Maya A.K. Stelzer, Jean L.J.M. Scheijen, Charlotte J. Teunis, Reindert F. Oostveen, Mark E. Cooper, Erik Stroes, Max Nieuwdorp, Daniël van Raalte, Casper Schalkwijk, Jeffrey Kroon, Philippe Vangrieken, Nordin M.J. Hanssen
Department of Vascular and Internal Medicine, Amsterdam University Medical Centre, Department of Internal Medicine, Cardiovascular Research Institute Maastricht (CARIM) School for Cardiovascular Diseases, Maastricht University
m.a.k.stelzer@amsterdamumc.nl
Background: Methylglyoxal (MGO), a highly reactive dicarbonyl compound, contributes to the development of diabetic complications through the formation of advanced glycation end products (AGEs) and activation of inflammatory pathways. Although glucagon-like peptide-1 receptor agonists improve glycemic control, their effects on MGO stress remain poorly understood. This study investigated whether semaglutide-induced improvements in glycemic control are accompanied by reductions in MGO stress and AGEs. Additionally, it explored associations between MGO and glycation- and immune-related biomarkers in individuals with type 2 diabetes (T2D).
Methods: Sixteen individuals with T2D received semaglutide (≤2.0 mg weekly) for 6 months. Urine and heparin plasma samples collected before and after treatment were analyzed for HbA1c. Reactive dicarbonyl compounds including MGO, and MGO-derived AGEs were measured with UPLC-MS/MS, and immune-related proteins with nELISA.
Results: Semaglutide treatment significantly reduced HbA1c (72 [69-77] vs 56 [50-59] mmol/mol; p<0.001) and weight (85.5 [74.0–96.0] vs 78,0 [63.0–88.0] kg; p<0.001). However, MGO concentrations remained unchanged in both urine (1063 [925–1797] vs 1223 [993–1681] nmol/mmol creatinine; p=0.45) and plasma (407 [340–471] vs 428 [356–486] nmol/L; p=0.72). In contrast, MG-H1 in urine (2320 [2040–2872] vs 3900 [3140–4443] nmol/mmol creatinine; p=0.011) and plasma (952 [867–1029] vs 1046 [980–1162] nmol/L; p=0.025) increased significantly. Urinary MGO was positively correlated with urinary glycation markers, with the strongest associations observed for MG-H1 (ρ=0.47), CEG (ρ=0.49), and CEdG (ρ=0.37). Higher MGO levels were also positively associated with 14 proteins involved in tissue repair and apoptosis and negative correlations with 16 proteins involved in chemotaxis and immune homeostasis.
Conclusion: Despite significant improvement in glycemic control and weight following semaglutide treatment, MGO concentrations remained unchanged, whereas MG-H1 increased. These findings suggest that MGO-related glycation pathways may persist despite improved glycemic control and could contribute to residual complication risk.
This research was supported by a research grant from Novo Nordisk (23130), NWO-VIDI (09150172210019) and Dutch Heart Foundation (2021T055).