Circulating amino acids and the risk of macrovascular, microvascular, and mortality outcomes in individuals with type 2 diabetes: results from the ADVANCE trial

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)

[img]
Preview
Text
159596.pdf - Published Version
Available under License Creative Commons Attribution.

817kB

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
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Woodward, Professor Mark and Mark, Dr Patrick and Sattar, Professor Naveed and Rankin, Dr Naomi and Welsh, Dr Paul
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 > Institute of Cardiovascular and Medical Sciences
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

University Staff: Request a correction | Enlighten Editors: Update this record

Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
621401Assessing the predictive value of quantitative high-throughput NMR metabolomic analysis for CVD events in a major study of diabetes: ADVANCEPaul WelshChest Heart & Stroke Scotland (CHSS)R13/A149RI CARDIOVASCULAR & MEDICAL SCIENCES
690421Glasgow Molecular Pathology (GMP) NodeKarin OienMedical Research Council (MRC)MR/N005813/1ICS - EXPERIMENTAL THERAPEUTICS