**8. Clinical studies – vitamin D and type 1 diabetes**

The data available from human studies is scant and controversial.

A few ecological studies support the theory that vitamin D is a major player in the autoimmune disease pathogenesis, including type 1 diabetes mellitus.

A study in Northern Europe described the seasonal pattern of disease onset for autoimmune diabetes mellitus (Karvonen et al., 1998). The Diabetes Epidemiology Research International Group reported in 1988 an increased incidence of autoimmune diabetes with lower average yearly temperatures, which, in turn, was strongly associated with increasing latitude distances from the equator. This variation is thought to be due to the decreased exposure of the skin to the UV radiation.

In a very large worldwide study, Mohr et al analyzed the data from the Diabetes Mondial Project Group and found that in children younger than 14 years of age, the incidence rates of type 1 diabetes mellitus were significantly increased at higher latitudes and with low UVB exposure. Incidence rates of type 1 diabetes mellitus approached zero in the region with high UVB irradiance (Mohr et al., 2008).

Several European studies reported a decreased risk of diabetes in infants supplemented with high doses of vitamin D. The EURODIAB substudy 2 study group in seven European centers reported that vitamin D supplementation in infancy decreased the risk of autoimmune diabetes in a fairly consistent manner (Dalquist et al., 1999). Hypponen et al published the results of a birth-cohort study in northern Finland that included all pregnant women who were due to give birth in 1966, and recorded the frequency and the dosing of the vitamin D supplementation in the first year of life, as well as the presence of suspected rickets. 30 years later, the authors found that there was a lower incidence of diabetes mellitus in children who took any dose of vitamin D as compared with children that did not

Role of Vitamin D in the Pathogenesis and Therapy of Type 1 Diabetes Mellitus 415

vitamin D nonhypercalcemic analogs need to be performed before the interaction between

We would like to thank Barbara Pietrzyk-Busta, RN, MA for her invaluable assistance in the preparation and editing of this manuscript, and to Jill Gregory, CMI, FAMI for designing an

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**10. Acknowledgements** 

illustration of Figure 1.

1860.

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**11. References** 

take any vitamin D supplementation. Even more so, the risk was lower in children that took the highest dose (2000 IU daily) as compared to the lower dose of vitamin D. Children with suspected rickets had a 3 fold increased risk of developing insulin-dependent diabetes mellitus (Hypponen et al., 2001). The risk of developing islet auto-antibodies in the children of mothers that took vitamin D during pregnancy was decreased in the Diabetes Autoimmunity Study in the Young (DAISY) (Fronczak et al., 2003). It is unclear from these studies if the protective effect is due to the supplementation with extra doses of vitamin D or prevention of vitamin D deficiency.

Two new interventional trials have been published in the last 2 years supporting the beneficial effect of vitamin D on the development of autoimmune diabetes.

A pilot study looking at patients with adult-onset latent autoimmune diabetes (LADA) demonstrated that supplementation with 1,25 dihydroxyvitamin D3 for 1 year resulted in beta cell preservation, as assessed by C-peptide levels (Li et al., 2009).

Aljabri et al conducted a prospective study in which patients with vitamin D deficiency were assigned to receive 4000 IU of vitamin D3 daily and had vitamin D 25 (OH) levels and hemoglobin A1c measured at baseline and at 12 weeks. The results revealed that the patients who achieved higher circulating levels of vitamin D 25 (OH) had a lower hemoglobin A1c (Aljabri et al., 2010).

Other studies, however, did not find similar results. A study which examined the effects of supplementation with cod liver oil during the first year of life, found that the infants who were supplemented had a decreased risk of developing childhood-onset type 1 diabetes. However, this decreased risk of type 1 diabetes mellitus was not observed in the infants if the cod liver oil was supplemented during pregnancy or if the vitamin D preparations were supplemented during the first year of the infant's life. Since cod liver oil has a high content of vitamin D along with the long-chain n-3 fatty acids (eicosapentaenoic and docosahexaenoic), it is not clear if these effects are due to the high vitamin D content of the cod liver oil or due to the fatty acids (Stene et al., 2003).

Pittoco et al reported the results of an interventional trial in children with newly diagnosed type 1 diabetes, in which the patients were administered calcitriol or nicotinamide in order to preserve beta-cell function. Even though there was a decrease in the insulin requirements at 3 and 6 months in the calcitriol treated group, at the end of the first year there was no difference between the C-peptide levels or hemoglobin A1c between the two groups (Pitocco et al., 2006).

Bizzarri et al investigated whether supplementation with calcitriol in recent onset autoimmune diabetes has a protective effect on the pancreatic beta cells and found that, at the doses used in the study, calcitriol did not confer protection against the autoimmune destruction of the beta cells (Bizzarri et al., 2010). In Germany, Walter et al supplemented newly diagnosed adult patients with 1,25(OH)2D3 for 18 months. At the end of the study there was no difference in the areas under the curve (AUC) for C-peptide, peak C-peptide, or fasting C-peptide after a mixed meal tolerance test between the treatment and the placebo groups (Walter et al., 2010).
