High-dose vitamin D may delay or prevent the progression of prediabetes to diabetes, but only in people with certain polymorphisms in the vitamin D receptor, new research suggested.

“We identified a common variant in the vitamin D receptor that appears to influence the relationship between high-dose vitamin D and the risk of developing type 2 diabetes,” lead author Bess Dawson-Hughes, MD, senior scientist in the diet & chronic disease prevention for healthy aging research directive at the Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University in Boston, told Medscape Medical News.

“It’s known that the active form of vitamin D acts through its receptor in the beta cell to influence insulin secretion,” said Dawson-Hughes, also a professor of medicine at Tufts University School of Medicine. “The receptor is also implicated in insulin resistance. So, it was plausible that common variants in the receptor could modify the effect of supplemental vitamin D on risk of conversion to T2D [type 2 diabetes],” she explained.

For the current study, published in JAMA Network Open, researchers analyzed data from adults with prediabetes who were enrolled in the earlier Vitamin D and Type 2 Diabetes (D2d) trial, with available intratrial 25(OH)D levels and genotyping.

In the initial study, participants were randomly assigned to receive 4000 IU/d of vitamin D₃ or a placebo daily for a median of 2.5 years. Although vitamin D led to a reduction in progression from prediabetes to T2D, the finding failed to reach statistical significance in the intent-to-treat analysis (hazard ratio [HR], 0.88; 95% CI, 0.75-1.04).

Genotype Analysis of the Vitamin D Receptor

In the genetic association study, Dawson-Hughes and colleagues evaluated whether three common polymorphisms (ApaI, BsmI, and FokI) in the vitamin D receptor were associated with reduced diabetes risk among participants (n = 1903) who achieved higher intratrial mean 25(OH)D levels. This aspect of the study was called the “discovery phase.”

The “test phase” then investigated whether participants’ vitamin D receptor genetic profile modified the response to vitamin D₃ supplementation compared with placebo. The researchers classified participants as “potential responders,” having alleles associated with decreased risk for diabetes at higher achieved 25(OH)D levels, or “potential nonresponders,” having alleles not associated with decreased risk for diabetes at higher achieved 25(OH)D levels.

In the discovery phase, participants with the ApaI CC genotype had HRs of 0.29 (95% CI, 0.13-0.65) for incident diabetes at 25(OH)D levels of 40-50 ng/mL and 0.17 (95% CI, 0.07-0.43) at ≥ 50 ng/mL. Among those with the AC genotype, HRs for incident diabetes were 0.51 (95% CI, 0.30-0.86) and 0.26 (95% CI, 0.14-0.48), respectively. 

These groups were classified as “responders,” while participants with the AA genotype showed no risk reduction and were considered “nonresponders.”

A similar pattern was observed for BsmI, but results for FokI were “less consistent,” so this polymorphism was not analyzed further.

The lack of risk reduction among ApaI AA carriers — along with the observation that most individuals with the nonresponsive BsmI TT genotype also carried ApaI AA — suggested that ApaI genotyping alone might be “sufficient to identify individuals with prediabetes who would be more or less likely to respond to high-dose vitamin D₃ supplementation,” said Dawson-Hughes.

Complete Apal Genotype Data

The researchers then analyzed participants with complete ApaI genotype data (n = 2098; mean [standard deviation] age, 60.2 [9.9] years; 55.7% men), stratifying them solely by ApaI genotype into two groups: 29.5% were classified as proposed nonresponders (those with the ApaI AA genotype), while 70.5% were classified as proposed responders (those with the ApaI CC or AC genotypes). The groups were “generally well balanced at baseline,” achieving similar intratrial serum 25(OH)D concentrations.

In participants with ApaI CC and AC alleles, vitamin D reduced the risk of developing diabetes by 19% (HR, 0.81; 95% CI, 0.66-0.99) compared with placebo, while among the participants with ApaI AA alleles, vitamin D did not appear to reduce the risk (HR, 1.02; 95% CI, 0.72-1.44). 

The researchers noted that the study was too small to examine the association between ApaI alleles and treatment response within individual groups by race and ethnicity, and did not address the mechanisms by which ApaI genotypes are associated with vitamin D response.

Nevertheless, the study has important implications, said Dawson-Hughes. “The technology is available, and the ApaI genotype measurement isn’t expensive. Our finding still needs to be verified, but once that occurs, then it may become common to identify and then treat selected high-risk adults with relatively high-dose vitamin D.”

This is a “useful, low-cost precision medicine strategy to reduce the risk of T2D,” she said.

Complex Puzzle

Commenting for Medscape Medical News, JoAnn Manson, MD, MPH, DrPH, chief of the Division of Preventive Medicine and professor of medicine and of Women’s Health at Brigham and Women’s Hospital, Harvard Medical School in Boston, said if the findings are replicated, “they could play an important role in helping identify those most likely to benefit from high-dose vitamin D supplementation to prevent T2D.”

Manson, principal investigator on the VITamin D and OmegA-3 (VITAL) trial, noted that in the original D2d trial, the overall result wasn’t statistically significant, but participants with BMI < 30 had a 29% lower diabetes risk, while those with BMI ≥ 30 had no apparent benefit.

“In VITAL, we’ve seen that the effects [of vitamin D] were stronger in those not in the obese category for cancer, autoimmune disease, diabetes, and many other health outcomes. So the D2d study may hold the key to understanding the modifying effect of BMI in many randomized trials of vitamin D — those with higher BMI may be more likely to have a genotype associated with less effect [of vitamin D] on the vitamin D receptor,” she suggested.

Manson and her colleagues are considering genotyping participants in the VITAL trial, “and looking at the same question investigated in the current D2d trial to see whether our results vary by vitamin D receptor polymorphisms.”

In an accompanying editorial, Michael Holick, PhD, MD, and Arash Shirvani, MD, PhD, both affiliated with Boston University School of Medicine, called the findings “only one small piece of the complex puzzle related to our genomics and risk for developing [T2D].”

Over 500 genetic loci are related to the risk for developing T2D, they noted, so “how the ApaI AA genotype may interact with these genetic variations remains to be determined.”

This study was supported by the US Department of Agriculture Agricultural Research Service and the National Institutes of Health for the D2d study. Dawson-Hughes and Manson reported having no relevant financial relationships. The other authors’ disclosures are listed in the original paper. Holick reported receiving grants from Carbogen-Amcis, KBD/Sperti, and Solius; personal fees from Solius, Biogena, Sanofi, Abbott, Pulse Pharmaceuticals, IJCP Health, Hyphens, PharmEVO, KBD/Sperti, and Medico Publications; and having developed an app for Ontometrics; and serving on a guidelines committee for the Endocrine Society. Holick also has a patent application for Carbogen Amcis B.V. and Aamanya AG pending. Shirvani reported receiving personal fees from Solius and grants from Carbogen Pharmacokenetic outside the submitted work.

Batya Swift Yasgur, MA, LSW, is a freelance writer with a counseling practice in Teaneck, New Jersey. She is a regular contributor to numerous medical publications, including Medscape and WebMD, and is the author of several consumer-oriented health books as well as Behind the Burqa: Our Lives in Afghanistan and How We Escaped to Freedom (the memoir of two brave Afghan sisters who told her their story).