Findings regarding the effects of vitamin D supplementation on diabetes risk are inconclusive. Because inflammation and vitamin D levels are interconnected, we hypothesized that higher inflammation levels moderate the effects of vitamin D deficiency on diabetes risk.

UK Biobank participants without pre-existing diabetes at baseline were included (N = 336,500). We first linked vitamin D and C-reactive protein (CRP; inflammation measure) levels with incident diabetes during a mean follow-up of 13.5 years (SD = 1.9). Then, we investigated the moderation effect of CRP on the associations between vitamin D deficiency (<10 ng/mL) and incident diabetes and performed subgroup analyses according to age (<60 vs.  60 years) and frailty status (frail; pre-frail; non-frail). Multivariate analyses were conducted using restricted cubic spline Cox proportional hazards regression models.

Lower vitamin D and higher CRP levels were significantly associated with an increased risk of diabetes during follow-up. There was a significant interaction between vitamin D deficiency and CRP on incident diabetes (p < 0.001). In participants with higher levels of CRP, the hazard ratio of developing diabetes comparing participants who had vitamin D deficiency to those who did not was lower than that in participants with lower levels of CRP. The moderation effect of CRP was similar between younger and older adults but was stronger in frail or pre-frail older adults than in non-frail older adults.

Our findings indicate that the effect of vitamin D deficiency on incident diabetes may be affected by inflammation. This finding may explain the inconsistent results from vitamin D supplementation trials. Vitamin D supplementation without considering the potential impact of inflammation might prove unsatisfactory.