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

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-one-out cross-validation approach. Results: Baseline circulating concentrations of hexose monophosphate, pyruvate, lactate, alanine, glycerol-3 phosphate, and isocitrate were significantly associated with higher T2D 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/gluconeogenesis-related 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.This trial was registered at controlled-trials.com as ISRCTN35739639. Supported by NIH research grant NIDDK-R01DK 102896 (to FBH). The PREDIMED trial was supported by the official funding agency for biomedical research of the Spanish government, Instituto de Salud Carlos III, through grants provided to research networks specifically developed for the trial (RTIC G03/140, to RE during 2003–2005; RTIC RD 06/0045, to MAM-G during 2006–2013; and through Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición); by Centro Nacional de Investigaciones Cardiovasculares grant CNIC 06/2007; Fondo de Investigación Sanitaria—Fondo Europeo de Desarrollo Regional grants PI04–2239, PI 05/2584, CP06/00100, PI07/0240, PI07/1138, PI07/0954, PI 07/0473, PI10/01407, PI10/02658, PI11/01647, P11/02505, PI13/00462, and JR17/00022; Ministerio de Ciencia e Innovación grants AGL-2009–13906-C02, AGL2010–22319-C03, and SAF2016–80532-R; Fundación Mapfre 2010; Consejería de Salud de la Junta de Andalucía grant PI0105/2007; Public Health Division of the Department of Health of the Autonomous Government of Catalonia, Generalitat Valenciana grants ACOMP06109, GVA-COMP2010–181, GVACOMP2011–151, CS2010-AP-111, PROMETEO 17/2017, and CS2011-AP-042; Fundació La Marató-TV3 grants 294/C/2015 and 538/U/2016; and by Regional Government of Navarra grant P27/2011. MG-F was supported by American Diabetes Association grant #1-18-PMF-029. JLS was supported by Fondo Nacional de Desarrollo Científico y Tecnológico (FONDECYT) grant 1150416.