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.

Design: We used data from The Maastricht Study, an extensive phenotyping study into the etiology of type 2 diabetes and its complications.

Participants: Data of 3017 participants, who underwent an oral glucose tolerance test and where data on MGO levels and inflammation were available, were used.

Main outcome measures: Linear regression analyses, adjusted for potential confounders, evaluated associations between fasting plasma glucose (FPG), 2-hours plasma glucose (2h-PG) and HbA1c and low-grade inflammation (stdβ, [95% confidence interval]), 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.

Conclusions: MGO mediates the association between post-load glucose excursions and HbA1c with inflammation, providing evidence for a role of postprandial MGO formation to hyperglycemia-induced low-grade inflammation.