Association of plasma Vitamin D metabolites with incident type 2 diabetes: EPIC-InterAct case-cohort study

Ju Sheng Zheng*, Fumiaki Imamura, Stephen J. Sharp, Yvonne T. Van Der Schouw, Ivonne Sluijs, Thomas E. Gundersen, Eva Ardanaz, Heiner Boeing, Catalina Bonet, Jesus Humberto Gómez, Courtney Dow, Guy Fagherazzi, Paul W. Franks, Mazda Jenab, Tilman Kuhn, Rudolf Kaaks, Timothy J. Key, Kay Tee Khaw, Cristina Lasheras, Olatz MokoroaFrancesca Romana Mancini, Peter M. Nilsson, Kim Overvad, Salvatore Panico, Domenico Palli, Olov Rolandsson, Sabina Sieri, Elena Salamanca-Fernández, Carlotta Sacerdote, Annemieke M.W. Spijkerman, Magdalena Stepien, Anne Tjonneland, Rosario Tumino, Adam S. Butterworth, Elio Riboli, John Danesh, Claudia Langenberg, Nita G. Forouhi, Nicholas J. Wareham

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

25 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)1293-1303
Number of pages11
JournalJournal of Clinical Endocrinology and Metabolism
Issue number4
Publication statusPublished - 1 Apr 2019
Externally publishedYes


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