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Glycolysis/gluconeogenesis- and tricarboxylic acid cycle-related metabolites, Mediterranean diet, and type 2 diabetes

Autores: Guasch-Ferré, M.; Santos, J. L.; Martínez González, Miguel Ángel; Clish, C. B.; Razquin Burillo, Cristina; Wang, D.; Liang, L. M. ; Li, J. ; Dennis, C. ; Corella, D. ; Muñoz-Bravo, C.; Romaguera, D.; Estruch, R.; Santos-Lozano, J. M.; Castaner, O.; Alonso-Gómez, A.; Serra-Majem, L.; Ros, E. ; Canudas, S.; Asensio, E. M. ; Fito, M.; Pierce, K.; Martínez Hernández, Alfredo; Salas-Salvado, J.; Toledo Atucha, Estefanía; Hu, F.B. ; Ruiz-Canela, Miguel (Autor de correspondencia)
ISSN: 0002-9165
Volumen: 111
Número: 4
Páginas: 835 - 844
Fecha de publicación: 2020
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.