**6. Vitamin D and type 1 diabetes**

Animal studies and clinical trials in patients with new onset of type 1 diabetes show that the replacement of vitamin D may arrest the deterioration of pancreatic function and improve C-peptide levels.

There is strong epidemiologic data showing that the population in countries with a high prevalence of type 1 diabetes mellitus is commonly vitamin D deficient. Vitamin D supplementation during pregnancy decreased the risk of the development of type 1 diabetes mellitus for offspring (Fronczak et al., 2003). Supplementation of vitamin D at an early age also decreases the risk for developing type 1 diabetes (Hypponen et al., 2001)

The vitamin D receptor (VDR) has been described on almost every tissue in the human body, including the cells of the immune system, as discussed earlier.

The VDR gene is located on chromosome 12, and has a few allelic variants. It has been reported that some of these allelic variations of the VDR gene are linked to an increased risk of type 1 diabetes mellitus in the German and the Indian Asian population (Pani et al., 2000, Chang et al., 2000). On the other hand, the same association was not found in another population sample (British, Portuguese and Finnish origin) (Guo et al., 2006, Lemos, 2008, Turpeinen, 2002).

An interaction between specific VDR polymorphisms and predisposing HLA DRB1 0301 allele was described in North Indian patients (Israni et al., 2009) and is associated with an increased risk of developing type 1 diabetes mellitus.

As discussed earlier, the last step in the activation of vitamin D is facilitated by the key enzyme 1-hydroxylase, encoded by the CYP27B1 gene on the chromosome 12q13.1-q13.3. Polymorphism in this gene is described as being associated with an increased risk of type 1 diabetes mellitus (Lopez et al., 2004, Bailey et al., 2007). The polymorphism in the CYP27B1 gene could potentially lead to the reduced expression of 1-hydroxylase, less production of the active 1,25 (OH) 2 D3, and ultimately, to the increased risk of type 1 diabetes.

### **6.1 Vitamin D and type 1 diabetes: The effects on the immune processes**

Vitamin D interacts with most immune cells and affects their cytokine production. Overall, vitamin D has a protective effect on the pancreatic beta cells (Figure 2).

DCs are affected by 1,25 (OH)2D3 in many ways. DCs mature after they engulf the antigen, increasing the expression of MHC-II molecules on their surface and secreting IL-12. Studies show that vitamin D analogs suppress the expression of MHC-II molecules (Griffin 2000) The cytokine secretion by DC is affected as well: the IL-12 is inhibited (D'Ambrosio 1998), while IL-10 production is increased (Penna 2000). Furthermore, DC apoptosis is promoted by exposure to vitamin D (Penna 2000).

If DC are exposed to 1,25 (OH)2 D3, they do not mature at a subsequent exposure to an antigen, becoming tolerogenic (Griffin et al., 2001). After being treated with a vitamin D analog, the DC do not simply remain immature, but instead are transformed into

research purposes, but some are part of standard treatment for certain autoimmune diseases

There are several theories that attempt to explain the link between Vitamin D and autoimmune diabetes. This relationship appears to be complex, with actions at multiples

Animal studies and clinical trials in patients with new onset of type 1 diabetes show that the replacement of vitamin D may arrest the deterioration of pancreatic function and improve

There is strong epidemiologic data showing that the population in countries with a high prevalence of type 1 diabetes mellitus is commonly vitamin D deficient. Vitamin D supplementation during pregnancy decreased the risk of the development of type 1 diabetes mellitus for offspring (Fronczak et al., 2003). Supplementation of vitamin D at an early age

The vitamin D receptor (VDR) has been described on almost every tissue in the human

The VDR gene is located on chromosome 12, and has a few allelic variants. It has been reported that some of these allelic variations of the VDR gene are linked to an increased risk of type 1 diabetes mellitus in the German and the Indian Asian population (Pani et al., 2000, Chang et al., 2000). On the other hand, the same association was not found in another population sample (British, Portuguese and Finnish origin) (Guo et al., 2006, Lemos, 2008,

An interaction between specific VDR polymorphisms and predisposing HLA DRB1 0301 allele was described in North Indian patients (Israni et al., 2009) and is associated with an

As discussed earlier, the last step in the activation of vitamin D is facilitated by the key enzyme 1-hydroxylase, encoded by the CYP27B1 gene on the chromosome 12q13.1-q13.3. Polymorphism in this gene is described as being associated with an increased risk of type 1 diabetes mellitus (Lopez et al., 2004, Bailey et al., 2007). The polymorphism in the CYP27B1 gene could potentially lead to the reduced expression of 1-hydroxylase, less production of

Vitamin D interacts with most immune cells and affects their cytokine production. Overall,

DCs are affected by 1,25 (OH)2D3 in many ways. DCs mature after they engulf the antigen, increasing the expression of MHC-II molecules on their surface and secreting IL-12. Studies show that vitamin D analogs suppress the expression of MHC-II molecules (Griffin 2000) The cytokine secretion by DC is affected as well: the IL-12 is inhibited (D'Ambrosio 1998), while IL-10 production is increased (Penna 2000). Furthermore, DC apoptosis is promoted

If DC are exposed to 1,25 (OH)2 D3, they do not mature at a subsequent exposure to an antigen, becoming tolerogenic (Griffin et al., 2001). After being treated with a vitamin D analog, the DC do not simply remain immature, but instead are transformed into

the active 1,25 (OH) 2 D3, and ultimately, to the increased risk of type 1 diabetes.

**6.1 Vitamin D and type 1 diabetes: The effects on the immune processes** 

vitamin D has a protective effect on the pancreatic beta cells (Figure 2).

levels: genetic, autoimmune and also direct action on the pancreatic beta cells.

also decreases the risk for developing type 1 diabetes (Hypponen et al., 2001)

body, including the cells of the immune system, as discussed earlier.

increased risk of developing type 1 diabetes mellitus.

by exposure to vitamin D (Penna 2000).

(for example, calcipotriol for psoriasis).

**6. Vitamin D and type 1 diabetes** 

C-peptide levels.

Turpeinen, 2002).

tolerogenic DC with special endocytic properties (Ferreira et al., 2009). Adorini et al published a paper describing how 1,25(OH)2 D3 can change the dendritic cells into a tolerogenic phenotype which is thought to induce T regulatory cells and inhibit autoimmune diseases, like type 1 diabetes (Adorini, 2003) (Fig 2).

Fig. 2. The immunomodulatory effects of 1,25(OH)2D3. At the level of the antigenpresenting cell (such as dendritic cells; DCs), 1,25(OH)2D3 inhibits the surface expression of MHC class II-complexed antigen and of co-stimulatory molecules, in addition to production of the cytokine IL-12, thereby indirectly shifting the polarization of T cells from a Th1 towards a Th2 phenotype. In addition, 1,25(OH)2D3 has immunomodulatory effects directly at the level of the T cell, by inhibiting the production of the Th1 cytokines IL-2 and IFN-γ and stimulating the production of Th2 cytokines. Moreover, 1,25(OH)2D3 favors the induction of regulatory T cells. Both Th2 and Tregs can inhibit Th1 cells through the production of counteracting or inhibitory cytokines. Together, these immunomodulatory effects of 1,25(OH)2D3 can lead to the protection of target tissues, such as β cells, in autoimmune diseases and transplantation. CD40L, CD40 ligand; Mf, macrophage; Tc, cytotoxic T cell; TGF- β, transforming growth factor β; Th1,T helper type 1; TNF-, tumor necrosis factor ; Treg, regulatory T cell. This figure was published in Trends in Endocrinology and Metabolism Vol.16 No.6 August 2005. Vitamin D and type 1 diabetes mellitus: state of art. Chantal Mathieu and Klaus Badenhoop. Copyright @ Elsevier 2005. Used with permission.

Descriptions of the VDR on T lymphocytes lead to the subsequent investigation of vitamin D actions on these immune cells. Interestingly, 1-hydroxylase is not expressed in the T cells, and vitamin D activated in the macrophages acts on the T cells, suggesting an autocrine action of 1,25 dihydroxyvitamin D3.

Rigby and his team proved that cytokine production by T cells is influenced by vitamin D analogs: IL-2 and IFN are inhibited (Rigby et al., 1987), while production of some of the type 2 cytokines (IL-4, 5, and 10) is enhanced (Boonstra et al., 2001)

Role of Vitamin D in the Pathogenesis and Therapy of Type 1 Diabetes Mellitus 413

Overbergh et al demonstrated that in NOD mice the immune shift between Th1/Th2 cells occurs in the periphery and is not limited to the pancreas (Overbergh et al., 2000). Furthermore, this change in the immune milieu occurs only in the autoantigen–specific immune response (exposure to GAD65, insulin B-chain, heat shock protein 65), and is not observed in the immune response associated with other antigens (ovalbumin, tetanus

The recurrence of autoimmune diabetes mellitus after islet cell transplant was prevented in NOD mice by treatment with vitamin D analogs in combination with cyclosporine A (Casteels et al., 1998). Further, the administration of a nonhypercalcemic vitamin D analog in combination with an immunosuppressant (cyclosporine A) prevented progression to overt diabetes mellitus, even after the insulitis developed (Casteels et al., 1998). This effect, however, could not be reproduced when the vitamin D analog was administered without

The NOD mice have an increased resistance to apoptosis in their immune cells. 1,25 dihydroxyvitamin D3 restores apoptosis in NOD mice in the thymus, leading to the

In the BB rat, another animal model for autoimmune diabetes mellitus, 1,25 dihydroxyvitamin D did not lead to any significant difference in the incidence of diabetes when given from weaning to 120 days (Mathieu et al., 1997). This finding illustrates the issue of potentially different disease mechanisms in various animals and the difficulty of

A few ecological studies support the theory that vitamin D is a major player in the

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

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

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

increased destruction of autoimmune effector cells (Casteels et al., 1998).

applying research findings from one animal model to another, or to humans.

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

The data available from human studies is scant and controversial.

autoimmune disease pathogenesis, including type 1 diabetes mellitus.

toxins, etc).

the addition of cyclosporine.

the skin to the UV radiation.

with high UVB irradiance (Mohr et al., 2008).

Inhibition of mitogen-stimulated T-cell cultures by vitamin D has been also reported (Rigby et al., 1984)

 On the other hand, suppressor T cells are stimulated by vitamin D, leading to the inhibition of T-cell mediated immunity (Mathieu et al., 1994).

While inhibiting the IL-12 production from the DC, vitamin D is able to shift the differentiation of T naïve cells into Th0 cells and further into Th2 cells (IL-12 is an important cytokine that preferentially promotes the Th1 cell formation from the Th0 cells) (Willheim et al., 1999).

A recent study reported the direct modulation of CD4+ T cell function by active vitamin D, describing the inhibition of IL-17, IL-21, IFN, and the induction of T reg cells expressing CTLA-4 and FoxP3. If the T cells are grown in an environment rich in IL-2 and vitamin D, they express the highest levels of CTLA-4 and FoxP3, and are able to suppress the proliferation of the resting CD4+ T cells (Jeffery et al., 2009).

VDR is normally expressed on the B cells only upon their activation. Chen reported that 1,25 (OH)2D3 decreased B cell proliferation and immunoglobulin production and induced cell death (Chen et al., 2007).

Vitamin D inhibits the production of inflammatory interleukins: IL-12, IL-2, interferon , tumor necrosis factor (TNF)-α, and TNF-β ,while the production of anti-inflammatory cytokines (IL-4, IL-10, TGF-β) is stimulated. This may disrupt the production of Th1 cells, which are destructive for the pancreatic beta cells, with a resultant beneficial effect on the beta cells (Lemire, 1995, van Etten & Mathieu 2005).
