Vitamin D in the prevention of type 1 diabetes: would increasing food fortiﬁcation reduce the incidence?
Keywords:type 1 diabetes, vitamin D, food supplements
This paper reviews data regarding the role of vitamin D in the genesis of type 1 diabetes (T1DM) and considers the hypothesis that vitamin D deﬁciency increases the incidence rate of T1DM. Vitamin D has actions on immune cells that would suppress autoimmunity with preservation of anti- infective actions. Geographical latitude and both season of diagnosis and of birth affect case numbers, most likely via the effect of UVB sunlight on vitamin D synthesis. Other factors, such as seasonal viral infections, may be important. Serum concentrations of 25(OH) vitamin D have mostly been found to be lower with diagnosis of T1DM.
Vitamin D deﬁciency is common, particularly in the UK. From data on vitamin D concentrations in non-diabetic controls in mostly southerly nations this review estimates the population mean serum 25(OH)D concentration associated with low T1DM incidence to be >80 nmol/l. Achieving this in Britain would require supplementing current intake with 1500-2000 IU vitamin D daily. Increased food fortiﬁcation would be the most effective method. An estimate based on the limited data available suggests this might generate a 25-30% reduction in the incidence of T1DM.
Infante M, Ricordi C, Sanchez J, et al. inﬂuence of vitamin D in islet autoimmunity and beta-cell function in type 1 diabetes. Nutrients 2019;11: 2185. https://doi.org/10.3390/nu11092185
Altieri B, Muscogiuri G, Barrea L, et al. Does vitamin D play a role in autoimmune endocrine disorders? A proof of concept. Rev Endocr Metab Disord 2017;18:335-46. https://doi.org/10.1007/s11154-016-9405-9
Rak K, Bronkowska M. Immunomodulatory effect of vitamin D and its potential role in the prevention and treatment of type 1 diabetes mellitus- a narrative review. Molecules 2019;24:53. https://doi.org/10.3390/molecules24010053
Whitﬁeld GK, Remus LS, Jurutka PW, et al. Functionally relevant polymorphisms in the human nuclear vitamin D receptor gene. Mol Cell Endocrinol 2001;177:145-59. https://doi.org/10.1016/s0303-7207(01)00406-3
Kahles H, Morahan G, Todd JA, Badenhoop K. Association analysis of the vitamin D receptor gene in 1654 families with type 1 diabetes. Genes Immun 2009;10(Suppl 1):S60-3. https://doi.org/10.1038/gene.2009.93
Tizaoui K, Kaabachi W, Hamzaoui A, Hamzaoui K. Contribution of VDR polymorphisms to type 1 diabetes susceptibility: Systematic review of case- control studies and meta-analysis. J Steroid Biochem Mol Biol 2014;143: 240-9. Doi??
Norris JM, Lee HS, Frederiksen B, et al. Plasma 25-hydroxyvitamin D con- centration and risk of islet autoimmunity. Diabetes 2018;67:146-54. https://doi.org/10.2337/db17-0802
Blanton D, Han Z, Bierschenk L, et al. Reduced serum vitamin D binding protein levels are associated with type 1 diabetes. Diabetes 2011;60:2566-70. https://doi.org/10.2337/db11-0576
CooperJD, Smyth DJ, Walker NM, et al. Inherited variation in vitamin D genes is associated with predisposition to autoimmune disease Type 1 diabetes. Diabetes 2011;60:1624-31. https://doi.org/10.2337/db10-1656
Harvey JN, Hibbs R, Maguire MJ, et al. The changing incidence of childhood-onset type 1 diabetes in Wales: Effect of gender and season at diagnosis and birth. Diab Res Clin Prac 2021;175:108739. https://doi.org/10.1016/j.diabres.2021.108739
Moltchanova EV, Schreier N, Lammi N, Karvonen M. Seasonal variation of diagnosis of type 1 diabetes mellitus in children worldwide. Diabet Med 2009;26:673-8. https://doi.org/10.1111/j.1464-5491.2009.02743.x
Mohr SB, Garland CF, Gorham ED, Garland FC. The association between ultraviolet B irradiance, vitamin D status and incidence rates of type 1 diabetes in 51 regions worldwide. Diabetologia 2008;51:1391-8. https://doi.org/10.1007/s00125-008-1061-5
Jacobsen R, Moldovan M, Vaag AA, et al. Vitamin D fortiﬁcation and seasonality of birth in type 1 diabetic cases: D-tect study – ERRATUM. J Dev Orig Health Dis 2016;7:429. https://doi.org/10.1017/S2040174416000155
Bin-Abbas BS, Jabari MA, Issa SD, et al. Vitamin D levels in Saudi children with type 1 diabetes. Saudi Med J 2011;32:589-92.
Rasoul MA, Al-Mahdi M, Al-Kandan H, et al. Low serum vitamin-D status is associated with high prevalence and early onset of type-1 diabetes mellitus in Kuwaiti children. BMC Pediatr 2016;16:95. https://doi.org/10.118s12887-016-0629-3
Littorin B, Blom P, Scholin A, et al. Lower levels of plasma 25-hydroxyvita- min D among young adults at diagnosis of autoimmune type 1 diabetes compared with control subjects: Results from the nationwide diabetes incidence study in Sweden (DISS). Diabetologia 2006;49:2847-52. https://doi.org/10.1007/s00125-006-0426-x
Pozzilli P, Manfrini S, Crino A, et al. Low levels of 25-hydroxyvitamin D3 and 1,25-dihydroxyvitamin D3 in patients with newly diagnosed type 1 diabetes. Horm Metab Res 2005;37:680-3. https://doi.org/10.1055/s- 2005-870578
Federico G, Genoni A, Puggioni A, et al. Vitamin D status, enterovirus infection, and type 1 diabetes in Italian children/adolescents. Pediatr Diabetes 2018;19:923-9. https://doi.org/10.1111/pedi.12673
Greer RM, Portelli SM, Hung BSM, et al. Serum vitamin D levels are lower in Australian children and adolescents with type 1 diabetes than in children without diabetes. Pediatr Diabetes 2013;14:31-41. https://doi.org/10.1111/j.1399-5448.2012.00890.x
Borkar VV, Verma S, Bhalla AK. Low levels of vitamin D in north Indian children with newly diagnosed type 1 diabetes. Pediatr Diabetes 2010;11: 345-50. https://doi.org/10.1111/j.1399-5448.2009.00589.x
Gorham ED, Garland CF, Burgi AA, et al. Lower prediagnostic serum 25-hydroxyvitamin D concentration is associated with higher risk of insulin- requiring diabetes: A nested case-control study. Diabetologia 2012;55: 3224-7. https://doi.org/10.1007/s00125-012-2709-8
Munger KL, Levin LI, Massa J, et al. Preclinical serum 25-hydroxyvitamin D levels and risk of type diabetes in a cohort of US military personnel. Am J Epidemiol 2013;177:411-19. https://doi.org/10.1093/aje/kws243
Bener A, Alsaied A, Al-Ali M, et al. High prevalence of vitamin D deﬁciency in type 1 diabetes mellitus and healthy children. Acta Diabetol 2009;46: 183-9. https://doi.org/10.1007/s00592-008-0071-6
Reinart-Hartwall L, Honkanen J, Harkonen T, et al. No association between vitamin D and β-cell autoimmunity in Finnish and Estonian children. Diabet Metab Res Rev 2014;30:749-60. https://doi.org/10.1002/dmrr.2550
Makinen M, Mykkanen J, Koskinen M, et al. Serum 25-hydroxyvitamin D concentrations in children progressing to autoimmunity and clinical type 1 diabetes. J Clin Endocrinol Metab 2016;101:723-9. https://doi.org/10.1210/jc.2015-3504
Simpson M, Brady H, Yin X, et al. No association of vitamin D intake or 25-hydroxyvitamin D levels in childhood with risk of islet autoimmunity and type 1 diabetes: The diabetes autoimmunity study in the young (DAISY). Diabetologia 2011;54:2779-88. https://doi.org/10.1007/s00125-011-2278-2
Bierschenk L, Haller M, Alexander J, et al. Vitamin D levels in subjects with and without type 1 diabetes residing in a solar rich environment. Diabetes Care 2009;32:1977-9. https://doi.org/10.2337/dc09-1089
The Scientiﬁc Advisory Committee on Nutrition. SACN vitamin D and health report. July 2016. Available at https://www.gov.uk/government/publications/sacn-vitamin-d-and-health-report. Accessed December 2020
Schleicher RL, Sternberg MR, Lacher DA, et al. The vitamin D status of the US population from 1988 to 2010 using standardized serum concentrations of 25-hydroxyvitamin D shows recent modest increases. Am J Clin Nutr 2016;104:454-61. https://doi.org/10.3945/ajcn.115.127985
Fulgoni VL, Keast DR, Bailey RL, Dwyer J. Foods, fortiﬁcants, and supplements: where do Americans get their nutrients? J Nutr 2011;141:1847-54. https://doi.org/10.3945/jn.111.142257
Andersson B, Swolen-Eide D, Magnusson P, Albertsson-Wikland K. Vitamin D status in children over three decades – do children get enough vitamin D? Bone Reports 2016;5:150-2. https://doi.org/10.1016.j.bonr.2016.03.002
Nalsen C, Becker W, Pearson M, et al. Vitamin D status in children and adults in Sweden: dietary intake and 25-hydroxyvitamin D concentrations in children aged 10-12 years and adults aged 18-80 years. J Nutr Sci 2020; 9:e47. https://doi.org/10.1017/jns.2020.40
Hypponen E, Laara E, Reunanen A, et al. Intake of vitamin D and risk of type 1 diabetes: a birth-cohort study. Lancet 2001;358:1500-3. https://doi.org/10.1016/S0140-6736(01)06580-1
The EURODIAB Substudy 2 Study Group. Vitamin D supplement in early childhood and risk for type 1 (insulin dependent) diabetes mellitus. Diabetologia 1999;42:51-4. https://doi.org/10.1007/s001250051112
Stene LC, Joner G, Norwegian Childhood Diabetes Study Group. Use of cod liver oil during the ﬁrst year of life is associated with lower risk of child- hood-onset type 1 diabetes: a large, population-based, case-control study. Am J Clin Nutr 2003;78:1128-34. https://doi.org/10.1093/ajcn/78.6.1128
Stene LC, Ulriksen J, Magnus P, Joner G. Use of cod liver oil during pregnancy associated with lower risk of type 1 diabetes in the offspring. Diabetologia 2000;43:1093-8. https://doi.org/10.1007/s001250051499
Brekke HK, Ludvigsson J. Vitamin D supplementation and diabetes-related autoimmunity in the ABIS study. Pediatr Diabetes 2007;8:11-14. https://doi.org/10.1111/j.1399-5448.2006.00223.x
Fronzcak CM, Baron AE, Chase HP, et al. In utero dietary exposures and risk of islet autoimmunity in children. Diabetes Care 2003;26:3237-42. https://doi.org/10.2337/diacare.26.12.3237
Marjamaki L, Niinisto S, Kenward MG, et al. Maternal intake of vitamin D during pregnancy and risk of advanced beta cell autoimmunity and type 1 diabetes in offspring. Diabetologia 2010;53:1599-1607. https://doi.org/10.1007/s00125-010-1734-8
Sorensen IM, Joner G, Jenum PA, et al. Maternal serum levels of 25-hydroxy vitamin D during pregnancy and risk of type 1 diabetes in the offspring. Diabetes 2012;61:175-8. https://doi.org/10.2337/bd11-0875
McKinney PA, Parslow R, Gurney KA, et al. Perinatal and neonatal determinants of childhood type 1 diabetes. A case-control study in Yorkshire, UK. Diabetes Care 1999;22:928-32. https://doi.org/10.2337/diacare.22.6.928
Makinen M, Simell V, Mykkanen J, et al. An increase in serum 25-hydroxyvitamin D concentrations preceded a plateau in type 1 diabetes incidence in Finnish children. J Clin Endocrinol Metab 2014;99:E2353-6. https://doi.org/10.1210/jc.2014-1455
Jaaskelainen T, Itkonen ST, Lundqvist A, et al. The positive impact of general vitamin D food fortiﬁcation policy on vitamin D status in a representative adult Finnish population: evidence from an 11-y follow-up based on standardized 25-hydroxyvitamin D data. Am J Clin Nutr 2017;105:1512-20. https://doi.org/10.3945/ajcn.116.151415
Roche EF, McKenna AM, Ryder KJ, et al. Is the incidence of type 1 diabetes in children and adolescents stabilising? The ﬁrst six years of a national register. Eur J Paed 2016;175:1913-9. https://doi.org/10.1007/s00431-016-2787-6
Berhan Y, Waernbaum I, Lind T, et al. Swedish Childhood Diabetes Study Group. Thirty years of prospective nationwide incidence of childhood type 1 diabetes: the accelerating increase by time trends to level off in Sweden. Diabetes 2011;60:577-81. https://doi.org/10.2337/db10-0813
Skrivarhaug T, Stene LC, Drivvoll AK, et al. Norwegian Childhood Diabetes Study Group. Incidence of type 1 diabetes in Norway among children aged 0-14 years between 1989 and 2012: has the incidence stopped rising? Results from the Norwegian Childhood Diabetes Registry. Diabetologia 2014; 57:57-62. https://doi.org/10.1007/s00125-013-3090-y
Mayer-Davis EJ, Lawrence JM, Dabelea D, et al. Incidence trends of type 1 and type 2 diabetes among youths, 2002-2012. N Engl J Med 2017;376: 1419-29. https://doi.org/10.1056/NEJMoa1610187
IDF Diabetes Atlas 10th Edition. 2021. http://www.diabetesatlas.org. Accessed 30 April 2021.
Parviainen A, But A, Siljander H, Knip M. Decreased incidence of Type 1 diabetes in young Finnish children. Diabetes Care 2020;43:2953-8. https://doi.org/10.2337/dc20-0604
Zhang R, Naughton DP. Vitamin D in health and disease: Current perspectives. Nutr J 2010;9:65. https://doi.org/10.1186/1475-2891-9-65
Kazantzidis A, Smedley A, Kift R, et al. A modelling approach to determine how much UV radiation is available across the UK and Ireland for health risk and beneﬁt studies. Photochem Photobiol Sci 2015;14:1073-81. https://doi.org/10.1039/c5pp00008d
Bolland MJ, Avenell A, Smith, et al. Vitamin D supplementation and testing in the UK is costly, but is it effective? BMJ 2021;372:n484. https://doi.org/10.1136/bmj.n484
Holick MF, Binkley NC, Bischoff-Ferrari HA, et al. Evaluation, treatment and prevention of vitamin D deﬁciency: An Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2011;96:1911-30. https://doi.org/10.1210/jc.2011-0385
Pludowski P, Karzmarewicz E, Bayer M, et al. Practical guidelines for the supplementation of vitamin D and the treatment of deﬁcits in central Europe-recommended vitamin D intakes in general population and groups at risk of vitamin D deﬁciency. Endokrynol Pol 2013;64:319-27. https://doi.org/10.5603/EP.2013.0012
Rusinska A, Pludowski P, Walczak M, et al. Vitamin D supplementation guidelines for general population and groups at risk of vitamin D deﬁciency in Poland-recommendations of the Polish Society of paediatric endocrinology and diabetes and the expert panel with participation of national specialist consultants and representatives of scientiﬁc societies-2018 update. Front Endocrinol 2018;9:246. https://doi.org/10.3389/fendo.2018.00246
Pilz S, Marz W, Cashman KD, et al. Rationale and plan for vitamin D food fortiﬁcation: A review and guidance paper. Front Endocrinol 2018;9:373. https://doi.org/10.3389/fendo.2018.00373
Hahn J, Cook NR, Alexander EK, et al. Vitamin D and marine omega 3 fatty acid supplementation and incident autoimmune disease: VITAL randomized controlled trial. BMJ 2022;376:e066452. https://doi.org/10.1136/bmj-2021-066452
IOM (Institute of Medicine); Committee to Review Dietary Reference Intakes for Calcium and Vitamin D. Dietary Reference Intakes for Calcium and Vitamin D. National Academies Press: Washington DC, USA, 2011.
Maffeis C, Mancioppi V, Piona C, et al. Type 1 diabetes prevalence and incidence rates in the pediatric population of Veneto Region (Italy) in 2015- 2020. Diab Res Clin Prac 2021;179:109020. https://doi.org/10.1016/j.diabres.2021.109020
Haynes A, Bulsara MK, Bergman P, et al. Incidence of type 1 diabetes in 0-14 year olds in Australia from 2002-2017. Pediatr Diab 2020;21:707-12. https://doi.org/10.1111/pedi.13025
Publish & Transfer of Copyright Agreement
For the mutual benefit and protection of the Author and the Journal Owner/Publisher it is necessary that the Author provides formal written Consent to Publish and Transfer of Copyright before publication of the Work.