Background: Several blood sugar metabolites and gluconeogenesis substrates, including glucose and fructose, are associated with type 2 diabetes (T2D) risk but the evidence remains unclear.

Objective: To determine the associations between baseline and 1-year changes in plasma glycolysis/gluconeogenesis-related metabolites with insulin resistance and incident T2D risk; and to examine whether these associations are mitigated by Mediterranean Diet (MedDiet) interventions in a population at high cardiovascular risk.

Research Design and Methods: We included251 incident T2D cases (occurring after a median follow-up of 3.8 years) and 638 non-cases in a nested case-cohort study. Participants were allocated to a MedDiet + extra-virgin olive oil, MedDiet + nuts or a control diet. Plasma metabolites were measured using a targeted approach by LC-MS. We tested the associations of baseline and 1-year changes in glycolysis/gluconeogenesis metabolites with subsequent T2D risk using weighted proportional hazards Cox regression models. We designed a weighted score combining all these metabolites and applying the leave-one-out cross-validation approach.

Results: Baseline fasting plasma levels of fructose 6-phosphate, pyruvate, lactate, alanine, glycerol-3 phosphate and the weighted score were significantly associated with higher T2D risk (23% to 44% higher risk for each 1SD increment). Fructose 6-phosphate was associated with a higher T2D risk in the control group but not in the MedDiet groups (Pfor interaction=0.05). Participants in the higher quartile of 1-year changes in lactate and aconitate had 3.87-fold (95% CI: 2.05-7.30) and 3.16-fold (95% CI: 1.76-5.68), higher risk of T2D, respectively.

Conclusions: We identified a panel of glycolysis/gluconeogenesis-related metabolites that was significantly associated with T2D risk in individuals at high cardiovascular risk.


M. Guasch: None. J.L. Santos: None. M.A. Martinez-Gonzalez: None. C.B. Clish: None. C. Razquin: None. D. Wang: None. L. Liang: None. J. Li: None. C. Dennis: None. D. Corella: None. R. Estruch: None. A.M. Alonso-Gomez: None. L. Serra-Majem: None. E. Ros: None. M. Fito Colomer: None. J. Martínez: None. J. Salas-Salvadó: None. E. Toledo: None. F. Hu: None. M. Ruiz-Canela: None.


American Diabetes Association (1-18-PMF-029 to M.G.); National Institutes of Health (R01DK102896); Instituto de Salud Carlos III; Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición; Centro Nacional de Investigaciones Cardiovasculares (06/2007); Fondo de Investigación Sanitaria-Fondo Europeo de Desarrollo Regional (PI04–2239, PI05/2584, CP06/00100, PI07/0240, PI07/1138, PI07/0954, PI 07/0473, PI10/01407, PI10/02658, PI11/01647, P11/02505, PI13/00462, JR17/00022); Ministerio de Ciencia e Innovación (AGL2009-13906-C02, AGL2010-22319-C03, SAF20168-0532-R); Fundación Mapfre 2010; Consejería de Salud de la Junta de Andalucía (PI0105/2007); Department of Health of the Autonomous Government of Catalonia; Generalitat Valenciana (ACOMP06109, GVA-COMP2010-181, GVACOMP2011-151, CS2010-AP-111, PROMETEO 17/2017, CS2011-AP-042); Fundació La Marató-TV3 (294/C/2015, 538/U/2016); Regional Government of Navarra (P27/2011); Fondo Nacional de Desarrollo Científico y Tecnológico (1150416 to J.L.S.)

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