients than controls [141 (53-345) vs. 735 (519-1001) pg/ml, median (interquartile range), P < 0.0001], whereas CML levels were higher in diabetic patients than controls [67.9 (46.0-84.7) vs. 43.4 (28.0-65.0) microg/ml, P < 0.0001]. In stepwise regression analysis of the whole data set, hemoglobin A1c, insulin resistance (as homeostasis model assessment), and C-reactive protein 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 yr), 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 cardiovascular disease (Framingham score). In this subgroup, the plasma S100A12 level was the only determinant of plasma sRAGE concentration.


CONCLUSIONS
Plasma level of sRAGE is down-regulated in chronic hyperglycemia; among its ligands, S100A12 protein, but not CML, appears to be associated with this effect.
Basta
Giuseppina
G
Consiglio Nazionale delle Richerche Institute of Clinical Physiology, Via Moruzzi, 1, 56124 Pisa, Italy. lapina@ifc.cnr.it
Sironi
Anna Maria
AM
Lazzerini
Guido
G
Del Turco
Serena
S
Buzzigoli
Emma
E
Casolaro
Arturo
A
Natali
Andrea
A
Ferrannini
Ele
E
Gastaldelli
Amalia
A
D000328:Adult; D000368:Aged; D001786:Blood Glucose / Q000032:analysis*; D001794:Blood Pressure; D002097:C-Reactive Protein / Q000032:analysis; D016022:Case-Control Studies; D003924:Diabetes Mellitus, Type 2 / Q000097:blood; D003925:Diabetic Angiopathies / Q000097:blood / Q000453:epidemiology; D005260:Female; D006442:Glycated Hemoglobin / Q000032:analysis; D017127:Glycation End Products, Advanced / Q000097:blood / Q000378:metabolism; D006801:Humans; D018836:Inflammation Mediators / Q000097:blood; D008239:Lysine / Q000031:analogs & derivatives / Q000097:blood; D008297:Male; D008875:Middle Aged; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000097:blood*; D012307:Risk Factors; D009418:S100 Proteins / Q000097:blood*; D000067616:S100A12 Protein; D013223:Statistics as Topic
D001786:Blood Glucose; D002097:C-Reactive Protein; D006442:Glycated Hemoglobin; D017127:Glycation End Products, Advanced; D018836:Inflammation Mediators; D008239:Lysine; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D009418:S100 Proteins; D000067616:S100A12 Protein; C090441:S100A12 protein, human; C048496:N(6)-carboxymethyllysine