Advanced Glycation End Products and Endothelial Dysfunction in Type 2 Diabetes

Advanced Glycation End Products and Endothelial Dysfunction in Type 2 Diabetes Kathryn C.B. Tan , MD 1 , Wing-Sun Chow , MBBS 1 , Victor H.G. Ai , MBBS 2 , Christine Metz , PHD 3 , Richard Bucala , MD, PHD 4 and Karen S.L. Lam , MD 1 1 Department of Medicine, University of Hong Kong, Queen Mary Hospital, Honk Kong 2 Department of Diagnostic Radiology, Queen Mary Hospital, Hong Kong 3 Picower Institute for Medical Research, Manhasset , New York 4 Yale University School of Medicine, New Haven, Connecticut Abstract OBJECTIVE —Data from experimental studies have suggested that the increased formation of advanced glycation end products (AGEs) is one of the causes of endothelial dysfunction in diabetes. This study was performed to investigate whether changes in endothelium-dependent vasodilation, a marker of endothelial function, were related to serum AGEs concentrations in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS —For this study, 170 patients with type 2 diabetes and 83 healthy nondiabetic control subjects of similar age were recruited. Serum AGEs were assayed by competitive enzyme-linked immunosorbent assay. Endothelium-dependent and -independent vasodilation of the brachial artery was measured by high-resolution vascular ultrasound. RESULTS —Serum AGEs were increased in diabetic patients compared with control subjects (4.6 ± 0.7 vs. 3.1 ± 0.8 unit/ml; P < 0.01), and both endothelium-dependent (5.1 ± 2.5 vs. 9.1 ± 4.1%; P < 0.01) and endothelium-independent vasodilation (13.2 ± 4.6 vs. 16.4 ± 5.5%; P < 0.01) were impaired. On univariate analysis of all subjects, serum AGEs correlated with endothelium-dependent vasodilation ( r = −0.51, P < 0.01); a weaker association was found with endothelium-independent vasodilation ( r = −0.24, P < 0.01). On multiple regression analyses including age, sex, smoking status, and plasma lipids, only serum AGEs remained a significant independent determinant of endothelium-dependent vasodilation ( r 2 = 0.34, P < 0.01). CONCLUSIONS —Increased serum concentrations of AGEs in patients with type 2 diabetes is associated with endothelial dysfunction, independent of other cardiovascular risk factors. Further studies to determine whether treatment targeting AGEs will lead to an amelioration of endothelial dysfunction are warranted. AGE, advanced glycation end product CML, Nε-[carboxymethyl]-lysine ELISA, enzyme-linked immunosorbent assay GTN, glyceryl trinitrate HPLC, high-performance liquid chromatography IMT, intima