Plasma branched chain/aromatic amino acids, enriched Mediterranean diet and risk of type 2 diabetes: case-cohort study within the PREDIMED Trial
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.
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.
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).
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)
KeywordsAromatic amino acids Branched-chain amino acids Mediterranean diet Type 2 diabetes
Aromatic amino acid
Branched-chain amino acid
Extra-virgin olive oil
Mediterranean diet (trial intervention)
Metabolic equivalent task
Mammalian target of rapamycin
PREvención con DIeta MEDiterránea
We are very grateful to all the participants for their enthusiastic collaboration, the PREDIMED personnel for their excellent assistance, and the personnel of all affiliated primary care centres. CIBEROBN is an initiative of Instituto de Salud Carlos III, Spain.
MR-C and MAM-G conducted the statistical analyses and drafted the article. MR-C, FBH, ET, CBC, LL, JS-S, and MAM-G made substantial contributions to the conception and design of the work. All authors contributed substantially in the acquisition of data or analysis and interpretation of data. All authors revised the article critically for important intellectual content. All authors approved the version to be published.
This study was supported by research grant NIDDK-R01DK 102896 from the National Institutes of Health. EY was supported with the grant F31 DK114938-01. MG-F was supported by EFSD (European Foundation for the Study of Diabetes)/Lilly through the Institut d’Investigacions Sanitàries Pere i Virgili (IISPV). CP was supported by a postdoctoral fellowship granted by the Autonomous Government of Catalonia (PERIS 2016–2020 Incorporació de Científics I Tecnòlegs, SLT002/0016/00428).
Duality of interest
ER has received honoraria for lectures and grants for research through his institution from the California Walnut Commission and is a nonpaid member of its Scientific Advisory Committee. JS-S has received grants for research through his institution from the International Nut and Dried Fruit Council and is a nonpaid member of its Scientific Advisory Committee. The rest of the authors declare that there is no duality of interest associated with this manuscript.
- 22.Blom G (1958) Statistical estimates and transformed beta-variables. Wiley, New YorkGoogle Scholar
- 23.Barlow WE, Ichikawa L, Rosner D, Izumi S (1999) Analysis of case-cohort designs. 52:1165–1172Google Scholar
- 33.Zhao X, Gang X, Liu Y et al (2016) Using metabolomic profiles as biomarkers for insulin resistance in childhood obesity: a systematic review. J Diabetes Res 2016:1–12Google Scholar