Feasibility Study of 2000 IU Per Day of Vitamin D for the Primary Prevention of Type 1 Diabetes
Feasibility Study of 2000 IU Per Day of Vitamin D for the Primary Prevention of Type 1 Diabetes
Type 1 diabetes is a common chronic disease of childhood. It is not yet preventable. Multiple
 daily injections of insulin, tests of blood sugar, and careful dietary planning are required
 lifelong to prevent long-term complications such as blindness and kidney failure. Recent
 studies of potential risk factors in children with diabetes, along with studies revealing the
 immunologic properties of vitamin D, and experiments in animals suggest higher doses of
 vitamin D may prevent type 1 diabetes. For proof for human children, a randomized trial will
 compare groups at risk randomly assigned to receive either the usual vitamin D supplement or
 a higher amount, 2000 IU daily. This initial study is a small scale test of procedures.
Type 1 diabetes is a multifactorial disease with both strong genetic and non-genetic
 components of disease susceptibility. The uniquely strong genetic risk factor region, the
 human leukocyte antigen region on chromosome 6p, contributes approximately half of the
 genetic component and can be used for screening for diabetes risk. For example, individuals
 with the highest risk compound heterozygote genotype comprise 2% of the general population,
 but have a twenty fold increased risk for type 1 diabetes with an absolute risk of
 approximately 7% by age 15 years.

 Studies of the non-inherited component of diabetes susceptibility implicate external
 environmental factors operating in the first year of life, suggesting the possibility to
 reverse the trend with the correct intervention. Recent data suggest that the vitamin D
 system is a potentially important target for therapeutic intervention to prevent type 1
 diabetes. These data include epidemiological studies showing that vitamin D supplementation
 in infancy is associated with a substantially decreased subsequent risk of the disease, and
 animal work in the non-obese diabetes mouse model of autoimmune diabetes showing that the
 incidence of autoimmune diabetes increases when the animals are nutritionally deprived of
 vitamin D, and that the disease can be prevented using 1,25-dihydroxyvitamin D, and
 non-hypercalcemic vitamin D analogues. In vitro experiments suggest that the prevention seen
 in NOD mice may be due to combined effects of vitamin D on antigen presenting cells and
 activated T-cells.

 Based on these epidemiological and animal model studies, we hypothesize that administration
 during infancy of cholecalciferol, the usual nutritional supplement form of vitamin D, at the
 increased dose of 2000 IU/day (instead of the current practice of 400 IU/day) will prevent
 type 1 diabetes in children from the general population at increased genetic risk.

 The main objective of this proposal is to pilot a two-arm randomized controlled trial
 comparing these two doses. The participants are infants from the general population
 identified at increased genetic risk for type 1 diabetes by cord blood or filter paper blood
 spot HLA class II genetic screening. The study will measure key safety, compliance and
 pharmacokinetic, surrogate efficacy, and process outcomes including growth parameters,
 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels, calcium levels in blood and urine,
 bone mineral content and body composition by densitometry, diabetes-related autoantibodies
 markers for beta-cell autoimmunity, and recruitment rates for both the screening and for the
 intervention trial.
Inclusion Criteria:

 -  HLA genotypes that increase risk of type 1 diabetes: heterozygous for DRB1*03,
 DQA1*0501, DQB1*0201 / DRB1*04, DQA1*03011, DQB1*0302 (DRB1*04 ≠ *0403 or related
 alleles), or homozygous for DRB1*03, DQA1*0501, DQB1*0201, or homozygous for DRB1*04,
 DQA1*03011, DQB1*0302 (DRB1*04 ≠ *0403 or related alleles).

 Exclusion Criteria:

 -  Premature, low birthweight, or major congenital malformations or serious chronic
 disease