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Plasma metabolites associated with type 2 diabetes in a Swedish population: a case-control study nested in a prospective cohort

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Date
2018
Author(s)
Shi, L
Brunius, C
Lehtonen, M
Auriola, S
Bergdahl, IA
Rolandsson, O
Hanhineva, K
Landberg, R
Unique identifier
10.1007/s00125-017-4521-y
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Citation
Shi, L. Brunius, C. Lehtonen, M. Auriola, S. Bergdahl, IA. Rolandsson, O. Hanhineva, K. Landberg, R. (2018). Plasma metabolites associated with type 2 diabetes in a Swedish population: a case-control study nested in a prospective cohort.  DIABETOLOGIA, 61 (4) , 849-861. 10.1007/s00125-017-4521-y.
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CC BY http://creativecommons.org/licenses/by/4.0/
Abstract

Aims/hypothesis
The aims of the present work were to identify plasma metabolites that predict future type 2 diabetes, to investigate the changes in identified metabolites among individuals who later did or did not develop type 2 diabetes over time, and to assess the extent to which inclusion of predictive metabolites could improve risk prediction.

Methods
We established a nested case–control study within the Swedish prospective population-based Västerbotten Intervention Programme cohort. Using untargeted liquid chromatography-MS metabolomics, we analysed plasma samples from 503 case–control pairs at baseline (a median time of 7 years prior to diagnosis) and samples from a subset of 187 case–control pairs at 10 years of follow-up. Discriminative metabolites between cases and controls at baseline were optimally selected using a multivariate data analysis pipeline adapted for large-scale metabolomics. Conditional logistic regression was used to assess associations between discriminative metabolites and future type 2 diabetes, adjusting for several known risk factors. Reproducibility of identified metabolites was estimated by intra-class correlation over the 10 year period among the subset of healthy participants; their systematic changes over time in relation to diagnosis among those who developed type 2 diabetes were investigated using mixed models. Risk prediction performance of models made from different predictors was evaluated using area under the receiver operating characteristic curve, discrimination improvement index and net reclassification index.

Results
We identified 46 predictive plasma metabolites of type 2 diabetes. Among novel findings, phosphatidylcholines (PCs) containing odd-chain fatty acids (C19:1 and C17:0) and 2-hydroxyethanesulfonate were associated with the likelihood of developing type 2 diabetes; we also confirmed previously identified predictive biomarkers. Identified metabolites strongly correlated with insulin resistance and/or beta cell dysfunction. Of 46 identified metabolites, 26 showed intermediate to high reproducibility among healthy individuals. Moreover, PCs with odd-chain fatty acids, branched-chain amino acids, 3-methyl-2-oxovaleric acid and glutamate changed over time along with disease progression among diabetes cases. Importantly, we found that a combination of five of the most robustly predictive metabolites significantly improved risk prediction if added to models with an a priori defined set of traditional risk factors, but only a marginal improvement was achieved when using models based on optimally selected traditional risk factors.

Conclusions/interpretation
Predictive metabolites may improve understanding of the pathophysiology of type 2 diabetes and reflect disease progression, but they provide limited incremental value in risk prediction beyond optimal use of traditional risk factors.

Subjects
metabolomics   multivariate modelling   predictive biomarker reproducibility   risk prediction   traditional risk factor   type 2 diabetes   
URI
https://erepo.uef.fi/handle/123456789/6252
Link to the original item
http://dx.doi.org/10.1007/s00125-017-4521-y
Publisher
Springer Nature
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  • Terveystieteiden tiedekunta [1336]
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