Plasma 25-hydroxyvitamin D and its genetic determinants in relation to incident type 2 diabetes: a prospective case-cohort study
Rent the article at a discountRent now
* Final gross prices may vary according to local VAT.Get Access
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.
- Johnson, JA, Grande, JP, Roche, PC, Kumar, R (1994) Immunohistochemical localization of the 1,25(OH)2D3 receptor and calbindin D28 k in human and rat pancreas. Am J Physiol 267: pp. E356-E360
- Bland, R, Markovic, D, Hills, CE (2004) Expression of 25-hydroxyvitamin D3-1alpha-hydroxylase in pancreatic islets. J Steroid Biochem Mol Biol 89–90: pp. 121-125 CrossRef
- Norman, AW, Frankel, JB, Heldt, AM, Grodsky, GM (1980) Vitamin D deficiency inhibits pancreatic secretion of insulin. Science 209: pp. 823-825 CrossRef
- Cade, C, Norman, AW (1986) Vitamin D3 improves impaired glucose tolerance and insulin secretion in the vitamin D-deficient rat in vivo. Endocrinology 119: pp. 84-90 CrossRef
- Nyomba, BL, Bouillon, R, Moor, P (1984) Influence of vitamin D status on insulin secretion and glucose tolerance in the rabbit. Endocrinology 115: pp. 191-197 CrossRef
- Maestro, B, Campion, J, Davila, N, Calle, C (2000) Stimulation by 1,25-dihydroxyvitamin D3 of insulin receptor expression and insulin responsiveness for glucose transport in U-937 human promonocytic cells. Endocr J 47: pp. 383-391 CrossRef
- Alvarez, JA, Ashraf, A (2009) Role of vitamin d in insulin secretion and insulin sensitivity for glucose homeostasis. Int J Endocrinol. 2010: pp. 351385
- Davidson, MB, Duran, P, Lee, ML, Friedman, TC (2013) High-dose vitamin D supplementation in people with prediabetes and hypovitaminosis D. Diabetes Care 36: pp. 260-266 CrossRef
- Mitri, J, Muraru, MD, Pittas, AG (2011) Vitamin D and type 2 diabetes: a systematic review. Eur J Clin Nutr 65: pp. 1005-1015 CrossRef
- Forouhi, NG, Ye, Z, Rickard, AP (2012) 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 55: pp. 2173-2182 CrossRef
- 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.
- Khan, H, Kunutsor, S, Franco, OH, Chowdhury, R (2013) Vitamin D, type 2 diabetes and other metabolic outcomes: a systematic review and meta-analysis of prospective studies. Proc Nutr Soc 72: pp. 89-97 CrossRef
- Riboli, E, Hunt, KJ, Slimani, N (2002) European Prospective Investigation into Cancer and Nutrition (EPIC): study populations and data collection. Public Health Nutr 5: pp. 1113-1124 CrossRef
- World Climate Guide. Germany Climate Guides. Source: http://www.worldclimateguide.co.uk/climateguides/germany/ (Accessed January 2, 2013).
- 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.
- Wang, TJ, Zhang, F, Richards, JB (2010) Common genetic determinants of vitamin D insufficiency: a genome-wide association study. Lancet 376: pp. 180-188 CrossRef
- Ahn, J, Yu, K, Stolzenberg-Solomon, R (2010) Genome-wide association study of circulating vitamin D levels. Hum Mol Genet 19: pp. 2739-2745 CrossRef
- Hypponen, E, Berry, DJ, Wjst, M, Power, C (2009) Serum 25-hydroxyvitamin D and IgE—a significant but nonlinear relationship. Allergy 64: pp. 613-620 CrossRef
- Wie wird ein Vitamin-D-Mangel festgestellt? Robert Koch Institute. Source:http://www.rki.de/SharedDocs/FAQ/vitamind3/vitamind3.html. (Accessed January 31, 2013).
- Royston, P, Sauerbrei, W (2008) Multivariable model-builing: a pragmatic approach to regression analysis based on fractional polynomials for modelling continuous variables. Wiley, Chichester
- Berry, DJ, Vimaleswaran, KS, Whittaker, JC, Hingorani, AD, Hypponen, E (2012) Evaluation of genetic markers as instruments for mendelian randomization studies on vitamin D. PLoS ONE 7: pp. e37465 CrossRef
- Pierce, BL, Ahsan, H, Vanderweele, TJ (2011) Power and instrument strength requirements for Mendelian randomization studies using multiple genetic variants. Int J Epidemiol 40: pp. 740-752 CrossRef
- Boer, IH, Tinker, LF, Connelly, S (2008) Calcium plus vitamin D supplementation and the risk of incident diabetes in the Women’s Health Initiative. Diabetes Care 31: pp. 701-707 CrossRef
- Pittas, AG, Harris, SS, Stark, PC, Dawson-Hughes, B (2007) The effects of calcium and vitamin D supplementation on blood glucose and markers of inflammation in nondiabetic adults. Diabetes Care 30: pp. 980-986 CrossRef
- Gagnon, C, Lu, ZX, Magliano, DJ (2011) 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 34: pp. 1133-1138 CrossRef
- Thorand, B, Zierer, A, Huth, C (2011) 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 34: pp. 2320-2322 CrossRef
- 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.
- 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.
- 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.
- Plasma 25-hydroxyvitamin D and its genetic determinants in relation to incident type 2 diabetes: a prospective case-cohort study
European Journal of Epidemiology
Volume 28, Issue 9 , pp 743-752
- Cover Date
- Print ISSN
- Online ISSN
- Springer Netherlands
- Additional Links
- Vitamin D
- Type 2 diabetes
- Single-nucleotide polymorphism
- Prospective study
- Industry Sectors
- Author Affiliations
- 1. Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Arthur-Scheunert-Allee 114-116, 14558, Nuthetal, Germany
- 3. Institute of Agricultural and Nutritional Sciences, Human Nutrition, Martin-Luther-University Halle-Wittenberg, Halle, Germany
- 2. Department of Molecular Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, Germany
- 5. Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany
- 4. Department of Clinical Medicine, University of Bergen, Bergen, Norway