Journal of Endocrinology and Metabolism, ISSN 1923-2861 print, 1923-287X online, Open Access
Article copyright, the authors; Journal compilation copyright, J Endocrinol Metab and Elmer Press Inc
Journal website http://www.jofem.org

Review

Volume 1, Number 2, June 2011, pages 47-56


Role of Vitamin D in Diabetes

Figures

Figure 1.
Figure 1. Synthesis and metabolism of vitamin D.Vitamin D can be obtained from food (vitamin D2 and D3) or by photobiogenesis in the skin (vitamin D3). In the blood, all vitamin D metabolites are bound to vitamin D-binding protein (DBP). Vitamin D3 is converted by two successive hydroxylations in the liver (25-hydroxylases) and kidney (1a-hydroxylase) into its active hormonal form, 1,25(OH)2D3.
Figure 2.
Figure 2. Genomic actions of 1,25-dihydroxyvitamin D3. Molecules of 1,25(OH)2D3 penetrate the plasma membrane with the help of DBP and exert their genomic effects by activating the VDR. Ligand binding to the VDR induces a conformational change in the receptor and subsequent heterodimerization with RXR. The RXR-VDR complex binds to the VDRE, which is located within the 5’ flanking region of target genes. Thereafter, co-repressor (CoR) proteins are released from the surface of the VDR, allowing interaction with co-activator (CoA) proteins. These molecules modulate chromatin structure and allow the interaction of the receptor with the RNA polymerase II transcriptional complex (POL II), thus activating transcription of the target gene.

Table

Table 1. Potential Mechanisms and Beneficial Effects of Vitamin D on Diabetes
 
FunctionsMechanism of Action
Effect of Vitamin D on Type 1 Diabetes
Immune modulatorPresence of vitamin D receptors (VDR) on antigen presenting cells (macrophages and dendritic cells) and activated T-Lymphocytes.
Vitamin D (VD) downregulates antigen presentation and expression of co-stimulatory molecule by dendritic cells, thus inhibiting the production of proinflammatory cytokines.
VD also promotes the induction of regulatory T-lymphocytes and the production of anti-inflammatory cytokine IL-4.
Protection of beta-cellVD prevents beta-cell damage caused by pro-inflammatory cytokines (IL-1β and IFN-γ) by inhibiting the synthesis of inflammatory cytokines.
Effect of Vitamin D on Type 2 Diabetes
Effect of vitamin D on insulin secretionPresence of vitamin D receptor in pancreatic beta-cells and expression of 1,25 hydroxylase enzyme in pancreatic beta-cells suggest a role of VD in insulin secretion.
Alterations in calcium flux can have adverse effects on insulin secretion, a calcium-dependent process.
VD improves insulin secretion and glucose tolerance through regulation of the calcium levels. VD may induce insulin secretion indirectly by increasing the intracellular calcium concentration.
Subsequently VD may mediate the activation of calcium dependent endopeptidases which facilitate the conversion of proinsulin to insulin.
Effect of vitamin D on insulin actionVD mediates the transcriptional activation of human insulin gene (Vitamin D Responsive Element [VDRE] is present in human insulin gene promoter region) and also stimulates the expression of insulin receptor thereby enhancing insulin responsiveness for glucose transport.
VD may have a beneficial effect on insulin action indirectly via its role in regulating extracellular calcium levels, as calcium is essential for insulin mediated processes in insulin responsive tissues.
Effect of vitamin D on cytokinesVD may improve insulin sensitivity and promote beta-cell survival by modulating the effects of cytokines.
VD interacts with vitamin D response elements in the promoter region of cytokine genes to interfere with nuclear transcription factors implicated in cytokine generation and action.
Vitamin D can downregulate the activation of NF-kB, which is an important regulator of genes encoding pro-inflammatory cytokines implicated in insulin resistance.
Vitamin D interferes with cytokine generation by upregulating expression of calbindin, a cytosolic calcium-binding protein found in many tissues including pancreatic beta-cells. Calbindin has been shown to protect against cytokine-induced apoptosis that may occur after a rise in cytosolic free calcium [Ca2+]I.