Plasma branched chain/aromatic amino acids, enriched Mediterranean
diet and risk of type 2 diabetes: case-cohort study within the PREDIMED
Clary B. Clish
Dong D. Wang
Frank B. Hu
Miguel A. Martínez-González
Received: 17 October 2017 /Accepted: 12 March 2018 /Published online: 16 April 2018
Springer-Verlag GmbH Germany, part of Springer Nature 2018
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),aMedDiet+nuts(n =324)ora
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 (www.controlled-trials.com)
Keywords Aromatic amino acids
Branched-chain amino acids
Type 2 diabetes
AAA Aromatic amino acid
BCAA Branched-chain amino acid
EVOO Extra-virgin olive oil
MedDiet Mediterranean diet (trial intervention)
MET Metabolic equivalent task
mTOR Mammalian target of rapamycin
PREDIMED PREvención con DIeta MEDiterránea
Electronic supplementary material The online version of this article
(https://doi.org/10.1007/s00125-018-4611-5) contains peer-reviewed but
unedited supplementary material, which is available to authorised users.
* Miguel Ruiz-Canela
Extended author information available on the last page of the article
Diabetologia (2018) 61:1560–1571