Type 1 diabetes melllitus (T1DM) is an autoimmune disease characterised by immune-mediated destruction of insulin-producing beta-cells in the pancreas. The incidence of T1DM in childhood is increasing at about 3% per year. T1DM is the most common metabolic disease in the young. In Europe, about two million people (around 0.5 % of the population) and several million people world-wide suffer from this disease. During the development of T1DM, the immune system inappropriately targets the body’s own beta-cells in the endocrine pancreas, leading to a progressive impairment of insulin producing and secretory abilities and ultimately resulting in cell death with only 10% to 30% of the functional beta-cell mass remaining at the time of diagnosis. The autoimmune assault on beta-cells is induced by infiltrating immune cells causing functional impairment, endoplasmic reticulum stress and ultimately apoptosis. The mechanisms by which the immune system affects the beta-cell include release of pro-inflammatory cytokines (such as interleukin 1 beta (IL-1β), interferon gamma (IFN-γ), and tumor necrosis factor alpha (TNF-α)) as well the production of reactive oxygen and nitrogen species, Fas receptor/Fas ligand (Fas/FasL), and perforin/granzyme. Several genetic as well as environmental factors are believed to contribute. One such environmental risk factor may be vitamin D deficiency.

In figure 1 a proposed pathogenic flow of T1DM is depicted.

Vitamin D

Vitamin D is well-known for its important effects in bone tissue and on calcium/phosphate homeostasis. In addition, vitamin D deficiency is being linked to a broadening field of health problems including several types of cancer and autoimmune or metabolic diseases such as T1DM and T2DM. Given that only a small part of the body’s vitamin D requirement can be obtained from the diet, the majority must be covered by sunlight UVB-induced conversion of 7-dehydrocholesterol to vitamin D₃ in the skin. However, this route of supply is limited by the reduced exposure to solar UVB due to indoor living, clothing, and the use of sunscreen, as well as by the geographical and seasonal variations in UVB irradiance. Indeed, evidence suggests that the incidence and prevalence of T1DM and T2DM may follow these patterns of variation as described in more detail below. It has been estimated that more than 30-50% of all children and adults are at risk of vitamin D deficiency, defined as serum 25-hydroxyvitamin D (25-OHD₃) levels below 50 nmol/L. The biologically active form of vitamin D, 1alpha,25-dihydroxyvitamin D3 (1,25-(OH)₂D₃), is generated in multiple steps. The majority of vitamin D is obtained from the skin by UVB-induced conversion of 7-dehydrocholesterol to vitamin D₃ followed by two hydroxylations: first, 25-hydroxyvitamin D₃ is produced in the liver by 25-hydroxylases, and next, the renal 1alpha-hydroxylase (1α-OHase) adds a second hydroxy group. Vitamin D signaling is mediated by binding of 1,25-(OH)₂D₃ to the intracellular vitamin D receptor (VDR) which forms homo- or heterodimers with the retinoid X receptor (RXR). After translocation to the nucleus, the complex binds to vitamin D response elements (VDREs) in target genes involved in various processes including cell proliferation, differentiation, and immunomodulation. Ultimately, active vitamin D is degraded locally by 24-hydroxylase (24-OHase). VDR is expressed in a wide variety of tissues including pancreatic islets and most cells of the immune system as are other vitamin D related genes such as vitamin D binding protein and 1-a-hydroxylase.

Vitamin D deficiency in T1DM

Vitamin D deficiency has a major impact on both the beta-cell and the immune function. Insulin secretion is impaired when levels of vitamin D are low, but hypocalcemia that accompanies vitamin D deficiency also plays a role in this phenomenon. When low vitamin D levels are present, the innate immune system dysfunctions, with defects in chemotaxis, phagocytosis and killing of bacteria and viruses, whereas the adaptive immune system seems hyperactive. In animal models of T1DM (in particular the NOD mouse), vitamin D deficiency in early life leads to an increase in risk for development of disease in later life. In humans, epidemiology also points to this correlation.

Vitamin D as an immune modulator

Restoring vitamin D levels in vitamin D deficient subjects improves beta-cell function and normalizes the immune function, with better innate function (immune defense). However, data indicating that supplementing vitamin D sufficient subjects over and above normal levels will lead to prevention of T1DM are lacking. At present, only data from animal studies are available, as well as human small studies that do not allow strong conclusions. In NOD mice, treating them with high doses of vitamin D and even better the active form of vitamin D, 1alpha,25-dihydroxyvitamin D3 (5µg/kg/2d), allows prevention of the disease. However, this is at the price of hypercalcemia. This can be avoided by the use of less calcemic structural analogues of vitamin D. At present large scale clinical trials on prevention of T1DM by vitamin D are lacking, although several good proposals have been made.

Adapted from ‘Vitamin D and diabetes: its importance for beta cell and immune function. Wolden-Kirk H, Overbergh L, Christesen HT, Brusgaard K, Mathieu C. Mol Cell Endocrinol. 2011 5;347:106-20.