Krul-Poel et al. (1) provided elegant evidence that vitamin D supplementation had no significant effect on insulin secretion, insulin sensitivity, and glycemic control in patients with type 2 diabetes. This randomized controlled trial (RCT) enrolled subjects with type 2 diabetes and vitamin D insufficiency, i.e., a cohort that according to previous studies should take advantage from vitamin D treatment (2). Although the findings of Krul-Poel et al. clearly did not show any effect of vitamin D supplementation on diabetes management, it must be highlighted that these data are of paramount importance regarding vitamin D safety. In this context, the Endocrine Society guidelines suggest that circulating levels of 25-hydroxyvitamin D [25(OH)D] after supplementation should reach a minimum threshold of 30 ng/mL, while the Institute of Medicine recommends circulating levels of 25(OH)D above 20 ng/mL in all adults aged 50–70 years and older (3). Krul-Poel et al. showed that keeping a 25(OH)D level of nearly 40 ng/mL was safe in such aged patients. Although several observational studies reported that 25(OH)D concentrations of 30–35 (or 40) ng/mL were optimal for multiple health outcomes including mortality, this could not be generalized to type 2 diabetes (4). As a matter of fact, several RCTs of vitamin D supplementation in both prediabetes and type 2 diabetes have shown that vitamin D was not a wonder drug for the treatment of these diseases (5). The explanation of these negative RCT results may be that starting vitamin D supplementation when glucose derangements have already been established could be too late to prevent the progression or improvement of the disease. Thus, subjects at high risk to develop but without already established glucose derangements (for example, obese subjects) could be an attractive target cohort to study the effect of vitamin D supplementation on glucose metabolism and mostly on diabetes prevention. Another intriguing hypothesis could be that vitamin D deficiency and glucose derangements are not linked by a cause-effect relation but that both may be related to chronic illness that prevents outdoor activities and sun exposure. Although observational studies reported a positive association between vitamin D status and glucose metabolism (2), it should be noted that they used single measurements of blood 25(OH)D as a proxy of vitamin D status that may not reflect vitamin D status over long periods and that risk factors for vitamin D deficiency increase with time (aging, declining physical activity, etc.). Therefore, inaccurate assessment of the exposure (vitamin D status) and uncontrolled or residual confounding may explain the conflicting results between observational studies and RCTs. Thus, given the negative RCT data on vitamin D and glycemic control, vitamin D supplementation should be encouraged in patients with diabetes only as a preventive therapy for osteoporosis and fractures.
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Duality of Interest. No potential conflicts of interest relevant to this article were reported.
