Thesis defense Chloé Chevalier

Equipe

Team IV - Cardiometabolic diseases

Directeur de thèse

Samy Hadjadj

Encadrant

Mikaël Croyal & Georges Nouadje

Rapporteurs

Sophie Beliard, MD, PhD, PU-PH, CHU Timone, Marseille
Thomas Gautier, PhD, CR, Centre de recherche Translationnelle, Dijon

Examinateurs

René Valéro, MD, PhD, PU-PH, CHU Timone, Marseille
Wienecke Djik, PhD, CR, INRAe, Nantes

Abstract

Type 2 diabetes (T2D) is a major cardiovascular (CV) risk factor, and methylglyoxal (MGO), a metabolite derived from glycolysis, is a highly potent protein glycation agent associated with increased risk in T2D. However, the use of MGO as a biomarker remains limited due to its instability in plasma. We hypothesized that the metabolic environment associated with T2D leads to an increased glycation of plasma proteins by MGO, playing a key role in the occurrence of CV events. Therefore, we searched for glycation biomarkers induced by MGO on major plama proteins: albumin and apolipoproteins, the latter playing a central role in lipid metabolism, which often altered in T2D. Our analysis identified glycation biomarkers of albumin, apoA-I, apoA-II, and apoB100, whose plasma concentrations are elevated in T2D and positively associated with incidence CV events in patients living with T2D and/or new onset of diabetes in individuals living with prediabetes. Through various in vitro and in vivo approaches, we established a link between the circulating levels of these biomarkers, lipoprotein metabolism abnormalities, and CV risk in T2D. We were also able to study the impact of different treatments on their plasma concentrations. Hence, these new biomarkers have revealed novel mechanisms of atherogenic dyslipidemia and highlighted the central role of MGO-induced stress in lipoprotein metabolism, paving the way for a more precise assessment of the CV risk associated with T2D.