Plasma branched chain/aromatic amino acids, enriched Mediterranean diet and risk of type 2 diabetes: case-cohort study within the PREDIMED Trial Academic Article uri icon


  • AIMS/HYPOTHESIS:Branched-chain amino acids (BCAAs) and aromatic amino acids (AAAs) are associated with type 2 diabetes. However, repeated measurements of BCAA/AAA and their interactions with dietary interventions have not been evaluated. We investigated the associations between baseline and changes at 1 year in BCAA/AAA with type 2 diabetes in the context of a Mediterranean diet (MedDiet) trial. METHODS:We included 251 participants with incident type 2 diabetes and a random sample of 694 participants (641 participants without type 2 diabetes and 53 overlapping cases) in a case-cohort study nested within the PREvención con DIeta MEDiterránea (PREDIMED) trial. Participants were randomised to a MedDiet+extra-virgin olive oil (n = 273), a MedDiet+nuts (n = 324) or a control diet (n = 295). We used LC-MS/MS to measure plasma levels of amino acids. Type 2 diabetes was a pre-specified secondary outcome of the PREDIMED trial. RESULTS:Elevated plasma levels of individual BCAAs/AAAs were associated with higher type 2 diabetes risk after a median follow-up of 3.8 years: multivariable HR for the highest vs lowest quartile ranged from 1.32 for phenylalanine ([95% CI 0.90, 1.92], p for trend = 0.015) to 3.29 for leucine ([95% CI 2.03, 5.34], p for trend<0.001). Increases in BCAA score at 1 year were associated with higher type 2 diabetes risk in the control group with HR per SD = 1.61 (95% CI 1.02, 2.54), but not in the MedDiet groups (p for interaction <0.001). The MedDiet+extra-virgin olive oil significantly reduced BCAA levels after 1 year of intervention (p = 0.005 vs the control group). CONCLUSIONS/INTERPRETATION:Our results support that higher baseline BCAAs and their increases at 1 year were associated with higher type 2 diabetes risk. A Mediterranean diet rich in extra-virgin olive oil significantly reduced the levels of BCAA and attenuated the positive association between plasma BCAA levels and type 2 diabetes incidence. Clinical trial number: SRCTN35739639 ( ).


  • Ruiz-Canela, Miguel
  • Guasch-Ferré, Marta
  • Toledo, Estefanía
  • Clish, Clary B
  • Razquin, Cristina
  • Liang, Liming
  • Wang, Dong D
  • Corella, Dolores
  • Estruch, Ramón
  • Hernáez, Álvaro
  • Yu, Edward
  • Gómez-Gracia, Enrique
  • Zheng, Yan
  • Arós, Fernando
  • Romaguera, Dora
  • Dennis, Courtney
  • Ros, Emilio
  • Lapetra, José
  • Serra-Majem, Lluis
  • Papandreou, Christopher
  • Portoles, Olga
  • Fitó, Montserrat
  • Salas-Salvadó, Jordi
  • Hu, Frank B
  • Martinez-Gonzalez, Miguel A

publication date

  • 2018