Philippe Vangrieken¹, Jean L.J.M. Scheijen¹, Elisa D’Alessandro2, Etto C. Eringa2, Casper G. Schalkwijk¹
¹School for Cardiovascular Diseases (CARIM), Department of Internal Medicine, Maastricht University Medical Center+, Maastricht, The Netherlands. ²School for Cardiovascular Diseases (CARIM), Department of Physiology, Maastricht University Medical Center+, Maastricht, The Netherlands.
p.vangrieken@maastrichtuniversity.nl
Background: Type 2 diabetes (T2D) is characterized by insulin resistance, vascular dysfunction, and increased cardiovascular risk. While endogenously formed methylglyoxal (MGO), a glycolytic byproduct, is typically associated with vascular damage, recent data suggest dietary MGO may have metabolic benefits. This study investigated whether dietary MGO supplementation could prevent hypertension, endothelial dysfunction, and insulin resistance in high-fat diet (HFD)-induced diabetic mice.
Methods: Male C57BL/6 mice were fed a control diet (n=12), HFD (n=12), or HFD with 1 mM MGO in drinking water (n=12) for 13 weeks. Blood pressure was assessed non-invasively. Endothelial function was evaluated via acetylcholine-induced vasodilation in isolated saphenous arteries using wire myography. Plasma levels of soluble ICAM-1 (sICAM-1) and E-selectin (sE-selectin) were measured by ELISA. Microvascular perfusion and insulin-mediated microvascular recruitment (IMMR) were measured using contrast-enhanced ultrasound (CEUS) under basal conditions and during a hyperinsulinemic-euglycemic clamp (HEC). Arterial stiffness was assessed by pulse wave velocity (PWV) using ultrasound.
Results: HFD-fed mice showed significantly increased systolic (+8%,p=0.030) and diastolic (+9%, p=0.020) blood pressure compared to controls, effects fully prevented by dietary MGO. HFD-induced endothelial dysfunction was reversed by MGO (p=0.012). Plasma sICAM-1 and sE-selectin levels were significantly lower in MGO-treated mice compared to HFD alone (−14%,p=0.010; −28%,p<0.001). Reduced microvascular perfusion in HFD mice (+64%,p=0.010) normalized with MGO supplementation. HEC analysis revealed markedly impaired whole-body insulin sensitivity in HFD mice (−73%, p<0.001), which was completely prevented by MGO (p=0.030). Similarly, MGO significantly improved IMMR (−43%, p=0.030). Finally, HFD-induced arterial stiffening, reflected by elevated PWV, was attenuated by MGO (−33%,p<0.001).
Discussion/Conclusion: Dietary MGO protects against key HFD-induced vascular and metabolic dysfunctions, including hypertension, endothelial impairment, insulin resistance, and arterial stiffness. These findings challenge the conventional view of MGO as solely harmful and suggest a protective role for dietary MGO in T2D-associated vascular complications.