The methylglyoxal-derived AGE tetrahydropyrimidine is increased in plasma of individuals with type 1 diabetes mellitus and in atherosclerotic lesions and is associated with sVCAM-1

TY - JOUR

T1 - The methylglyoxal-derived AGE tetrahydropyrimidine is increased in plasma of individuals with type 1 diabetes mellitus and in atherosclerotic lesions and is associated with sVCAM-1

AU - van Eupen, M. G. A.

AU - Schram, M. T.

AU - Colhoun, H. M.

AU - Hanssen, N. M. J.

AU - Niessen, H. W. M.

AU - Tarnow, L.

AU - Parving, H. H.

AU - Rossing, P.

AU - Stehouwer, C. D. A.

AU - Schalkwijk, C. G.

PY - 2013

Y1 - 2013

N2 - Methylglyoxal (MGO) is a major precursor for advanced glycation end-products (AGEs), which are thought to play a role in vascular complications in diabetes. Known MGO-arginine-derived AGEs are 5-hydro-5-methylimidazolone (MG-H1), argpyrimidine and tetrahydropyrimidine (THP). We studied THP in relation to type 1 diabetes, endothelial dysfunction, low-grade inflammation, vascular complications and atherosclerosis.We raised and characterised a monoclonal antibody against MGO-derived THP. We measured plasma THP with a competitive ELISA in two cohort studies: study A (198 individuals with type 1 diabetes and 197 controls); study B (individuals with type 1 diabetes, 175 with normoalbuminuria and 198 with macroalbuminuria [> 300 mg/24 h]). We measured plasma markers of endothelial dysfunction and low-grade inflammation, and evaluated the presence of THP and N (epsilon)-(carboxymethyl)lysine (CML) in atherosclerotic arteries.THP was higher in individuals with type 1 diabetes than in those without (median [interquartile range] 115.5 U/mu l [102.4-133.2] and 109.8 U/mu l [91.8-122.3], respectively; p = 0.03). THP was associated with plasma soluble vascular cell adhesion molecule 1 in both study A (standardised beta = 0.48 [95% CI 0.38, 0.58]; p <0.001) and study B (standardised beta = 0.31 [95% CI 0.23, 0.40]; p <0.001), and with secreted phospholipase A2 (standardised beta = 0.26 [95% CI 0.17, 0.36]; p <0.001) in study B. We found no association of THP with micro- or macro-vascular complications. Both THP and CML were detected in atherosclerotic arteries.Our results suggest that MGO-derived THP may reflect endothelial dysfunction among individuals with and without type 1 diabetes, and therefore may potentially play a role in the development of atherosclerosis and vascular disease.

AB - Methylglyoxal (MGO) is a major precursor for advanced glycation end-products (AGEs), which are thought to play a role in vascular complications in diabetes. Known MGO-arginine-derived AGEs are 5-hydro-5-methylimidazolone (MG-H1), argpyrimidine and tetrahydropyrimidine (THP). We studied THP in relation to type 1 diabetes, endothelial dysfunction, low-grade inflammation, vascular complications and atherosclerosis.We raised and characterised a monoclonal antibody against MGO-derived THP. We measured plasma THP with a competitive ELISA in two cohort studies: study A (198 individuals with type 1 diabetes and 197 controls); study B (individuals with type 1 diabetes, 175 with normoalbuminuria and 198 with macroalbuminuria [> 300 mg/24 h]). We measured plasma markers of endothelial dysfunction and low-grade inflammation, and evaluated the presence of THP and N (epsilon)-(carboxymethyl)lysine (CML) in atherosclerotic arteries.THP was higher in individuals with type 1 diabetes than in those without (median [interquartile range] 115.5 U/mu l [102.4-133.2] and 109.8 U/mu l [91.8-122.3], respectively; p = 0.03). THP was associated with plasma soluble vascular cell adhesion molecule 1 in both study A (standardised beta = 0.48 [95% CI 0.38, 0.58]; p <0.001) and study B (standardised beta = 0.31 [95% CI 0.23, 0.40]; p <0.001), and with secreted phospholipase A2 (standardised beta = 0.26 [95% CI 0.17, 0.36]; p <0.001) in study B. We found no association of THP with micro- or macro-vascular complications. Both THP and CML were detected in atherosclerotic arteries.Our results suggest that MGO-derived THP may reflect endothelial dysfunction among individuals with and without type 1 diabetes, and therefore may potentially play a role in the development of atherosclerosis and vascular disease.

KW - CARBOXYMETHYL-LYSINE

KW - Atherosclerosis

KW - ADVANCED GLYCATION ENDPRODUCTS

KW - MITOCHONDRIAL PROTEINS

KW - Methylglyoxal

KW - Macrovascular complications

KW - Tetrahydropyrimidine

KW - HUMAN ENDOTHELIAL-CELLS

KW - ARGININE MODIFICATIONS

KW - CARDIOVASCULAR-DISEASE

KW - Cardiovascular disease

KW - END-PRODUCTS

KW - Advanced glycation end-products

KW - Soluble vascular cell adhesion molecule

KW - MONOCYTIC THP-1 CELLS

KW - Endothelial dysfunction

KW - Microvascular complications

KW - INCREASED SERUM-LEVELS

KW - CELL-ADHESION MOLECULE-1

KW - Type 1 diabetes mellitus

U2 - 10.1007/s00125-013-2919-8

DO - 10.1007/s00125-013-2919-8

M3 - Article

C2 - 23620061

SN - 0012-186X

VL - 56

SP - 1845

EP - 1855

JO - Diabetologia

JF - Diabetologia

IS - 8

ER -