Glycolysis/gluconeogenesis- and tricarboxylic acid cycle-related metabolites

Identificador:  imarina:6246213

Handle: https://hdl.handle.net/20.500.11797/imarina6246213

Autors:  Guasch-Ferre, Marta; Santos, Jose L; Martinez-Gonzalez, Miguel A; Clish, Clary B; Razquin, Cristina; Wang, Dong; Liang, Liming; Li, Jun; Dennis, Courtney; Corella, Dolores; Munoz-Bravo, Carlos; Romaguera, Dora; Estruch, Ramon; Manuel Santos-Lozano, Jose; Castaner, Olga; Alonso-Gomez, Angel; Serra-Majem, Luis; Ros, Emilio; Canudas, Silvia; Asensio, Eva M; Fito, Montserrat; Pierce, Kerry; Alfredo Martinez, J; Salas-Salvado, Jordi; Toledo, Estefania; Hu, Frank B; Ruiz-Canela, Miguel

Resum:
Background: Glycolysis/gluconeogenesis and tricarboxylic acid (TCA) cycle metabolites have been associated with type 2 diabetes (T2D). However, the associations of these metabolites with T2D incidence and the potential effect of dietary interventions remain unclear. Objectives: We aimed to evaluate the association of baseline and 1-y changes in glycolysis/gluconeogenesis and TCA cycle metabolites with insulin resistance and T2D incidence, and the potential modifying effect of Mediterranean diet (MedDiet) interventions. Methods: We included 251 incident T2D cases and 638 noncases in a nested case-cohort study within the PREDIMED Study during median follow-up of 3.8 y. Participants were allocated to MedDiet + extra-virgin olive oil. MedDiet + nuts, or control diet. Plasma metabolites were measured using a targeted approach by LC-tandem MS. We tested the associations of baseline and 1-y changes in glycolysis/gluconeogenesis and TCA cycle metabolites with subsequent T2D risk using weighted Cox regression models and adjusting for potential confounders. We designed a weighted score combining all these metabolites and applying the leave-oneout cross-validation approach. Results: Baseline circulating concentrations of hexose monophosphate. pyruvate, lactate, alanine, glycerol-3 phosphate, and isocitrate were significantly associated with higher T21) risk (17-44% higher risk for each 1-SD increment). The weighted score including all metabolites was associated with a 30% (95% CI: 1.12, 1.51) higher relative risk of T2D for each 1-SD increment. Baseline lactate and alanine were associated with baseline and 1-y changes of homeostasis model assessment of insulin resistance. One-year increases in most metabolites and in the weighted score were associated with higher relative risk of T2D after 1-y of follow-up. Lower risks were observed in the MedDiet groups than in the control group although no significant interactions were found after adjusting for multiple comparisons. Conclusions: We identified a panel of glycolysis/gluconeogenesisrelated metabolites that was significantly associated with T2D risk in a Mediterranean population at high cardiovascular disease risk. A MedDiet could counteract the detrimental effects of these metabolites.