Abstract
Aims/hypothesesWe aimed to quantify the association of individual circulating amino acids with macrovascular disease, microvascular disease and all-cause mortality in individuals with type 2 diabetes.MethodsWe performed a case-cohort study (N = 3587), including 655 macrovascular events, 342 microvascular events (new or worsening nephropathy or retinopathy) and 632 all-cause mortality events during follow-up, in a secondary analysis of the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) study. For this study, phenylalanine, isoleucine, glutamine, leucine, alanine, tyrosine, histidine and valine were measured in stored plasma samples by proton NMR metabolomics. Hazard ratios were modelled per SD increase in each amino acid.ResultsIn models investigating associations and potential mechanisms, after adjusting for age, sex and randomised treatment, phenylalanine was positively, and histidine inversely, associated with macrovascular disease risk. These associations were attenuated to the null on further adjustment for extended classical risk factors (including eGFR and urinary albumin/creatinine ratio). After adjustment for extended classical risk factors, higher tyrosine and alanine levels were associated with decreased risk of microvascular disease (HR 0.78; 95% CI 0.67, 0.91 and HR 0.86; 95% CI 0.76, 0.98, respectively). Higher leucine (HR 0.79; 95% CI 0.69, 0.90), histidine (HR 0.89; 95% CI 0.81, 0.99) and valine (HR 0.79; 95% CI 0.70, 0.88) levels were associated with lower risk of mortality. Investigating the predictive ability of amino acids, addition of all amino acids to a risk score modestly improved classification of participants for macrovascular (continuous net reclassification index [NRI] +35.5%, p < 0.001) and microvascular events (continuous NRI +14.4%, p = 0.012).Conclusions/interpretationWe report distinct associations between circulating amino acids and risk of different major complications of diabetes. Low tyrosine appears to be a marker of microvascular risk in individuals with type 2 diabetes independently of fundamental markers of kidney function.
Highlights
Prior to an individual developing overt type 2 diabetes, there appears to be a period of subclinical metabolic abnormality, manifesting in the altered circulating levels of many metabolites [1, 2]
A nested case–control study from the Framingham Offspring study showed that branched-chain amino acids (BCAAs) isoleucine, leucine and valine and aromatic amino acids (AAAs) tyrosine and phenylalanine showed positive associations with insulin resistance and risk of type 2 diabetes [3]
The associations of amino acids with classical cardiovascular disease (CVD) risk factors are shown in ESM Tables 2– 9
Summary
Prior to an individual developing overt type 2 diabetes, there appears to be a period of subclinical metabolic abnormality, manifesting in the altered circulating levels of many metabolites [1, 2]. Several studies have reported that circulating concentrations of amino acids predict the development of type 2 diabetes. In general population studies, elevated levels of BCAAs and AAAs appear to be associated with increased risk of cardiovascular disease [9,10,11,12], these associations have not been entirely consistent [13]. In the large Estonian Biobank study, inverse associations between the concentration of several amino acids (including BCAAs) and allcause mortality were observed [14]. We have recently reported in a randomised placebo-controlled trial that metformin treatment (for 18 months in men with CHD but without type 2 diabetes) led to improved insulin sensitivity and was associated with increases in alanine and histidine and reductions in phenylalanine and tyrosine concentrations, with no effect on BCAAs [16]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
