Welsh, P. et al. (2018) Circulating amino acids and the risk of macrovascular, microvascular, and mortality outcomes in individuals with type 2 diabetes: results from the ADVANCE trial. Diabetologia, 61(7), pp. 1581-1591. (doi: 10.1007/s00125-018-4619-x) (PMID:29728717) (PMCID:PMC6445481)
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Abstract
Aims/hypotheses: We 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. Methods: We 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. Results: In 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/interpretation: We 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.
Item Type: | Articles |
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Status: | Published |
Refereed: | Yes |
Glasgow Author(s) Enlighten ID: | Woodward, Professor Mark and Mark, Professor Patrick and Welsh, Professor Paul and Rankin, Dr Naomi and Sattar, Professor Naveed |
Authors: | Welsh, P., Rankin, N., Li, Q., Mark, P. B., Würtz, P., Ala-Korpela, M., Marre, M., Poulter, N., Hamet, P., Chalmers, J., Woodward, M., and Sattar, N. |
College/School: | College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health |
Journal Name: | Diabetologia |
Publisher: | Springer |
ISSN: | 0012-186X |
ISSN (Online): | 1432-0428 |
Published Online: | 04 May 2018 |
Copyright Holders: | Copyright © 2018 The Authors |
First Published: | First published in Diabetologia 61(7):1581–1591 |
Publisher Policy: | Reproduced under a Creative Commons License |
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