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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Welsh , P , Rankin , N , Li , Q , Mark , P B , Würtz , P , Ala-Korpela , M , Marre , M , Poulter , N , Hamet , P , Chalmers , J , Woodward , M & Sattar , N 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 , vol. 61 , no. 7 , pp. 1581-1591 . https://doi.org/10.1007/s00125-018-4619-x

Title: Circulating amino acids and the risk of macrovascular, microvascular and mortality outcomes in individuals with type 2 diabetes : results from the ADVANCE trial
Author: Welsh, Paul; Rankin, Naomi; Li, Qiang; Mark, Patrick B.; Würtz, Peter; Ala-Korpela, Mika; Marre, Michel; Poulter, Neil; Hamet, Pavel; Chalmers, John; Woodward, Mark; Sattar, Naveed
Contributor: University of Helsinki, Research Programs Unit
Date: 2018-07
Language: eng
Number of pages: 11
Belongs to series: Diabetologia
ISSN: 0012-186X
URI: http://hdl.handle.net/10138/302453
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.
Subject: Amino acid
Diabetes complications
Metabolomics
Risk factors
Type 2 diabetes
MAGNETIC-RESONANCE METABOLOMICS
BRANCHED-CHAIN
INSULIN-RESISTANCE
DISEASE
PHENYLALANINE
EPIDEMIOLOGY
ASSOCIATION
METABOLITES
POPULATION
PROFILES
3121 Internal medicine
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