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

M. G. A. van Eupen, M. T. Schram, H. M. Colhoun, N. M. J. Hanssen, H. W. M. Niessen, L. Tarnow, H. H. Parving, P. Rossing, C. D. A. Stehouwer, C. G. Schalkwijk*

*Corresponding author for this work

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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.
Original languageEnglish
Pages (from-to)1845-1855
Issue number8
Publication statusPublished - Aug 2013


  • Advanced glycation end-products
  • Atherosclerosis
  • Cardiovascular disease
  • Endothelial dysfunction
  • Macrovascular complications
  • Methylglyoxal
  • Microvascular complications
  • Soluble vascular cell adhesion molecule
  • Tetrahydropyrimidine
  • Type 1 diabetes mellitus

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