Increased Levels of the Vitamin D Metabolite Ratio Are Protective Against Progression From Islet Autoimmunity to T1D

Context: Increased levels of 25-hydroxyvitamin D (25OHD) have been protective against islet autoimmunity (IA), a preclinical type 1 diabetes (T1D) disease state. However, the role of 25OHD and downstream metabolites in progression from IA to T1D is not well understood. Objective: We hypothesized that downstream vitamin D metabolites and metabolite ratios would be associated with progression from IA to T1D. Methods: Among participants at high genetic risk for T1D who developed IA (n = 143) in the Diabetes Autoimmunity Study in the Young (DAISY), a T1D birth cohort study, we quantified vitamin D3, 25OHD2, 3-epi-25OHD3, 25OHD3, 24,25(OH)2D3, and 1α,25(OH)2D3 metabolites from plasma samples using LC-MS/MS. We calculated the vitamin D metabolite ratio (VMR) (ie, 24,25(OH)2D3/25OHD3) and the epimer ratio (3-epi-25OHD3/25OHD3). We also tested the correlation between metabolite levels and gene expression in a subset of participants (n = 53). Results: A total of 57/143 progressed to T1D. Higher VMR (hazard ratio (HR) per 1 SD increase: 0.65; 95% CI: 0.49-0.88) and levels of 24,25(OH)2D3 (HR per 1 SD increase: 0.72; 95% CI: 0.55-0.94) at IA seroconversion were associated with a lower risk of progression to T1D, adjusting for seroconversion age, season, HLA-DR3/4 genotype, and ancestry. Functional enrichment analysis suggests higher VMR resulted in a gene expression pattern in whole blood characteristic of decreased activation of inflammatory pathways related to neutrophil infiltration. Conclusion: A higher VMR, a more functional measure of vitamin D status, was protective against T1D progression, perhaps by decreasing activation of inflammatory pathways.