Optimization of 25(OH) vitamin D levels in African Americans Public Health Issue: Low circulating levels of 25(OH) vitamin D (VD) have been correlated with many adverse health conditions and health disparities in African Americans (AA). Supraphysiological high-dose VD supplementation is required to eliminate the differences observed in the levels of circulating 25(OH)VD in AA and white subjects. However, recent studies have questioned the therapeutic effects of high-dose VD supplementation. Rationale: Glutathione (GSH) is a major physiological antioxidant. Recent studies report that low levels of GSH are linked to 25(OH)VD deficiencies in both animal and human studies. Animal studies using ZDF rats and a mouse model of 25(OH)VD deficiency have shown that, compared to supplementation with VD-alone, co-supplementation with VD (cholecalciferol) + L-cysteine (LC, a GSH precursor) led to an improvement in GSH status that resulted in significant increases in circulating levels of 25(OH)VD and reduced oxidative stress, TNF-α, and insulin resistance (IR). Approach: AA have reduced levels of glutathione (GSH), as well as a high incidence of insulin resistance (IR) and inflammatory disorders. This R33 application presents our design for a randomized, double-blind, placebo- controlled clinical trial to test the hypothesis that supplementation with VD in combination with L-cysteine (a GSH precursor) is more successful at optimizing the statuses of 25(OH)VD and GSH [biological signatures] and simultaneously decreasing TNF-α and IR [functional or clinical outcomes], suggesting a better therapeutic approach compared with supplementation with VD alone in AA subjects. Impact on Public Health: The successful completion of this R33 clinical trial will have a significant impact on the design of future efficacy clinical trials examining co-supplementation using a GSH precursor coupled with lower VD doses to reduce 25(OH)VD deficiency/inadequacy, inflammation, and IR biomarkers. The development of a safe, low-cost dietary supplement that can improve 25-hydroxy vitamin D status and reduce insulin resistance and inflammation would provide significant benefits in the treatment of pre-diabetes and health disparities, including chronic pain, in the African American population. This application, which is highly responsive to PAR-18-828, will replicate previous human studies and examine the outcome of biological signatures by combining the natural product L-cysteine with VD to optimize its supplementation and efficacy.

NARRATIVE SUMMARY/RELEVANCE Two-thirds of our population is at risk for 25-hydroxy vitamin D deficiency and its associated health hazards, according to the National Center for Health Statistics. This has led to widespread vitamin D supplementation by the public. However, supraphysiological supplementation of vitamin D is needed to achieve normal circulating 25-hydroxy VD levels, and some subjects respond poorly to supplementation or experience side effects. The African-American (AA) population has been reported to have a higher incidence of 25-hydroxy VD deficiency as well as clinical pain. This study will investigate whether the combined use of the nutrients VD and L-cysteine exerts measurable and beneficial effects on 25-hydroxy vitamin D levels and insulin resistance biomarkers. The translation and validation of our novel hypothesis could have a tremendous impact on medical practice, leading to the novel recommendation that supplementation that combines the use of vitamin D and a GSH precursor is superior to the current practice of supplementation with high-dose vitamin D alone. The long-term goal is to discover new approaches to ensure adequate 25(OH)VD status and to prevent the adverse effects of vitamin D deficiency on health conditions in the African-American population.