University of Oulu

Welsh, P., Rankin, N., Li, Q. et al. Diabetologia (2018) 61: 1581.

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

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Author: Welsh, Paul1; Rankin, Naomi1; Li, Qiang2;
Organizations: 1BHF Glasgow Cardiovascular Research Centre, Institute of Cardiovascular & Medical Sciences, University of Glasgow, Glasgow, UK
2The George Institute for Global Health, University of New South Wales, Sydney, Australia
3Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki, Finland
4Nightingale Health Ltd, Helsinki, Finland
5Computational Medicine, Faculty of Medicine, University of Oulu and Biocenter Oulu, Oulu, Finland
6NMR Metabolomics Laboratory, School of Pharmacy, University of Eastern Finland, Kuopio, Finland
7Population Health Science, Bristol Medical School, University of Bristol and Medical Research Council Integrative Epidemiology Unit at the University of Bristol, Bristol, UK
8Systems Epidemiology, Baker Heart and Diabetes Institute, Melbourne, Australia
9Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Faculty of Medicine, Nursing and Health Sciences, The Alfred Hospital, Monash University, Melbourne, Australia
10Inserm, UMRS 1138, Centre de Recherche des Cordeliers, Paris, France
11Assistance Publique Hôpitaux de Paris, Bichat Hospital, DHU FIRE, Department of Diabetology, Endocrinology and Nutrition, Paris, France
12University Paris Diderot, Sorbonne Paris Cité, UFR de Médecine, Paris, France
13International Centre for Circulatory Health, Imperial College, London, UK
14Department of Experimental Medicine, McGill University, Montreal, Canada
15Department of Medicine, CRCHUM, Université de Montréal, Montreal, Canada
16Department of Medicine, Gene Medicine Services, CRCHUM, Université de Montréal, Montreal, Canada
17The George Institute for Global Health, University of Oxford, Oxford, UK
18Department of Epidemiology, Johns Hopkins University, Baltimore, USA
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 0.8 MB)
Persistent link:
Language: English
Published: Springer Nature, 2018
Publish Date: 2019-07-10


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.

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Series: Diabetologia
ISSN: 0012-186X
ISSN-E: 1432-0428
ISSN-L: 0012-186X
Volume: 61
Issue: 7
Pages: 1581 - 1591
DOI: 10.1007/s00125-018-4619-x
Type of Publication: A1 Journal article – refereed
Field of Science: 3121 General medicine, internal medicine and other clinical medicine
Funding: The biomarker work in the present study was funded by the Chest Heart and Stroke Association Scotland (R13/A149) and by the Glasgow Molecular Pathology NODE, which is funded by The Medical Research Council and The Engineering and Physical Sciences Research Council (MR/N005813/1). The ADVANCE trial ( registration no. NCT00145925) was funded by the National Health and Medical Research Council (NHMRC) of Australia (project grant ID 211086 and program grant IDs 358395 and 571281) and by Servier. PWu is supported by the Academy of Finland (312476 and 312477) and the Novo Nordisk Foundation. MAK was supported by the Sigrid Juselius Foundation, Finland. MAK works in a Unit that is supported by the University of Bristol and UK Medical Research Council (MC_UU_12013/1). The study sponsors were not involved in the design of the study, the collection, analysis, and interpretation of data, writing the report or the decision to submit the report for publication.
Copyright information: © The Author(s) 2018. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (, which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.