Dionne EM Maessen, Jean LJM Scheijen, Katrien H Gaens, Marleen MJ van Greevenbroek, Carla J van der Kallen, Coen DA Stehouwer and Casper G Schalkwijk
Objective: Methylglyoxal (MGO), a highly reactive dicarbonyl compound generated by the spontaneous degradation of glycolytic intermediates, is a major precursor for advanced glycation endproducts and can potentially disrupt cellular functions. MGO can be detoxified by the glyoxalase system into D-lactate. Although experimental studies have shown that increased levels of MGO are associated with insulin resistance, epidemiological evidence of such an association in human studies is lacking. The aim of this study was to investigate the association between plasma D-lactate, as a reflection of plasma MGO concentrations, and insulin resistance. Methods: Cross-sectional, complete case analyses were performed in the Cohort study on Diabetes and Atherosclerosis Maastricht (CODAM). 513 participants were included in the study population: 59.4 ± 6.9 years of age, 63% men, and, by design, 23% impaired glucose metabolism (IGM) and 23% type 2 diabetes mellitus (T2DM). Plasma D-lactate was measured by UPLC-MS/MS. The main outcome measure was HOMA2-IR, as a measure of insulin resistance. The association between plasma D-lactate and HOMA2-IR was studied by multiple linear regression analysis. Results: The prevalence of T2DM increased significantly over the tertiles of plasma D-lactate concentrations. Moreover, plasma D-lactate was positively associated with HOMA2-IR, when adjusted for age and sex (β=0.429; 95% CI: 0.350-0.507; p<0.001), as well as in the fully adjusted model, additionally adjusted for glucose metabolism status, smoking status, prior cardiovascular disease, use of medication (glucose-, lipid-, and blood pressure lowering), estimated glomerular filtration rate, waist circumference, glycated hemoglobin (HbA1C) and plasma L-lactate levels (β=0.145; 95% CI: 0.051-0.239; p=0.003). Additional data indicate that other sources of D-lactate can be excluded. Conclusion: We found a positive association between plasma D-lactate and HOMA2-IR, independently of putative confounders. These results suggest that MGO plays a role in insulin resistance, although direct measurement of MGO is necessary to confirm this.