Methylglyoxal Mediates the Association Between 2-Hour Plasma Glucose and HbA1c With Inflammation: The Maastricht Study

Context Glucose excursions in persons with diabetes may drive chronic inflammation. Methylglyoxal (MGO) is formed from glucose, is elevated in persons with diabetes, and is a potent glycating agent linked with inflammation.Objective We investigated whether glucose excursions are associated with low-grade inflammation and whether MGO mediates this association.Methods We used data from The Maastricht Study, an extensive phenotyping study into the etiology of type 2 diabetes and its complications. Data of 3017 participants, who underwent an oral glucose tolerance test and where data on MGO levels and inflammation were available, were used. Linear regression analyses, adjusted for potential confounders, evaluated associations between fasting plasma glucose (FPG), 2-hour plasma glucose (2h-PG) and HbA1c, and low-grade inflammation (std beta, [95% CI]) were calculated from plasma concentrations of C-reactive protein, serum amyloid A, interleukin-6, interleukin-8, tumor necrosis factor, and soluble intercellular adhesion molecule-1. Mediation analyses investigated whether MGO mediated these associations.Results 2h-PG (0.172, [0.110; 0.234]) and HbA1c (0.148, [0.101; 0.196]), but not FPG (0.049, [-0.002; 0.100]), were associated with low-grade inflammation. 2h-PG and HbA1c were also associated with 2h-MGO (0.471, [0.407; 0.534], and 0.244, [0.195; 0.294], respectively). Furthermore, 2h-MGO was independently and positively associated with low-grade inflammation (0.078, [0.037; 0.120]). 2h-MGO mediated 23% of the association between 2h-PG and inflammation, and 16% of the association between HbA1c and inflammation.Conclusion MGO mediates the association between postload glucose excursions and HbA1c with inflammation, providing evidence for a role of postprandial MGO formation to hyperglycemia-induced low-grade inflammation.