title: Dietary supplementation with high doses of regular vitamin D3 safely reduces diabetes incidence in NOD mice when given early and long term.
abstract: High doses of the active form of vitamin D3, 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], prevent diabetes in the NOD mouse but also elicit unwanted calcemic side effects. Because immune cells themselves can convert vitamin D3 into 1,25(OH)2D3 locally, we hypothesized that dietary vitamin D3 can also prevent disease. Thus, we evaluated whether dietary administration of high doses of regular vitamin D3 (800 IU/day) during different periods of life (pregnancy and lactation, early life [3-14 weeks of age], or lifelong [3-35 weeks of age]) safely prevents diabetes in NOD mice. We found that only lifelong treatment raised serum 25-hydroxyvitamin D3 from 173 nmol/L in controls to 290 nmol/L, without inducing signs of calcemic or bone toxicity, and significantly reduced diabetes development in both male and female NOD mice. This diabetes protection by vitamin D3 correlated with preserved pancreatic insulin content and improved insulitis scores. Moreover, vitamin D3 treatment decreased interferon-γ-positive CD8(+) T cells and increased CD4(+)(CD25(+))FoxP3(+) T cells in pancreatic draining lymph nodes. In conclusion, this study shows for the first time that high doses of regular dietary vitamin D3 can safely prevent diabetes in NOD mice when administered lifelong, although caution is warranted with regards to administering equivalently high doses in humans.
authors.affiliation: Clinical and Experimental Endocrinology (CEE), Department of Clinical and Experimental Medicine, Katholieke Universiteit Leuven, Campus Gasthuisberg, Leuven, Belgium.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Takiishi
authors.affiliation: Clinical and Experimental Endocrinology (CEE), Department of Clinical and Experimental Medicine, Katholieke Universiteit Leuven, Campus Gasthuisberg, Leuven, Belgium.
authors.forename: Lei
authors.initials: L
authors.lastname: Ding
authors.affiliation: Clinical and Experimental Endocrinology (CEE), Department of Clinical and Experimental Medicine, Katholieke Universiteit Leuven, Campus Gasthuisberg, Leuven, Belgium.
authors.forename: Femke
authors.initials: F
authors.lastname: Baeke
authors.affiliation: Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena and Fondazione Umberto Di Mario Organizzazione Non Lucrativa di Utilità Sociale, Siena, Italy.
authors.forename: Isabella
authors.initials: I
authors.lastname: Spagnuolo
authors.affiliation: Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena and Fondazione Umberto Di Mario Organizzazione Non Lucrativa di Utilità Sociale, Siena, Italy.
authors.forename: Guido
authors.initials: G
authors.lastname: Sebastiani
authors.affiliation: Clinical and Experimental Endocrinology (CEE), Department of Clinical and Experimental Medicine, Katholieke Universiteit Leuven, Campus Gasthuisberg, Leuven, Belgium.
authors.forename: Jos
authors.initials: J
authors.lastname: Laureys
authors.affiliation: Clinical and Experimental Endocrinology (CEE), Department of Clinical and Experimental Medicine, Katholieke Universiteit Leuven, Campus Gasthuisberg, Leuven, Belgium.
authors.forename: Annemieke
authors.initials: A
authors.lastname: Verstuyf
authors.affiliation: Clinical and Experimental Endocrinology (CEE), Department of Clinical and Experimental Medicine, Katholieke Universiteit Leuven, Campus Gasthuisberg, Leuven, Belgium.
authors.forename: Geert
authors.initials: G
authors.lastname: Carmeliet
authors.affiliation: Diabetes Unit, Department of Medicine, Surgery and Neurosciences, University of Siena and Fondazione Umberto Di Mario Organizzazione Non Lucrativa di Utilità Sociale, Siena, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Dotta
authors.affiliation: Clinical and Experimental Endocrinology (CEE), Department of Clinical and Experimental Medicine, Katholieke Universiteit Leuven, Campus Gasthuisberg, Leuven, Belgium.
authors.forename: Tom L
authors.initials: TL
authors.lastname: Van Belle
authors.affiliation: Clinical and Experimental Endocrinology (CEE), Department of Clinical and Experimental Medicine, Katholieke Universiteit Leuven, Campus Gasthuisberg, Leuven, Belgium.
authors.forename: Conny A
authors.initials: CA
authors.lastname: Gysemans
authors.affiliation: Clinical and Experimental Endocrinology (CEE), Department of Clinical and Experimental Medicine, Katholieke Universiteit Leuven, Campus Gasthuisberg, Leuven, Belgium chantal.mathieu@uzleuven.be.
authors.forename: Chantal
authors.initials: C
authors.lastname: Mathieu
mesh_terms: D000818:Animals; D002762:Cholecalciferol / Q000008:administration & dosage* / Q000494:pharmacology*; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000517:prevention & control*; D019587:Dietary Supplements; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D016219:Immunotherapy, Adoptive; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects; D013997:Time Factors; D014815:Vitamins / Q000008:administration & dosage* / Q000494:pharmacology*
chemical_list: D014815:Vitamins; D002762:Cholecalciferol