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J Clin Endocrinol Metab. 2019 Apr 1;104(4):1293-1303. doi: 10.1210/jc.2018-01522.

Association of Plasma Vitamin D Metabolites With Incident Type 2 Diabetes: EPIC-InterAct Case-Cohort Study.

Author information

1
Medical Research Council Epidemiology Unit, University of Cambridge, Cambridge, United Kingdom.
2
University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.
3
Vitas AS, Oslo, Norway.
4
Navarra Public Health Institute, Pamplona, Spain.
5
Navarra Institute for Health Research, Pamplona, Spain.
6
Biomedical Research Center Network of Epidemiology and Public Health, Madrid, Spain.
7
Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany.
8
Catalan Institute of Oncology-Bellvitge Biomedical Research Institute, Barcelona, Spain.
9
Department of Epidemiology, Murcia Regional Health Council, IMIB-Arrixaca, Murcia, Spain.
10
Center for Research in Epidemiology and Population Health, Faculty of Medicine - University Paris-South, Faculty of Medicine INSERM U1018, University Paris-Saclay, Villejuif, France.
11
Gustave Roussy, Université Paris-Sud, Université Paris-Saclay, Villejuif, France.
12
Department of Clinical Sciences, Lund University, Malmö, Sweden.
13
International Agency for Research on Cancer, Lyon, France.
14
Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany.
15
University of Oxford, Oxford, United Kingdom.
16
Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
17
Department of Functional Biology, Faculty of Medicine, University of Oviedo, Oviedo, Spain.
18
Public Health Division of Gipuzkoa, BioDonostia Research Institute, San Sebastian, Spain.
19
Department of Public Health, Section for Epidemiology, Aarhus University, Aarhus, Denmark.
20
Dipartimento di Medicina Clinica e Chirurgia, Federico II University, Naples, Italy.
21
Cancer Risk Factors and Life-Style Epidemiology Unit, Institute for Cancer Research, Prevention and Clinical Network, Florence, Italy.
22
Umeå University, Umeå, Sweden.
23
Epidemiology and Prevention Unit, Fondazione IRCSS Istituto Nazionale dei Tumori, Milan, Italy.
24
Escuela Andaluza de Salud Pública, Instituto de Investigación Biosanitaria ibs and Hospitales Universitarios de Granada/Universidad de Granada, Granada, Spain.
25
Unit of Cancer Epidemiology, Città della Salute e della Scienza Hospital-University of Turin and Center for Cancer Prevention, Torino, Italy.
26
National Institute for Public Health and the Environment, Bilthoven, Netherlands.
27
Danish Cancer Society Research Center, Copenhagen, Denmark.
28
Azienda Sanitaria Provinciale di Ragusa, Ragus, Italy.
29
Medical Research Council/ British Heart Foundation Cardiovascular Epidemiology Unit and NIHR Blood and Transplant Research Unit in Donor Health and Genomics, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
30
School of Public Health, Imperial College London, London, United Kingdom.
31
British Heart Foundation Cambridge Centre of Excellence, Division of Cardiovascular Medicine, Addenbrooke's Hospital, Cambridge, United Kingdom.
32
Department of Human Genetics, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom.

Abstract

BACKGROUND:

Existing evidence for the prospective association of vitamin D status with type 2 diabetes (T2D) is focused almost exclusively on circulating total 25-hydroxyvitamin D [25(OH)D] without distinction between its subtypes: nonepimeric and epimeric 25(OH)D3 stereoisomers, and 25(OH)D2, the minor component of 25(OH)D. We aimed to investigate the prospective associations of circulating levels of the sum and each of these three metabolites with incident T2D.

METHODS:

This analysis in the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct case-cohort study for T2D included 9671 incident T2D cases and 13,562 subcohort members. Plasma vitamin D metabolites were quantified by liquid chromatography-mass spectrometry. We used a multivariable Prentice-weighted Cox regression to estimate hazard ratios (HRs) of T2D for each metabolite. Analyses were performed separately within country, and estimates were combined across countries using random-effects meta-analysis.

RESULTS:

The mean concentrations (SD) of total 25(OH)D, nonepimeric 25(OH)D3, epimeric 25(OH)D3, and 25(OH)D2 were 41.1 (17.2), 40.7 (17.3), 2.13 (1.31), and 8.16 (6.52) nmol/L, respectively. Plasma total 25(OH)D and nonepimeric 25(OH)D3 were inversely associated with incident T2D [multivariable-adjusted HR per 1 SD = 0.81 (95% CI, 0.77, 0.86) for both variables], whereas epimeric 25(OH)D3 was positively associated [per 1 SD HR = 1.16 (1.09, 1.25)]. There was no statistically significant association with T2D for 25(OH)D2 [per 1 SD HR = 0.94 (0.76, 1.18)].

CONCLUSIONS:

Plasma nonepimeric 25(OH)D3 was inversely associated with incident T2D, consistent with it being the major metabolite contributing to total 25(OH)D. The positive association of the epimeric form of 25(OH)D3 with incident T2D provides novel information to assess the biological relevance of vitamin D epimerization and vitamin D subtypes in diabetes etiology.

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