The possible ‘non-calcemic’ effects of Vitamin D in numerous diseases has become a large area of research. Historically, Vitamin D is known for its regulatory role in calcium absorption and bone metabolism but the identification of vitamin D receptor (VDR) expression in more than 30 tissues led to the possibility of pleiotropic effects of vitamin D [Diabetes Forouhi 2008]. In vitro and animal studies suggested an anti-inflammatory and immunomodulatory effect of Vitamin D [The Review of Diabetic Studies, Gregoriu 2017]. Moreover, preclinical studies uncovered a potential regulatory role of Vitamin D in insulin secretion, β-cell survival and calcium flux in pancreatic β-cells [Mitri J, Endocrinol Metab Clin North Am 2014].
The need to identify factors associated with the development of type 1 diabetes (T1D) is obvious since there is no cure and the estimated incidence in children and adolescents is increasing worldwide, with an overall annual increase of around 3% [IDF Diabetes Atlas – 8th edition]. As an example, Finland has the highest incidence rates worldwide and a potential relationship to Vitamin D deficiency in children was suggested. The recommended dose of Vitamin D supplementation in Finland has been reduced gradually to one-tenth from the 1950s until the early 1990s, which was subsequently followed by a 5-fold increase in the incidence rates of T1D in children under the age of 15. Of course other factors could have played a role in this increase, but after the decision by the authorities in 2003 to fortify all dairy products with cholecalceferol, the numbers plateaued until 2011 [Harjutsalo et al. JAMA. 2013 Incidence of Type 1 Diabetes in Finland].
Numerous trials in the past tried to demonstrate a positive effect of Vitamin D supplementation on glycemic control in Type 1 and Type 2 Diabetes. However, the outcomes of these trials were conflicting so that a clear recommendation for Vitamin D treatment in diabetic patients seemed not justified [Rev Diabet Stud. 2017 Gregoriu et al.]. Newer studies correlating serum levels of Vitamin D with glycemic markers such as HbA1c indicate that at least patients with low serum levels may profit from Vitamin D supplementation [Giri et al. BMC Res Notes (2017)]. In this context, the dose for Vitamin D supplementation is still under discussion particularly since a statistical error for dose recommendations was identified and published by Papadimitriou [J Prev Med Public Health Papadimitriou 2017].
Moreover, several studies proposed an association between vitamin D deficiency during childhood and an increased risk of T1D. For example, the EURODIAB case-control trial reported a 1.5 times higher risk of T1D in children who did not receive a vitamin D supplementation during infancy [Diabetologia, The EURODIAB Substudy 2 Study Group, 1999) and even a higher risk was described in a birth-cohort study by Hypponen et al. where children who received less than 2000 IU of Vitamin D had a 4.5 times higher risk compared to children who received at least 2000 IU of Vitamin D per day to develop T1D [Lancet, Hypponen, 2001].
However, epidemiological associations should be confirmed by randomized clinical trials before recommendations for supplementation can be made. A recent systemic review by Gregoriou et al. summarised randomised controlled trials (RCTs), in which patients with newly diagnosed diabetes mellitus type 1 received supplementation with Vitamin D. Only four of the seven included RCTs were evaluated as high methodological quality trials pointing to a lack of well-designed RCTs. The analysis of these RCTs indicated that the form of Vitamin D supplementation as well as its dose may play an important role on the outcome of such trials. The most promising forms of Vitamin D supplementation were alphacalcidiole and cholecalciferol due to improvements in fasting c-peptide level and daily insulin dose as compared to a control group. In addition, both forms are known to be well tolerated. In contrast, trials using calcitriol, which is known to have side effects, showed either no or only minor effects on daily insulin dose and diminished after a treatment period of 12 months. However, these trials used a relatively low dose of 0.25 µg per day so that the authors considered this dose being too low to demonstrate significant effects on T1D progression [Rev Diabet Stud. 2017 Gregoriu et al.]. Antico et al. suggested already in 2012 in a systemic review that doses of vitamin supplementation in human trials of autoimmune diseases such as T1D are insufficient to attenuate disease progression. Unfortunately, no recent RCT had a follow-up period over 24-months so that potential positive long-term effects of Vitamin D supplementation on T1D progression including beta-cell preservation and glycemic control cannot be estimated. However, while not providing unequivocal support for supplementation, these trials demonstrate that short-term positive effects may exist with Vitamin D supplementation in patients with newly diagnosed T1D that may depend on the form and dose of Vitamin D.
The current literature indicates that vitamin D deficiency is associated with disease progression in diabetes but further trials are required to increase the knowledge on the potential role of Vitamin D and to justify its supplementation in diabetes treatment. Nevertheless, large trials with convincing outcomes would be needed to influence treatment guidelines.