Exposure to disinfection byproducts and risk of type 2 diabetes: a nested case–control study in the HUNT and Lifelines cohorts
Environmental chemicals acting as metabolic disruptors have been implicated with diabetogenesis, but evidence is weak among short-lived chemicals, such as disinfection byproducts (trihalomethanes, THM composed of chloroform, TCM and brominated trihalomethanes, BrTHM).
We assessed whether THM were associated with type 2 diabetes (T2D) and we explored alterations in metabolic profiles due to THM exposures or T2D status.
A prospective 1:1 matched case–control study (n = 430) and a cross-sectional 1:1 matched case–control study (n = 362) nested within the HUNT cohort (Norway) and the Lifelines cohort (Netherlands), respectively, were set up. Urinary biomarkers of THM exposure and mass spectrometry-based serum metabolomics were measured. Associations between THM, clinical markers, metabolites and disease status were evaluated using logistic regressions with Least Absolute Shrinkage and Selection Operator procedure.
Low median THM exposures (ng/g, IQR) were measured in both cohorts (cases and controls of HUNT and Lifelines, respectively, 193 (76, 470), 208 (77, 502) and 292 (162, 595), 342 (180, 602). Neither BrTHM (OR = 0.87; 95% CI: 0.67, 1.11 | OR = 1.09; 95% CI: 0.73, 1.61), nor TCM (OR = 1.03; 95% CI: 0.88, 1.2 | OR = 1.03; 95% CI: 0.79, 1.35) were associated with incident or prevalent T2D, respectively. Metabolomics showed 48 metabolites associated with incident T2D after adjusting for sex, age and BMI, whereas a total of 244 metabolites were associated with prevalent T2D. A total of 34 metabolites were associated with the progression of T2D. In data driven logistic regression, novel biomarkers, such as cinnamoylglycine or 1-methylurate, being protective of T2D were identified. The incident T2D risk prediction model (HUNT) predicted well incident Lifelines cases (AUC = 0.845; 95% CI: 0.72, 0.97).
Such exposome-based approaches in cohort-nested studies are warranted to better understand the environmental origins of diabetogenesis.
KeywordsType 2 diabetes Metabolomics Disinfection byproducts Trihalomethanes HUNT Lifelines LASSO Brominated disinfection byproducts
Type 2 diabetes
Finnish diabetes risk score
High density lipoprotein
Least absolute shrinkage and selection operator
Limit of detection
Limit of quantification
This research was funded by a Biobanking and Biomolecular Resources Research Infrastructure -Large prospective cohort (BBMRI-LPC) grant given to Dr. K.C. Makris. The research leading to these results has received funding from the European Union Seventh Framework Programme (FP7/2007–2013) under Grant Agreement No 313010 (BBMRI-LPC). We would like to thank the Lifelines Biobank initiative, which has been made possible by funds from FESS (Fonds Economische Structuurversterking), SNN (Samenwerkingsverband Noord Nederland) and REP (Ruimtelijk Economisch Programma). The Lifelines Cohort Study is supported by the Netherlands Organization of Scientific Research NWO (Grant 175.010.2007.006), the Ministry of Economic Affairs, the Ministry of Education, Culture and Science, the Ministry for Health, Welfare and Sports, the Northern Netherlands Collaboration of Provinces (SNN), The Province of Groningen, University Medical Center Groningen, the University of Groningen, Dutch Kidney Foundation and Dutch Diabetes Research Foundation. We would also like to thank the The Nord-Trøndelag Health Study (The HUNT Study), which is a collaboration between HUNT Research Centre (Faculty of Medicine, Norwegian University of Science and Technology NTNU), Nord-Trøndelag County Council, Central Norway Health Authority, and the Norwegian Institute of Public Health. J.V. van Vliet-Ostaptchouk was supported by a Diabetes Funds Junior Fellowship from the Dutch Diabetes Research Foundation (Project No. 2013.81.1673).
KCM conceived and designed the study. KCM, EPS, JvVO and JB acquired the cohort data. SG and MW, AA and JA acquired biomarker and metabolomics data. SG and KCM undertook the statistical analyses. All authors were involved in data interpretation. SG wrote the initial draft of the manuscript. These drafts were revised for important scientific content by all authors. All authors gave final approval of the version to be published. KCM is the guarantor of this work.
Compliance with ethical standards
Conflict of interest
The authors declare they have no conflict of interest.
Human and animal rights
The respective bioethics committees of the University Medical Center Groningen (UMCG), the Netherlands, and the Regional Committee for Ethics in Medical Research in Norway approved this study.
Informed consent was obtained for all participants.
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