Against this backdrop, better evidence is needed to understand if vitamin D insufficiency, which affects up to 40% of children and adolescents among different ethnicities, predisposes youth to early-onset T2D. A recent study from Iran demonstrated the cost-effectiveness of population-wide supplementation with 50,000 units of vitamin D monthly in youth to prevent T2D in adulthood. A meta-analysis of vitamin D randomized controlled trials (RCTs) in obese adolescents has shown an improvement in HOMA-IR, a marker of insulin resistance. The available evidence on the benefit of vitamin D supplementation in preventing T2D in adolescents with insulin resistance is contradictory. In a meta-analysis combining the results of the D2d trial with two other trials, vitamin D supplementation reduced the risk of developing T2D by up to 13% in participants who had prediabetes but were not necessarily vitamin D deficient. In the D2d trial, a daily dose of 4000 units of vitamin D showed a non-significant trend to delay the progression of prediabetes into T2D, but in post hoc analysis, a significant effect was found in overweight individuals with severe vitamin D deficiency at baseline, who displayed an increase in serum 25OHD. Many large randomized controlled trials have investigated a potential effect of vitamin D in adult T2D, with mostly negative results. Various studies suggest that vitamin D supplementation can reverse the progression of prediabetes, a condition present in up to 20% of adolescents, to overt type 2 diabetes. Case-control studies have demonstrated that adolescents with insulin resistance display lower levels of 25 hydroxyvitamin D (25OHD), the biomarker of vitamin D in humans, but this does not necessarily apply to pediatric patients with prediabetes or T2D. In conclusion, 25OHD levels are unlikely to have significant effects on the risk of youth-onset T2D across different ethnicities.ĭue to its potential immune-modulating and anti-inflammatory properties, vitamin D has been extensively studied as a biomarker for the autoimmune type 1 diabetes, but data on its role on youth-onset T2D are sparse. Our study had limited power to detect small/moderate effects of 25OHD (OR of pediatric T2D < 1.39 to 2.1). We found that a standard deviation increase in 25OHD in the logarithmic scale did not affect youth-onset T2D risk (IVW MR odds ratio (OR) = 1.04, 95% CI = 0.96–1.13, p = 0.35) in the multi-ethnic analysis, and sensitivity, ancestry-specific and multivariable MR analyses showed consistent results. Multivariable MR accounted for the mediating effects of body mass index. We undertook sensitivity analyses in ethnic sub-cohorts of PRODIGY, using SNPs in core vitamin D genes or ancestry-informed 25OHD SNPs. We applied inverse variance weighted (IVW) MR and a series of MR methods to control for pleiotropy. We selected 54 single-nucleotide polymorphisms (SNPs) associated with 25OHD in a European genome-wide association study (GWAS) on 443,734 individuals and obtained their effects on pediatric T2D from the multi-ethnic PRODIGY GWAS (3006 cases/6061 controls). We tested whether serum 25-hydroxyvitamin D (25OHD) levels are causally linked to youth-onset T2D risk using Mendelian randomization (MR). Given the rising prevalence of pediatric T2D in all ethnicities, determining the protective role of vitamin D has significant public health importance. Observational studies have linked vitamin D insufficiency to pediatric type 2 diabetes (T2D), but evidence from vitamin D supplementation trials is sparse.
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