European Journal of Epidemiology

, Volume 28, Issue 9, pp 743–752

Plasma 25-hydroxyvitamin D and its genetic determinants in relation to incident type 2 diabetes: a prospective case-cohort study

  • Brian Buijsse
  • Heiner Boeing
  • Frank Hirche
  • Cornelia Weikert
  • Matthias B. Schulze
  • Marion Gottschald
  • Tilman Kühn
  • Verena A. Katzke
  • Birgit Teucher
  • Jutta Dierkes
  • Gabriele I. Stangl
  • Rudolf Kaaks


It is unclear whether vitamin D lowers risk of type 2 diabetes (T2D). In an observational study, we assessed the prospective association between plasma 25-hydroxyvitamin D (25(OH)D) and incident T2D, and evaluated whether it holds up for genetically determined elevated 25(OH)D. We used a case-cohort study nested within the German arm of the European Prospective Investigation into Cancer. From a total cohort of 53,088 participants with a mean follow-up of 6.6 years, we identified a random subcohort of 2,121 participants (57 % women) and 1,572 incident cases of T2D. 25(OH)D was measured in baseline plasma samples retrieved from frozen storage. Mean plasma 25(OH)D in the subcohort was 47.1 (5th–95th percentile 19.6–80.7) nmol/L. After controlling for age, sex, center, season of blood draw, education, and lifestyle, the hazard of T2D decreased across increasing plasma concentrations of 25(OH)D (P linear trend <0.0001). The association became non-linear after adjustment for BMI and waist circumference (P non-linearity <0.0001), with the inverse association being restricted to participants with 25(OH)D concentrations below ~45 nmol/L (hazard ratio per 5 nmol/L higher 25(OH)D 0.91, 95 % CI 0.84–0.98). A score predicting genetically determined plasma 25(OH)D by weighting four independent single-nucleotide polymorphisms by their effect on 25(OH)D, explained 3.7 % of the variance in 25(OH)D. The hazard ratio (95 % CI) per 5 nmol/L higher genetically predicted 25(OH)D was 0.98 (0.89–1.08) in the entire study sample and 1.06 (0.93–1.21) in the sub-sample with 25(OH)D <45 nmol/L. This latter finding casts doubt on a strong causal association of 25(OH)D with T2D, but further research in large-scale consortia is needed.


Vitamin D Type 2 diabetes Single-nucleotide polymorphism Prospective study 

Supplementary material

10654_2013_9844_MOESM1_ESM.doc (56 kb)
Online Resources 1 and 3(DOC 56 kb)
10654_2013_9844_MOESM2_ESM.bmp (2.2 mb)
Online Resource 2Seasonal variation in plasma 25(OH)D during the baseline measurement of participants in the subcohort of the EPIC-Germany Study. For clarity, two 25(OH)D values above 200 nmol/L were omitted from the figure. (BMP 2269 kb)


  1. 1.
    Johnson JA, Grande JP, Roche PC, Kumar R. Immunohistochemical localization of the 1,25(OH)2D3 receptor and calbindin D28 k in human and rat pancreas. Am J Physiol. 1994;267(3 Pt 1):E356–60.PubMedGoogle Scholar
  2. 2.
    Bland R, Markovic D, Hills CE, et al. Expression of 25-hydroxyvitamin D3-1alpha-hydroxylase in pancreatic islets. J Steroid Biochem Mol Biol. 2004;89–90(1–5):121–5.PubMedCrossRefGoogle Scholar
  3. 3.
    Norman AW, Frankel JB, Heldt AM, Grodsky GM. Vitamin D deficiency inhibits pancreatic secretion of insulin. Science. 1980;209(4458):823–5.PubMedCrossRefGoogle Scholar
  4. 4.
    Cade C, Norman AW. Vitamin D3 improves impaired glucose tolerance and insulin secretion in the vitamin D-deficient rat in vivo. Endocrinology. 1986;119(1):84–90.PubMedCrossRefGoogle Scholar
  5. 5.
    Nyomba BL, Bouillon R, De Moor P. Influence of vitamin D status on insulin secretion and glucose tolerance in the rabbit. Endocrinology. 1984;115(1):191–7.PubMedCrossRefGoogle Scholar
  6. 6.
    Maestro B, Campion J, Davila N, Calle C. Stimulation by 1,25-dihydroxyvitamin D3 of insulin receptor expression and insulin responsiveness for glucose transport in U-937 human promonocytic cells. Endocr J. 2000;47(4):383–91.PubMedCrossRefGoogle Scholar
  7. 7.
    Alvarez JA, Ashraf A. Role of vitamin d in insulin secretion and insulin sensitivity for glucose homeostasis. Int J Endocrinol. 2009;2010:351385.Google Scholar
  8. 8.
    Davidson MB, Duran P, Lee ML, Friedman TC. High-dose vitamin D supplementation in people with prediabetes and hypovitaminosis D. Diabetes Care. 2013;36:260–6.PubMedCrossRefGoogle Scholar
  9. 9.
    Mitri J, Muraru MD, Pittas AG. Vitamin D and type 2 diabetes: a systematic review. Eur J Clin Nutr. 2011;65(9):1005–15.PubMedCrossRefGoogle Scholar
  10. 10.
    Forouhi NG, Ye Z, Rickard AP, et al. Circulating 25-hydroxyvitamin D concentration and the risk of type 2 diabetes: results from the European Prospective Investigation into Cancer (EPIC)-Norfolk cohort and updated meta-analysis of prospective studies. Diabetologia. 2012;55(8):2173–82.PubMedCrossRefGoogle Scholar
  11. 11.
    Afzal S, Bojesen SE, Nordestgaard BG. Low 25-Hydroxyvitamin D and Risk of Type 2 Diabetes: A Prospective Cohort Study and Meta-analysis. Clin Chem. 2012;59(2):381–91.Google Scholar
  12. 12.
    Khan H, Kunutsor S, Franco OH, Chowdhury R. Vitamin D, type 2 diabetes and other metabolic outcomes: a systematic review and meta-analysis of prospective studies. Proc Nutr Soc. 2013;72(1):89–97. doi:10.1017/S0029665112002765.PubMedCrossRefGoogle Scholar
  13. 13.
    Riboli E, Hunt KJ, Slimani N, et al. European Prospective Investigation into Cancer and Nutrition (EPIC): study populations and data collection. Public Health Nutr. 2002;5(6B):1113–24.PubMedCrossRefGoogle Scholar
  14. 14.
    World Climate Guide. Germany Climate Guides. Source: (Accessed January 2, 2013).
  15. 15.
    di Giuseppe R, Hirche F, Montonen J, et al. Reliability of plasma fibroblast growth factor 23 as risk biomarker in epidemiological studies measured over a four-month period. Ann Clin Biochem. 2012;49(Pt 6):542-5.Google Scholar
  16. 16.
    Wang TJ, Zhang F, Richards JB, et al. Common genetic determinants of vitamin D insufficiency: a genome-wide association study. Lancet. 2010;376(9736):180–8.PubMedCrossRefGoogle Scholar
  17. 17.
    Ahn J, Yu K, Stolzenberg-Solomon R, et al. Genome-wide association study of circulating vitamin D levels. Hum Mol Genet. 2010;19(13):2739–45.PubMedCrossRefGoogle Scholar
  18. 18.
    Hypponen E, Berry DJ, Wjst M, Power C. Serum 25-hydroxyvitamin D and IgE—a significant but nonlinear relationship. Allergy. 2009;64(4):613–20.PubMedCrossRefGoogle Scholar
  19. 19.
    Wie wird ein Vitamin-D-Mangel festgestellt? Robert Koch Institute. Source: (Accessed January 31, 2013).
  20. 20.
    Royston P, Sauerbrei W. Multivariable model-builing: a pragmatic approach to regression analysis based on fractional polynomials for modelling continuous variables. Chichester: Wiley; 2008.Google Scholar
  21. 21.
    Berry DJ, Vimaleswaran KS, Whittaker JC, Hingorani AD, Hypponen E. Evaluation of genetic markers as instruments for mendelian randomization studies on vitamin D. PLoS ONE. 2012;7(5):e37465.PubMedCrossRefGoogle Scholar
  22. 22.
    Pierce BL, Ahsan H, Vanderweele TJ. Power and instrument strength requirements for Mendelian randomization studies using multiple genetic variants. Int J Epidemiol. 2011;40(3):740–52. doi:10.1093/ije/dyq151.PubMedCrossRefGoogle Scholar
  23. 23.
    de Boer IH, Tinker LF, Connelly S, et al. Calcium plus vitamin D supplementation and the risk of incident diabetes in the Women’s Health Initiative. Diabetes Care. 2008;31(4):701–7.PubMedCrossRefGoogle Scholar
  24. 24.
    Pittas AG, Harris SS, Stark PC, Dawson-Hughes B. The effects of calcium and vitamin D supplementation on blood glucose and markers of inflammation in nondiabetic adults. Diabetes Care. 2007;30(4):980–6.PubMedCrossRefGoogle Scholar
  25. 25.
    Gagnon C, Lu ZX, Magliano DJ, et al. Serum 25-hydroxyvitamin D, calcium intake, and risk of type 2 diabetes after 5 years: results from a national, population-based prospective study (the Australian Diabetes, Obesity and Lifestyle study). Diabetes Care. 2011;34(5):1133–8.PubMedCrossRefGoogle Scholar
  26. 26.
    Thorand B, Zierer A, Huth C, et al. Effect of serum 25-hydroxyvitamin D on risk for type 2 diabetes may be partially mediated by subclinical inflammation: results from the MONICA/KORA Augsburg study. Diabetes Care. 2011;34(10):2320–2.PubMedCrossRefGoogle Scholar
  27. 27.
    Husemoen LL, Skaaby T, Thuesen BH, Jorgensen T, Fenger RV, Linneberg A. Serum 25(OH)D and incident type 2 diabetes: a cohort study. Eur J Clin Nutr. 2012;66(12):1309–14. Google Scholar
  28. 28.
    Schottker B, Herder C, Rothenbacher D, Perna L, Muller H, Brenner H. Serum 25-hydroxyvitamin D levels and incident diabetes mellitus type 2: a competing risk analysis in a large population-based cohort of older adults. Eur J Epidemiol. 2013. doi 10.1007/s10654-013-9769-z.
  29. 29.
    Jorde R, Schirmer H, Wilsgaard T, et al. Polymorphisms related to the serum 25-hydroxyvitamin D level and risk of myocardial infarction, diabetes, cancer and mortality. The Tromso Study. PLoS ONE. 2012;7(5):e37295.Google Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2013

Authors and Affiliations

  • Brian Buijsse
    • 1
  • Heiner Boeing
    • 1
  • Frank Hirche
    • 3
  • Cornelia Weikert
    • 1
  • Matthias B. Schulze
    • 2
  • Marion Gottschald
    • 1
  • Tilman Kühn
    • 5
  • Verena A. Katzke
    • 5
  • Birgit Teucher
    • 5
  • Jutta Dierkes
    • 4
  • Gabriele I. Stangl
    • 3
  • Rudolf Kaaks
    • 5
  1. 1.Department of EpidemiologyGerman Institute of Human Nutrition Potsdam-RehbrueckeNuthetalGermany
  2. 2.Department of Molecular EpidemiologyGerman Institute of Human Nutrition Potsdam-RehbrueckeNuthetalGermany
  3. 3.Institute of Agricultural and Nutritional Sciences, Human NutritionMartin-Luther-University Halle-WittenbergHalleGermany
  4. 4.Department of Clinical MedicineUniversity of BergenBergenNorway
  5. 5.Division of Cancer EpidemiologyGerman Cancer Research CenterHeidelbergGermany

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