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

Abstract

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 ( www.controlled-trials.com ).

Keywords: Aromatic amino acids; Branched-chain amino acids; Mediterranean diet; Type 2 diabetes.

Fig. 1

Flow chart showing the case-cohort design. T2D, type 2 diabetes

Fig. 2

HRs (95% CI) for type 2 diabetes by quartiles of baseline plasma amino acid levels. HRs are stratified by recruitment centre and adjusted for age (years), sex (male, female) and intervention group (MedDiet+EVOO, MedDiet+nuts), BMI (kg/m²), smoking (never/current/former), leisure-time physical activity (MET-min/day), dyslipidaemia, hypertension and mean + quadratic term of baseline plasma glucose (centred on the sample mean). Circles, quartile 1 (reference); triangles, quartile 2; diamonds, quartile 3; squares, quartile 4. p values for trend: <0.001 (leucine); <0.001 (isoleucine); 0.002 (valine); 0.181 (phenylalanine); 0.004 (tyrosine). The y-axis is on a log scale

Fig. 3

Joint effect of MedDiet (MedDiet+EVOO, MedDiet+nuts) and baseline BCAA and AAA scores, adjusted for age (years), sex (male, female), BMI (kg/m²), smoking (never/current/former), leisure-time physical activity (MET-min/day), dyslipidaemia, hypertension, baseline fasting glucose (mean + quadratic term of centred mean) and stratified by recruitment centre. BCCA, black; AAA, grey. Control groups with low BCCA or AAA are reference groups. p50, 50th percentile. The y-axis is on a log scale

Fig. 4

Changes in BCAA and AAA scores after 1 year of intervention, by intervention group, adjusted for age (years), sex (male, female), BMI (kg/m²), smoking (never/current/former), leisure-time physical activity (MET-min/day), dyslipidaemia, hypertension, baseline fasting glucose and baseline BCAA (or AAA) score. Circles, control; triangles, MedDiet+EVOO; diamonds, MedDiet+nuts