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

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    Abstract

    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
    Number of pages11
    JournalDiabetologia
    Volume56
    Issue number8
    DOIs
    Publication statusPublished - 2013

    Keywords

    • CARBOXYMETHYL-LYSINE
    • Atherosclerosis
    • ADVANCED GLYCATION ENDPRODUCTS
    • MITOCHONDRIAL PROTEINS
    • Methylglyoxal
    • Macrovascular complications
    • Tetrahydropyrimidine
    • HUMAN ENDOTHELIAL-CELLS
    • ARGININE MODIFICATIONS
    • CARDIOVASCULAR-DISEASE
    • Cardiovascular disease
    • END-PRODUCTS
    • Advanced glycation end-products
    • Soluble vascular cell adhesion molecule
    • MONOCYTIC THP-1 CELLS
    • Endothelial dysfunction
    • Microvascular complications
    • INCREASED SERUM-LEVELS
    • CELL-ADHESION MOLECULE-1
    • Type 1 diabetes mellitus

    Cite this

    van Eupen, M. G. A., Schram, M. T., Colhoun, H. M., Hanssen, N. M. J., Niessen, H. W. M., Tarnow, L., Parving, H. H., Rossing, P., Stehouwer, C. D. A., & Schalkwijk, C. G. (2013). 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. Diabetologia, 56(8), 1845-1855. https://doi.org/10.1007/s00125-013-2919-8