Vitamin D

Vitamin D can be obtained from the diet or generated in the skin in response to sunlight; its metabolically active form is 1,25(OH)2D3. People with type 1 diabetes have lower circulating levels of this metabolite than controls, and lack of sunlight correlates well with the increased incidence of type 1 diabetes at higher latitudes. Three key genes involved in 1,25(OH)2D3 metabolism are associated with increased risk of type 1 diabetes, and functional studies confirm that this metabolite is under genetic control but set at lower levels than in control populations. 1,25(OH)2D3 receptors are present on pancreatic beta cells and on immunocytes, and vitamin D deficiency is a reversible cause of type 1 diabetes in the non-obese diabetic (NOD) mouse. It has, however, yet to be demonstrated that administration of vitamin D or its analogues can delay the onset of of type 1 diabetes or influence its clinical course. Intervention studies are needed to resolve these issues.


Vitamin D is strictly speaking not a vitamin, since humans can synthesise it for themselves under the influence of UV light; dietary sources are, however, essential under some conditions. In some respects it behaves more like a hormone. Vitamin D is available to the body in two main forms: ergocalciferol (vitamin D2) and cholecalciferol (vitamin D3). These are collectively referred to as vitamin D or calciferol. Vitamin D3 is generated in the skin by sunlight and is present in animal sources, especially fatty fish or their liver oils. Smaller amounts are present in dairy foods, and vitamin D is added to margarines and other products in some countries. Vitamin D2 is not produced by land plants, but is generated by fungi and other unicellular organisms in response to UV light. Vitamin D deficiency, whether caused by dietary deficiency or lack of sunlight, is the cause of rickets. The definition of 'normal' or healthy levels of vitamin D in the bloodstream remains controversial.

Vitamin D metabolism

The D vitamins are structurally similar to the steroids, with the difference that one of the bonds in the steroid ring is broken. Vitamin D3 is biologically inert until sequentially hydroxylated in the liver and kidney to its active form 1,25(OH)2D3. Parathyroid hormone plays an important role in regulation of 1,25(OH)2D3 production by the kidney. Circulating metabolites of vitamin D are bound to a carrier protein known as vitamin D binding protein.

The vitamin D receptor (VDR)

The VDR belongs to the steroid and thyroid hormone receptor family, and is similarly present in the nucleus of target cells. Binding of 1,25(OH)2D3 to its receptor results in transcription of its target genes. It is present mainly in bone, but is also expressed in the beta cell and in some white blood cells, including macrophages. One important difference is that much lower circulating levels of vitamin D are required to activate the receptor in bone than in other tissues. This means that attempted therapeutic use of vitamin D for its 'non-calcaemic' effects quickly results in unacceptable mobilisation of calcium and potentially dangerous hypercalcaemia.

Possible links with type 1 diabetes

Indirect pointers to a role of vitamin D in modulating susceptibility to type 1 diabetes include observations that type 1 diabetes is more common in high latitudes and in children with suspected rickets. Several studies have suggested an inverse relationship between vitamin D intake in pregnancy or early life and type 1 diabetes. The observation that vitamin D supplementation does not affect development of diabetes in the NOD mouse, whereas mice rendered deficient in vitamin D more readily develop diabetes, suggests that the presumed benefit of vitamin supplementation in humans is mainly due to avoidance of vitamin D deficiency.

Vitamin D and immune function

The vitamin D receptor is present on almost all immunocytes, especially antigen-presenting cells such as macrophages and dendritic cells. As in the kidney, final activation of 1,25(OH)2D3 prior to release is achieved by the enzyme 1-alpha-hydroxylase, but in immunocytes this enzyme responds to immune signals rather than parathyroid hormone. Release of 1,25(OH)2D3 seems likely to achieve local concentrations sufficient for immune signalling without unwanted systemic effects. The action of vitamin D upon immune cells may be summarised as inhibition of antigen presentation and its downstream effects, and diversion of T lymphocytes into Th2 or regulatory pathways. There is a corresponding inhibition of release of the pro-inflammatory cytokines interleukin (IL)-2 and interferon (IFN)-alpha, and increased production of the Th2 cytokine IL-4.

Vitamin D and the beta cell

The vitamin D receptor is expressed in beta cells, and secretion of insulin (but not of other islet hormones) is depressed by vitamin D deficiency and reversed by addition of vitamin D. This is associated with an increase in cytosolic calcium levels in the presence of 1,25(OH)2D3. Glucose tolerance improves when individuals with rickets are treated with vitamin D.

Vitamin D genes and diabetes

Three key genes involved in 1,25(OH)2D3 metabolism are associated with increased risk of type 1 diabetes, and functional studies confirm that, although under genetic control, this metabolite is present at lower levels than in control populations.

Vitamin D binding protein and diabetes

One study has reported that individuals with type 1 diabetes have reduced levels of the vitamin D binding protein, providing an alternative possible explanation for the low circulating levels of vitamin D seen in this condition.


In summary, relative vitamin D deficiency is not easily defined, but is associated with reversible impairment of insulin secretion which may be of relevance to type 2 diabetes, and altered immunomodulatory function which might potentially predispose to loss of immune tolerance. Furthermore, genes involved in 1,25(OH)2D3 metabolism have recently been shown to predispose to type 1 diabetes. Circulating levels of vitamin D are reduced in those with type 1 diabetes relative to control populations. Possible reasons include altered genetic regulation, deficient dietary intake or exposure to sunlight, and reduced transport in the circulation due to reduced levels of vitamin D binding protein.

Epidemiological clues for a role for vitamin D in the pathogenesis of type 1 diabetes include the increased prevalence of the condition in higher latitudes, and the observation that vitamin D supplementation in pregnancy or neonatal life appears to be protective.

It therefore seems reasonable to conclude that vitamin D deficiency should be avoided in those at increased risk of diabetes, but the benefit (if any) of an increased intake of vitamin D upon immune or beta cell function remains unknown. Since administration of vitamin D itself has unwanted effects upon calcium metabolism, analogues targeted to immune or beta cell function may hold some therapeutic promise.


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