Dietary Supplementation With High Doses of Regular Vitamin D3 Safely Reduces Diabetes Incidence in NOD Mice When Given Early and Long Term

High doses of the active form of vitamin D-3, 1,25-dihydroxyvitamin D-3 [1,25(OH)2133], prevent diabetes in the NOD mouse but also elicit unwanted calcemic side effects. Because immune cells themselves can convert vitamin D-3 into 1,25(OH)(2)D-3 locally, we hypothesized that dietary vitamin D-3 can also prevent disease. Thus, we evaluated whether dietary administration of high doses of regular vitamin D-3 (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 D-3 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 D-3 correlated with preserved pancreatic insulin content and improved insulitis scores. Moreover, vitamin D-3 treatment decreased interferon-gamma-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 D-3 can safely prevent diabetes in NOD mice when administered lifelong, although caution is warranted with regards to administering equivalently high doses in humans.