Feasibility Study of 2000 IU Per Day of Vitamin D for the Primary Prevention of Type 1 Diabetes

• change in 25(OH)D from baseline [ Time Frame: at baseline (1 month of age), 2 months of age, 6 months of age, 9 months of age, 1 year of age ] [ Designated as safety issue: Yes ]
  25-hydroxyvitamin D levels
  
  

• renal ultrasound [ Time Frame: 1 year of age ] [ Designated as safety issue: Yes ]
  to detect nephrocalcinosis
  
  
• bone densitometry [ Time Frame: at 6 months and 1 year of age ] [ Designated as safety issue: No ]
  
• diabetes autoantibody levels [ Time Frame: 1 year of age ] [ Designated as safety issue: No ]
  GADA, ICA-512, IAA
  
  
• recruitment and retention rates [ Time Frame: 1 year of age ] [ Designated as safety issue: No ]
  
• Change from baseline in serum calcium levels [ Time Frame: at baseline (1 month of age), 2 months of age, 6 months of age, 9 months of age, 1 year of age ] [ Designated as safety issue: Yes ]
  
• changes in urine calcium:creatinine ratio [ Time Frame: monthly in the first year of life ] [ Designated as safety issue: Yes ]
  

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.