Diabetes is a huge problem worldwide with more than 10,000 people being diagnosed with diabetes every year it is not hard to understand why. With the discovery of insulin as a primary treatment for type 1 diabetes and numerous drugs that have been implicated for the management of type 2 diabetes have proved extremely effective but as the problem is on the increase, many researchers have looked into the possible effect of natural substances such as vitamin D which may have a possible role in diabetes (0).
Vitamin deficiency is a pandemic and according to the department of health, a staggering 25% of the population have low levels of vitamin D in their blood . Many clinicians have looked at the possible role of vitamin D in diabetes.
Vitamin D is regarded a steroid hormone which can be obtained naturally from diet (30%) and the majority coming from photochemical conversion in the skin from sunlight. Vitamin D is not activated when it comes from these two sources and has to be hydroxylated twice before it can exist in its active form. The first step of hydroxylation takes place in the liver and the enzyme responsible converts vitamin D into 25, hydroxyvitamin D (inactive form). The second part of hydroxylation takes place in the kidneys and this converts 25, hydroxyvitamin D to the active form 1,25 hydoxyvitamin D. 1,25 hydroxyvitamin D is released into the circulation where it is transported in association with a vitamin D binding protein until it reaches its target tissues where it interacts with vitamin D receptors. When the vitamin D receptor binds to the vitamin D ligand a heterodimer is formed with another receptor called retinoic acid receptor located in the cell's nucleus. The ligand/receptor complex then migrates into the DNA to increase the expression of vitamin D related genes. (8,9)
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The essential role of Vitamin D is to maintain calcium homeostasis particularly for function of the skeletal system. Vitamin D deficiency has been implicated in a number of disease processes most commonly rickets and other skeletal disorders. However is also correlated with increased risk of cardiovascular disease, severe asthma in children and even cancer. (10)
Low levels of vitamin D has become exceedingly prevalent worldwide (11) and is associated with an increased risk of type 2 diabetes and all cause cardiovascular death. (12,13) In recent years there has been discovery of vitamin D receptors located in pancreatic beta cells as well as vitamin D dependent calcium proteins in pancreatic tissue (14,15,16). There is apparently also expression of 1-alpha hydroxylase in pancreatic beta cells (17), this enzyme being involved in the conversion of hydroxyvitamin D into its active vitamin D form. It has been reported that vitamin D deficiency is associated with diabetes and that the replenishment of vitamin D can improve glycaemic control (4,5,6). Apparently vitamin D has been shown to alter insulin synthesis and secretion in both human and animal models (2,3,22,23). Conversely other studies have shown that vitamin D has no effect on diabetes and that this is simply a myth. (7)
The compelling evidence suggests that vitamin D may have an exciting role in diabetes mellitus. This raises many questions for instance; does vitamin D deficiency play a possible role in the pathogenesis of diabetes? Can vitamin D supplementation be used to prevent and possibly treat diabetes? This essay will address these issues by discussing the possible physiological and pharmacological role of vitamin D in type 1 and type 2 diabetes mellitus by looking at evidence from trials and possible mechanism of vitamin D in Diabetes mellitus.
Possible role of vitamin D in type 1 diabetes
Vitamin D and the immune system in type 1 diabetes:
Type 1 diabetes is characterised by chronic hyperglycaemia due to a complete lack of insulin caused by the production of inflammatory cells most likely macrophages, dendritic cells, B lymphocytes which lead to the destruction pancreatic beta cells. Type 1 diabetes is therefore considered to be an autoimmune disease in which the pathogenesis heavily relies on the immune system (18). To prove that the immune system was the culprit for the development of diabetes, Miller et all irradiated to the immune system of non-diabetic rodents, spleen cells from a diabetic mouse were then injected in the non-diabetic mice who then all developed diabetes, he then went onto to find that the administration of T-cells alone were sufficient enough for the development of diabetes, indicating that this was mainly a T-cell mediated disease (28).
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Numerous studies have shown that vitamin D may have a role in regulating the immune system. (19) There is an existence of vitamin D receptors located on certain cells of the immune system such as activated T lymphocytes and macrophages. There is evidence of these receptors in tissues which are responsible for the tolerance of immune cells such as the thymus gland (20,21,22). Furthermore, stimulated macrophages and dendritic cells are able to synthesise and secrete 1,25 hydroxyvitamin D by expressing the enzyme, 1 alpha hydroxylase (?).Evidence now exists to demonstrate the roles that vitamin D has on the immune system: (26,27,
Elina et al in 2001 looked at whether vitamin D supplementation or deficiency during infancy would affect whether the infants went on to develop type 1 diabetes. This birth cohort study that only looked at certain populations found that regular supplementation of vitamin D reduced the frequency of type 1 diabetes compared with those that received no vitamin D supplementation (ratio ratio= 0.12). Furthermore studies have shown that vitamin deficiency during pregnancy increases the likelihood of developing autoimmune conditions such as type 1 diabetes in later life.
This possible risk reduction is probably due to the role of vitamin D in regulating the immune system. For any autoimmune disease there needs to be a genetic predisposition, a trigger and a loss of tolerance (RST). As discussed earlier, type 1 diabetes seems to be T-cell driven and the effect of vitamin D in suppressing T helper cells and cytotoxic T cells (killer T-cells) may directly prevent these cells from wrongly identifying self-islet antigens as foreign and as a consequence destroying them. The direct effect of vitamin D in suppressing antigen professional cells (macrophages, dendritic cells and B cells) and indirectly by down regulating MHC class 2 molecules may stop these cells from presenting islet-self antigens to helper T-cells. Helper T-cells are required to produce specific cytokines that activate killer T-cells. Vitamin D prevents helper T-cells by doing this by inhibiting them from releasing key cytokines such as IL-2. Vitamin D can also inhibit killer T-cells by the induction of regulatory T-cells which suppress those T-cells which are considered to be self-destructive. Vitamin D therefore inhibits cytotoxic (killer T-cells) directly and indirectly to stop them from potentially destroying pancreatic beta cells. (31)
Overall from the study mentioned earlier and many others producing similar results, conclusions can be drawn that a recommended amount of vitamin D should be given to all infants (29,30 and the EURODIAB substudy 2 study group (1999) vitamin d supplement study in early childhood and risk for type 1 (insulin dependent diabetes mellitus. as avoiding vitamin D deficiency has proved vital for Beta cell function and may well stop the development of type 1 diabetes in later life.
Polymorphisms of Vitamin D receptors in type 1 diabetics.
There is very mixed evidence to suggest whether polymorphisms in the vitamin D receptors have any role in the pathogenesis of type 1 diabetes.
In some populations there seems to be a positive correlation between vitamin D receptor polymorphisms. (1,2,3,4,5). For instance McDermott et al found a relationship between a particular vitamin D receptor allele and insulin dependent diabetes in South Indians and Yoshiyuki et al found that in Japanese populations vitamin D receptor start codon polymorphism effects genetic susceptibility to type 1 diabetes.(3) On the other side, the same is not true for other populations (6).
The fact that there are positive correlations between different polymorphisms in the vitamin D receptor in some populations and there are negative correlations in other populations, the role that vitamin D receptor polymorphisms play in the pathogenesis of type 1 diabetes is extremely complex and confusing. The evidence suggests that polymorphisms may play a role in some populations but it is very difficult to make any sound conclusions based on the studies that have been done and therefore there remains an element of doubt in this area.
Possible Role of vitamin D in type 2 diabetes:
Vitamin D and the immune system in type 2 diabetes
Similarly with Type 1 diabetes, the pathogenesis of type 2 diabetes also involves the immune system (18). Patients with metabolic syndrome but are non-diabetic have an increased amount of serum inflammatory markers for instance CRP, compared with non-diabetics and diabetic patients have a higher amount of inflammatory markers than both (Pickup et al 1997) (18). Studies have found that there are particular cytokines for instance IL-6 and TNF alpha that are abundant in patients with obesity/ metabolic syndrome and type 2 diabetes, indicating that these are the key cytokines which interplay in the disease process. (32)
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How do these cytokines possibly play a role in the pathogenesis of type 2 diabetes? Well It is thought to have a direct effect on insulin signalling pathways particularly on insulin receptor substrates, which are a family of proteins when phosphorylated by the insulin receptor they bind to downstream signalling molecules that are involved in the biosynthesis of insulin. Increased circulating adipokines and cytokines particularly TNF alpha and interleukin-6 are thought to interfere with insulin receptor substrates. TNF alpha is understood to activate c-jun N-terminal kinases (JNK). JNK phosphorylates many proteins at the level of the mitochondria and nucleus to affect their function. When TNF alpha activates JNK this phosphorylates insulin receptor substrates to stop them from activating the insulin signalling pathway, as a result insulin receptor substrates are degraded and insulin synthesis is suppressed. Similarly IL-6 is thought to activate a protein called suppressor cytokine signalling 3 (SOC-3) which subsequently binds to the c-terminus of insulin receptor to block the potential interaction of insulin receptor substrate with phosphotyrosine on receptor. (33,34)
It has been claimed that vitamin D down regulates the production of the key inflammatory cytokines IL-2, IL-6 and TNF alpha and Beta. As mentioned before vitamin D receptors located on T-cells (20,21) and these include helper T-cells which produce some of the key inflammatory cytokines (TH2 cytokines). Therefore it is very possible that vitamin D could be exerting an immunoregulatory effect on T-cells by binding to the vitamin D receptors located on the T-cells and preventing them from producing these cytokines, therefore suppressing the activations of the JNK pathway and SOC-3 and so insulin receptor substrates can still function and subsquently insulin biosynthesis can still take place. There is no published data however looking at the whether vitamin D has an influence on inflammatory mediators particularly cytokines and therefore until this is explored, it Is difficult to make the conclusion that Vitamin D has a firm role in type 2 diabetes through its action on the immune system.
Possible role of vitamin D on insulin secretion in type 2 diabetes:
In type 2 diabetes, there is usually a progressive loss of beta cells over many years and the insulin producing cells still have a residual function and produce insulin in small qunatities and with reduced sensitivity. (#) This is why potential drugs can be used to enhance the production of insulin which simply cannot be used in type 1 diabetes. Can the same be applied for vitamin D?
It has been reported that vitamin D has a possible role in stimulating insulin secretion in the pancreatic beta cells of both animals and humans. (2,3, 37,). Similarly Chui et al found that vitamin D supplementation has a rapid effect on improving insulin secretion in response to an oral glucose load in patients with mild type 2 diabetes (38). The most plausible mechanism of this achievement is to do with the effect that vitamin D has on calcium levels and Sergeevin et al found that 1,25 hydroxyvitamin D (active vitamin D) causes oscillations of intracellular calcium in a pancreatic beta cell line (37). According to sources it is likely that vitamin D acts on pancreatic beta cells via calcium dependent endopeptidases. Theses endopeptidases cleave pro-insulin into insulin. In addition to this Calcium does not only increase insulin secretion by exocytosis but it works by promoting beta cell glycolysis (39).
As well as vitamin D increasing intracellular calcium levels, a deficiency of vitamin D results in an increased production of parathyroid hormone by the parathyroid gland (40). Elevated levels of parathyroid transiently raises intracellular calcium levels (41), however continuous high levels of calcium in cells can eventually inhibit beta cells from sensing rapid influxes of calcium which is required for insulin secretion (42, 43). There is supporting evidence of this mechanism as studies have shown that parathyroid hormone levels are inversely proportional to insulin sensitivity. (44)
Another proposed mechanism is that high intracellular calcium levels may bind to the camodulin protein of insulin like growth factor receptor substrate, which then interferes with tyrosine phosphorylation and protein kinase C activation (45,46). This mechanism like many other described is still controversial as kamycheva et al found that there was no statistically significant different between patients with secondary hyperparathyroidism and glucose homeostasis. (47)
On the other hand previous studies have been observational and so there may be an apparent causal relationship between vitamin D and insulin secretion due to confounding factors for instance. Mayer Davidson et al very recently wanted to end this speculation by conducting a 'once and for all' double blinded randomised control trial investigating the role of vitamin D. Subjects with pre-diabetes were randomised to placebo or a very high dose vitamin D supplement. Results showed that there were no differences between subjects that were receiving a placebo and those which received high dose vitamin D in terms on insulin sensitivity, insulin secretion and fasting glucose levels. Davidson called claimed that vitamin D was a 'dead end for diabetes'. (48) There were deficiencies to this study according to other researchers such as Cliff Rosen who argued that only 100 people completed the trial and that longer and more trials are required before a conclusion can be drawn. (49)
Vitamin D receptor polymorphisms in type 2 diabetes
Similarly with type 1 diabetes there is an association between certain vitamin D receptor polymorphisms and the onset of type 2 diabetes in selective populations.
One particular study which was based on a Bangladeshi population yielded promising results. They found that a particular allele called APA RFLP was linked to glucose induced insulin secretion (11). Furthermore, there was supporting evidence that this allele was correlated to higher fasting glucose levels and glucose tolerance in elderly patients who were not known to have diabetes. (12)
In a more recent published article, genotyping for a selected amount of gene revealed that bsm1RFLP was linked with high fasting glucose concentrations in young male individuals. (13) The APA A1 and BSM1 vitamin D receptor polymorphisms were also associated with rises in fasting glucose concentrations in Germans (14). Overall these VDR polymorphisms have shown that associations can be made between particular gene polymorphisms in the VDR and type 2 diabetes but only in certain populations, therefore although it has a possible role, it continues to remain a very complex issue and until it is studied in further depth and using more direct alternative techniques such as clamp studies (15) there seems to be a little role for its use in type 2 diabetes. Moreover, many case control studies haven't actually found any statistical significance between VDR polymorphisms and type 2 diabetics when compared to controls. (16, 17)
Possible role of vitamin D in Diabetic complications.
Diabetic patients over time inevitably end up with diabetic complications. Principally these are divided into micro and macrovascular complications (50). 50% of type 2 diabetic patients suffer from complications at the time of diagnosis according to the UKPDS (51) and the majority cause of death in diabetic patients is cardiovascular disease (52-56).
In recent years, vitamin D deficiency has been linked as a potential modifiable risk factor for many diseases including CVD (57). Furthermore, Zitter man et al found that cardiovascular diseases was elevated at higher latitudes and increased during the winter months when vitamin D deficiency is more prevalent. The exact mechanism is not fully understood but can be broadly associated with the effect of vitamin D on blood pressure, parathyroid hormone levels, inflammation and vascular calcification. (24) In addition, Wang et al found that Individuals with low 25, hydroxyvitamin D had a higher risk cardiovascular events (hazard ratio 1.62) compared with those high levels and that this effect however was only evident in participants with hypertension (hazard ratio of 2.13. (58) This study illustrated that vitamin D deficiency is a possible risk factor for cardiovascular disease and particularly demonstrates that this may be associated with its decreasing blood pressure properties, although there are conflicting results to show otherwise (62,63).
It is thought that vitamin D reduces blood pressure by inhibiting the RAAS system (59) and given the fact that type 2 diabetes and hypertension are commonly associated conditions (abcde), there may well be a role of vitamin D in reducing hypertension in diabetics. The RAAS system plays a vital role in controlling blood pressure and when this system is activated, blood pressure is raised by a range of mechanisms (see figure below). Emerging studies in recent years have shown that vitamin D is a potential suppressor in the production of key components of the renin angiotensin aldosterone system (60), Knockout vitamin D receptor rodents had increased production of renin and angiotensin 2 leading to hypertension and its complications and the administration of 1,25 hydroxyvitamin D (active form) reduces the expression of renin. (61) Assumptions can therefore be made that vitamin D has a potential role in reducing the macrovascular complications in diabetes probably by reducing blood pressure via its effects on RAAS:
Specifically focussing on diabetic linked complications alone, a study showed that patients with severe vitamin D deficiency had a much higher risk of mortality (hazard ratio 2.7) but there were no differences found with microvascular complications hinting that vitamin D supplementation may only play a role in macrovascular but not microvascular complications (64)
In theory the immunomodulatory effect of vitamin D should have a role in macro and microvascular complications given that these associated with inflammation (65). Inflammation plays a key role in the process of atherosclerosis. Stable plaque formation is associated with chronic inflammatory infiltrate and unstable or ruptured plaque is linked with acute inflammatory processes (66). Possible ways in which vitamin D may anti-atherosclerotic is by immunosuppressive effects and inhibiting enzymes which damage blood vessels (metalloproteinases) (66).
Recent emerging evidence suggests that vitamin D may be exerting an anti-atherosclerotic effect by having regulatory effect on vascular smooth muscle (VSM). Vascular smooth muscles play a key role in the development of atherosclerotic plaques through its proliferation and cytokine release to influence other cells. (67) Both Vascular smooth muscles and endothelial cells express vitamin D receptors of high affinity which respond to circulating levels of vitamin D producing numerous effects on both parts of the vasculature. These effects include contractility, migration and growth for example. (68-70) however it's apparent anti atherogenic effect is probably caused by reduction in vascular smooth muscle cell proliferation by reducing VSM responsiveness to growth factors such as PDGF (71). Furthermore calcification of coronary arteries is inversely proportional with circulating active vitamin D levels (72).
There seems to be a substantial amount of evidence to suggest that Vitamin D has a possible role in type 1 and type 2 diabetes, although a greater amount of evidence exists for type 2 diabetes. It would be hard to ignore the evidence and the plausible mechanisms of vitamin D in diabetes.
Vitamin D has proved to have an immunoregulatory effect which may play a big role in vitamin D deficient infants who have the potential to develop type 1 diabetes. Given that vitamin D receptors are located in various immune cells and tissues that regulate immune tolerance and type 1 diabetes is an autoimmune driven disease, in theory suggests that there is a probable role. Furthermore cohort studies have shown that vitamin D deficient infants who were given adequate supplementation of vitamin D had a lower risk of developing type 1 diabetes compared to controls. Vitamin D is strongly recommended for growing children in order to prevent them from developing conditions such as rickets but evidence exists that it should be implemented for the purpose of preventing autoimmune conditions such as type 1 diabetes too. Vitamin D can also have important immune effects in type 2 diabetes as they have an increased amount of circulating inflammatory cytokines which are thought to play a vital role in insulin resistance. Although mechanisms indicate that vitamin D supplementation should be given to patients with type 2 diabetes for this purpose, there seems to be very little published data investigating the effects of vitamin D and inflammation in type 2 diabetes
Vitamin D receptor polymorphisms are linked with type 1 and type 2 diabetes but these are only evident in some populations and it is hard to interpret data due to confusing conflicting results. However, further research and better techniques need to be done before we can make confident interpretations.
As mentioned before most patients with type 2 diabetes have pancreatic beta cells with residual capacity and vitamin D has proved to have a direct effect of increasing insulin secretion mainly by raising intracellcular calcium levels in the beta cells. Furthermore studies in both human and animal models have yielded promising results.
Although the management of diabetes is focused on reducing blood glucose levels, most diabetic patients actually die as a result of macrovascular complications which are not entirely glucose related. Diabetic patients with severe vitamin D deficiency have a higher mortality and this may well be due to the role of vitamin D in reducing blood pressure, inflammation and smooth muscle cell proliferation, which are features of atherosclerosis.
In general, most observational studies that have been performed support the role of vitamin D in type 1 and type 2 diabetics but cross sectional and prospective studies do not account for potential confounders. Further robust randomised controlled trials with a large sample sizes and evidence of optimal therapeutic serum vitamin D concentrations are required before we can make a firm inference. Nevertheless there seems to be much more evidence to suggest that vitamin D does more good than harm for diabetics.