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

AIMS/HYPOTHESIS: 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.

METHODS: 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 (ε)-(carboxymethyl)lysine (CML) in atherosclerotic arteries.

RESULTS: THP was higher in individuals with type 1 diabetes than in those without (median [interquartile range] 115.5 U/μl [102.4-133.2] and 109.8 U/μl [91.8-122.3], respectively; p = 0.03). THP was associated with plasma soluble vascular cell adhesion molecule 1 in both study A (standardised β = 0.48 [95% CI 0.38, 0.58]; p < 0.001) and study B (standardised β = 0.31 [95% CI 0.23, 0.40]; p < 0.001), and with secreted phospholipase A2 (standardised β = 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.

CONCLUSIONS/INTERPRETATION: 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.