(Boston)—The Center for Disease Control estimates nearly 50% of the U.S. population has either prediabetes (38%) or type 2 diabetes (T2D). Vitamin D deficiency is common in individuals with T2D with a prevalence of more than 80%. Past studies have reported pre-diabetic adults on 4000 IUs vitamin D3/d (median of 2.5 years) received no benefit in reducing progression to type 2 diabetes (T2D) compared to placebo. While other studies have shown participants receiving vitamin D who maintained certain levels of serum 25-hydroxyvitamin D [25(OH)D], resulted in approximately 52% and 71% risk reductions.
In the latest issue of JAMA Network Open, Dawson-Hughes et al., examined four common vitamin D receptor (VDR) polymorphisms (common genetic variations in DNA sequences) and observed that subjects with the vitamin D receptor (VDR) ApaI AA alleles, received no benefit from vitamin D treatment. However, subjects with ApaI AC and CC genotypes showed a 19% decreased risk of progressing to T2D. Polymorphisms are associated with chronic disorders including autoimmune diseases, diabetes, heart disease, deadly cancers and Alzheimer's disease. Polymorphisms also disrupt drug responses by alterations in enzyme function, drug transport and receptors.
“It is of no surprise that polymorphisms in the vitamin D receptors would be associated with alterations in vitamin D's associated health benefits,” says Michael F. Holick, PhD, MD, professor of medicine, pharmacology, physiology & biophysics and molecular medicine at Boston University Chobanian & Avedisian School of Medicine in an accompanying commentary in the journal.
Holick points out that this observation is only one small piece of the complex puzzle related to genomics and the risk for developing type 2 diabetes. “The active form of vitamin D, 1,25-dihydroxyvitamin D [1,25(OH)2D] interacting with VDR is responsible for vitamin D's effect on improving glucose metabolism and reducing risk for T2D. It provides further insight into individual differences in response to vitamin D supplementation and helps explain the disparity of conclusions regarding studies that have evaluated the impact of supplementation with vitamin D on serum concentrations of 25(OH)D and clinical outcomes including T2D,” he explains.
According to Holick, the enormity of the disease burden of diabetes worldwide and the confirmation that vitamin D supplementation of 4000 IUs/d markedly reduces risk of developing it, should be a wake-up call. “While it is unrealistic to determine everyone’s VDR polymorphisms and other polymorphisms that have been related to T2D, these findings should be the impetus for health organizations to develop strategies to improve vitamin D status for children and adults with food fortification programs, implementation of supplementation and sensible sun exposure recommendations for those who are at risk.”
JAMA Network Open
10.1001/jamanetworkopen.2026.7332
Commentary/editorial
Not applicable
Vitamin D Receptor Polymorphisms and the Effect of Vitamin D Supplementation on Diabetes Risk Among Adults With Prediabetes
23-Apr-2026