Diabetess is a immense job worldwide with more than 10,000 people being diagnosed with diabetes every twelvemonth it is non difficult to understand why. With the find of insulin as a primary intervention for type 1 diabetes and legion drugs that have been implicated for the direction of type 2 diabetes have proved highly effectual but as the job is on the addition, many research workers have looked into the possible consequence of natural substances such as vitamin D which may hold a possible function in diabetes ( 0 ) .
Vitamin lack is a pandemic and harmonizing to the section of wellness, a astonishing 25 % of the population have low degrees of vitamin D in their blood. Many clinicians have looked at the possible function of vitamin D in diabetes.
Vitamin D is regarded a steroid endocrine which can be obtained of course from diet ( 30 % ) and the bulk coming from photochemical transition in the tegument from sunshine. Vitamin D is non activated when it comes from these two beginnings and has to be hydroxylated twice before it can be in its active signifier. The first measure of hydroxylation takes topographic point in the liver and the enzyme responsible converts vitamin D into 25, hydroxyvitamin D ( inactive signifier ) . The 2nd portion of hydroxylation takes topographic point in the kidneys and this converts 25, hydroxyvitamin D to the active signifier 1,25 hydoxyvitamin D. 1,25 hydroxyvitamin D is released into the circulation where it is transported in association with a vitamin D adhering protein until it reaches its mark 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 karyon. The ligand/receptor complex so migrates into the Deoxyribonucleic acid to increase the look of vitamin D related cistrons. ( 8,9 )
The indispensable function of Vitamin D is to keep calcium homeostasis peculiarly for map of the skeletal system. Vitamin D lack has been implicated in a figure of disease processes most commonly rachitiss and other skeletal upsets. However is besides correlated with increased hazard of cardiovascular disease, terrible asthma in kids and even malignant neoplastic disease. ( 10 )
Low degrees of vitamin D has become extremely prevailing worldwide ( 11 ) and is associated with an increased hazard of type 2 diabetes and all cause cardiovascular decease. ( 12,13 ) In recent old ages at that place has been find of vitamin D receptors located in pancreatic beta cells every bit good as vitamin D dependent Ca proteins in pancreatic tissue ( 14,15,16 ) . There is seemingly besides look of 1-alpha hydroxylase in pancreatic beta cells ( 17 ) , this enzyme being involved in the transition of hydroxyvitamin D into its active vitamin D signifier. It has been reported that vitamin D lack is associated with diabetes and that the refilling of vitamin D can better glycaemic control ( 4,5,6 ) . Apparently vitamin D has been shown to change insulin synthesis and secernment in both human and carnal theoretical accounts ( 2,3,22,23 ) . Conversely other surveies have shown that vitamin D has no consequence on diabetes and that this is merely a myth. ( 7 )
The compelling grounds suggests that vitamin D may hold an exciting function in diabetes mellitus. This raises many inquiries for case ; does vitamin D lack play a possible function in the pathogenesis of diabetes? Can vitamin D supplementation be used to forestall and perchance handle diabetes? This essay will turn to these issues by discoursing the possible physiological and pharmacological function of vitamin D in type 1 and type 2 diabetes mellitus by looking at grounds from tests and possible mechanism of vitamin D in Diabetes mellitus.
Possible function of vitamin D in type 1 diabetes
Vitamin D and the immune system in type 1 diabetes:
Type 1 diabetes is characterised by chronic hyperglycemia due to a complete deficiency of insulin caused by the production of inflammatory cells most likely macrophages, dendritic cells, B lymphocytes which lead to the devastation pancreatic beta cells. Type 1 diabetes is hence considered to be an autoimmune disease in which the pathogenesis to a great extent relies on the immune system ( 18 ) . To turn out that the immune system was the perpetrator for the development of diabetes, Miller et all irradiated to the immune system of non-diabetic gnawers, spleen cells from a diabetic mouse were so injected in the non-diabetic mice who so all developed diabetes, he so went onto to happen that the disposal of T-cells entirely were sufficient plenty for the development of diabetes, bespeaking that this was chiefly a T-cell mediated disease ( 28 ) .
Numerous surveies have shown that vitamin D may hold a function in modulating the immune system. ( 19 ) There is an being of vitamin D receptors located on certain cells of the immune system such as activated T lymph cells and macrophages. There is grounds of these receptors in tissues which are responsible for the tolerance of immune cells such as the Thymus secretory organ ( 20,21,22 ) . Furthermore, stimulated macrophages and dendritic cells are able to synthesize and release 1,25 hydroxyvitamin D by showing the enzyme, 1 alpha hydroxylase ( ? ) .Evidence now exists to show the functions that vitamin D has on the immune system: ( 26,27,
Elina et Al in 2001 looked at whether vitamin D supplementation or lack during babyhood would impact whether the babies went on to develop type 1 diabetes. This birth cohort survey that merely looked at certain populations found that regular supplementation of vitamin D reduced the frequence of type 1 diabetes compared with those that received no vitamin D supplementation ( ratio ratio= 0.12 ) . Furthermore surveies have shown that vitamin lack during gestation increases the likeliness of developing autoimmune conditions such as type 1 diabetes in ulterior life.
This possible hazard decrease is likely due to the function of vitamin D in modulating the immune system. For any autoimmune disease at that place needs to be a familial sensitivity, a trigger and a loss of tolerance ( RST ) . As discussed earlier, type 1 diabetes seems to be T-cell driven and the consequence of vitamin D in stamp downing T assistant cells and cytotoxic T cells ( killer T-cells ) may straight forestall these cells from wrongly placing self-islet antigens as foreign and as a effect destructing them. The direct consequence of vitamin D in stamp downing antigen professional cells ( macrophages, dendritic cells and B cells ) and indirectly by down modulating MHC category 2 molecules may halt these cells from showing islet-self antigens to helper T-cells. Helper T-cells are required to bring forth specific cytokines that activate killer T-cells. Vitamin D prevents helper T-cells by making this by suppressing them from let go ofing cardinal cytokines such as IL-2. Vitamin D can besides suppress killer T-cells by the initiation of regulative T-cells which suppress those T-cells which are considered to be suicidal. Vitamin D hence inhibits cytotoxic ( killer T-cells ) straight and indirectly to halt them from potentially destructing pancreatic beta cells. ( 31 )
Overall from the survey mentioned earlier and many others bring forthing similar consequences, decisions can be drawn that a recommended sum of vitamin D should be given to all babies ( 29,30 and the EURODIAB substudy 2 survey group ( 1999 ) vitamin vitamin D addendum survey in early childhood and hazard for type 1 ( insulin dependant diabetes mellitus. as avoiding vitamin D lack has proved critical for Beta cell map and may good halt the development of type 1 diabetes in ulterior life.
Polymorphisms of Vitamin D receptors in type 1 diabetics.
There is really assorted grounds to propose whether polymorphisms in the vitamin D receptors have any function in the pathogenesis of type 1 diabetes.
In some populations at that place seems to be a positive correlativity between vitamin D receptor polymorphisms. ( 1,2,3,4,5 ) . For case McDermott et Al found a relationship between a peculiar vitamin D receptor allelomorph and insulin dependant diabetes in South Indians and Yoshiyuki et Al found that in Nipponese populations vitamin D receptor start codon polymorphism effects familial susceptibleness to type 1 diabetes. ( 3 ) On the other side, the same is non true for other populations ( 6 ) .
The fact that there are positive correlativities between different polymorphisms in the vitamin D receptor in some populations and there are negative correlativities in other populations, the function that vitamin D receptor polymorphisms drama in the pathogenesis of type 1 diabetes is highly complex and confounding. The grounds suggests that polymorphisms may play a function in some populations but it is really hard to do any sound decisions based on the surveies that have been done and hence there remains an component of uncertainty in this country.
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 besides involves the immune system ( 18 ) . Patients with metabolic syndrome but are non-diabetic have an increased sum of serum inflammatory markers for case CRP, compared with non-diabetics and diabetic patients have a higher sum of inflammatory markers than both ( Pickup et al 1997 ) ( 18 ) . Surveies have found that there are peculiar cytokines for case IL-6 and TNF alpha that are abundant in patients with obesity/ metabolic syndrome and type 2 diabetes, bespeaking that these are the cardinal cytokines which interplay in the disease procedure. ( 32 )
How make these cytokines perchance play a function in the pathogenesis of type 2 diabetes? Well It is thought to hold a direct consequence on insulin signalling tracts peculiarly on insulin receptor substrates, which are a household of proteins when phosphorylated by the insulin receptor they bind to downstream signalling molecules that are involved in the biogenesis of insulin. Increased go arounding adipokines and cytokines peculiarly TNF alpha and interleukin-6 are thought to interfere with insulin receptor substrates. TNF alpha is understood to trip c-jun N-terminal kinases ( JNK ) . JNK phosphorylates many proteins at the degree of the chondriosome and karyon to impact their map. When TNF alpha activates JNK this phosphorylates insulin receptor substrates to halt them from triping the insulin signalling pathway, as a consequence insulin receptor substrates are degraded and insulin synthesis is suppressed. Similarly IL-6 is thought to trip a protein called suppresser cytokine signalling 3 ( SOC-3 ) which later binds to the c-terminus of insulin receptor to barricade the possible interaction of insulin receptor substrate with phosphotyrosine on receptor. ( 33,34 )
( 35,36 )
It has been claimed that vitamin D down regulates the production of the cardinal 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 cardinal inflammatory cytokines ( TH2 cytokines ) . Therefore it is really possible that vitamin D could be exercising an immunoregulatory consequence on T-cells by adhering to the vitamin D receptors located on the T-cells and forestalling them from bring forthing these cytokines, hence stamp downing the activations of the JNK tract and SOC-3 and so insulin receptor substrates can still work and subsquently insulin biogenesis can still take topographic point. There is no published informations nevertheless looking at the whether vitamin D has an influence on inflammatory go-betweens peculiarly cytokines and hence until this is explored, it Is hard to do the decision that Vitamin D has a steadfast function in type 2 diabetes through its action on the immune system.
Possible function of vitamin D on insulin secernment in type 2 diabetes:
In type 2 diabetes, there is normally a progressive loss of beta cells over many old ages and the insulin bring forthing cells still have a residuary map and produce insulin in little qunatities and with decreased sensitiveness. ( # ) This is why possible drugs can be used to heighten the production of insulin which merely can non be used in type 1 diabetes. Can the same be applied for vitamin D?
It has been reported that vitamin D has a possible function in exciting insulin secernment in the pancreatic beta cells of both animate beings and worlds. ( 2,3, 37, ) . Similarly Chui et Al found that vitamin D supplementation has a rapid consequence on bettering insulin secernment in response to an unwritten glucose burden in patients with mild type 2 diabetes ( 38 ) . The most plausible mechanism of this accomplishment is to make with the consequence that vitamin D has on Ca degrees and Sergeevin et Al found that 1,25 hydroxyvitamin D ( active vitamin D ) causes oscillations of intracellular Ca in a pancreatic beta cell line ( 37 ) . Harmonizing to beginnings it is likely that vitamin D Acts of the Apostless on pancreatic beta cells via Ca dependent endopeptidases. Theses endopeptidases cleave pro-insulin into insulin. In add-on to this Calcium does non merely increase insulin secernment by exocytosis but it works by advancing beta cell glycolysis ( 39 ) .
Equally good as vitamin D increasing intracellular Ca degrees, a lack of vitamin D consequences in an increased production of parathyroid endocrine by the parathyroid secretory organ ( 40 ) . Elevated degrees of parathyroid transiently raises intracellular Ca degrees ( 41 ) , nevertheless uninterrupted high degrees of Ca in cells can finally suppress beta cells from feeling rapid inflows of Ca which is required for insulin secernment ( 42, 43 ) . There is back uping grounds of this mechanism as surveies have shown that parathyroid endocrine degrees are reciprocally relative to insulin sensitiveness. ( 44 )
Another proposed mechanism is that high intracellular Ca degrees may adhere to the camodulin protein of insulin like growing factor receptor substrate, which so 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 important different between patients with secondary hyperparathyroidism and glucose homeostasis. ( 47 )
On the other manus old surveies have been experimental and so there may be an evident causal relationship between vitamin D and insulin secernment due to confusing factors for case. Mayer Davidson et al really late wanted to stop this guess by carry oning a ‘once and for all ‘ dual blinded randomised control test look intoing the function of vitamin D. Subjects with pre-diabetes were randomised to placebo or a really high dosage vitamin D addendum. Consequences showed that there were no differences between topics that were having a placebo and those which received high dose vitamin D in footings on insulin sensitiveness, insulin secernment and fasting glucose degrees. Davidson called claimed that vitamin D was a ‘dead terminal for diabetes ‘ . ( 48 ) There were lacks to this survey harmonizing to other research workers such as Cliff Rosen who argued that merely 100 people completed the test and that longer and more tests are required before a decision 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 oncoming of type 2 diabetes in selective populations.
One specific survey which was based on a Bangladeshi population yielded promising consequences. They found that a peculiar allelomorph called APA RFLP was linked to glucose induced insulin secernment ( 11 ) . Furthermore, there was back uping grounds that this allelomorph was correlated to higher fasting glucose degrees and glucose tolerance in aged patients who were non known to hold diabetes. ( 12 )
In a more recent published article, genotyping for a selected sum of cistron revealed that bsm1RFLP was linked with high fasting glucose concentrations in immature male persons. ( 13 ) The APA A1 and BSM1 vitamin D receptor polymorphisms were besides associated with rises in fasting glucose concentrations in Germans ( 14 ) . Overall these VDR polymorphisms have shown that associations can be made between peculiar cistron polymorphisms in the VDR and type 2 diabetes but merely in certain populations, hence although it has a possible function, it continues to stay a really complex issue and until it is studied in farther deepness and utilizing more direct option techniques such as clinch surveies ( 15 ) at that place seems to be a small function for its usage in type 2 diabetes. Furthermore, many instance control surveies have n’t really found any statistical significance between VDR polymorphisms and type 2 diabetics when compared to controls. ( 16, 17 )
Possible function of vitamin D in Diabetic complications.
Diabetic patients over clip necessarily stop up with diabetic complications. Chiefly these are divided into micro and macrovascular complications ( 50 ) . 50 % of type 2 diabetic patients suffer from complications at the clip of diagnosing harmonizing to the UKPDS ( 51 ) and the bulk cause of decease in diabetic patients is cardiovascular disease ( 52-56 ) .
In recent old ages, vitamin D lack has been linked as a possible modifiable hazard factor for many diseases including CVD ( 57 ) . Furthermore, Zitter adult male et al found that cardiovascular diseases was elevated at higher latitudes and increased during the winter months when vitamin D lack is more prevailing. The exact mechanism is non to the full understood but can be loosely associated with the consequence of vitamin D on blood force per unit area, parathyroid endocrine degrees, redness and vascular calcification. ( 24 ) In add-on, Wang et Al found that Persons with low 25, hydroxyvitamin D had a higher hazard cardiovascular events ( jeopardy ratio 1.62 ) compared with those high degrees and that this consequence nevertheless was merely apparent in participants with high blood pressure ( hazard ratio of 2.13. ( 58 ) This survey illustrated that vitamin D lack is a possible hazard factor for cardiovascular disease and peculiarly demonstrates that this may be associated with its diminishing blood force per unit area belongingss, although there are conflicting consequences to demo otherwise ( 62,63 ) .
It is thought that vitamin D reduces blood force per unit area by suppressing the RAAS system ( 59 ) and given the fact that type 2 diabetes and high blood pressure are normally associated conditions ( abcde ) , there may good be a function of vitamin D in cut downing high blood pressure in diabetics. The RAAS system plays a critical function in commanding blood force per unit area and when this system is activated, blood force per unit area is raised by a scope of mechanisms ( see figure below ) . Emerging surveies in recent old ages have shown that vitamin D is a possible suppresser in the production of cardinal constituents of the renin angiotonin aldosterone system ( 60 ) , Knockout vitamin D receptor gnawers had increased production of renin and angiotonin 2 taking to high blood pressure and its complications and the disposal of 1,25 hydroxyvitamin D ( active signifier ) reduces the look of renin. ( 61 ) Premises can hence be made that vitamin D has a possible function in cut downing the macrovascular complications in diabetes likely by cut downing blood force per unit area via its effects on RAAS:
Specifically concentrating on diabetic linked complications entirely, a survey showed that patients with terrible vitamin D lack had a much higher hazard of mortality ( hazard ratio 2.7 ) but there were no differences found with microvascular complications suggesting that vitamin D supplementation may merely play a function in macrovascular but non microvascular complications ( 64 )
In theory the immunomodulatory consequence of vitamin D should hold a function in macro and microvascular complications given that these associated with redness ( 65 ) . Inflammation plays a cardinal function in the procedure of coronary artery disease. Stable plaque formation is associated with chronic inflammatory infiltrate and unstable or ruptured plaque is linked with acute inflammatory procedures ( 66 ) . Possible ways in which vitamin D may anti-atherosclerotic is by immunosuppressive effects and suppressing enzymes which damage blood vass ( metalloproteinases ) ( 66 ) .
Recent emerging grounds suggests that vitamin D may be exercising an anti-atherosclerotic consequence by holding regulative consequence on vascular smooth musculus ( VSM ) . Vascular smooth musculuss play a cardinal function in the development of atherosclerotic plaques through its proliferation and cytokine release to act upon other cells. ( 67 ) Both Vascular smooth musculuss and endothelial cells express vitamin D receptors of high affinity which respond to go arounding degrees of vitamin D bring forthing legion effects on both parts of the vasculature. These effects include contractility, migration and growing for illustration. ( 68-70 ) nevertheless it ‘s evident anti atherogenic consequence is likely caused by decrease in vascular smooth musculus cell proliferation by cut downing VSM reactivity to growing factors such as PDGF ( 71 ) . Furthermore calcification of coronary arterias is inversely relative with go arounding active vitamin D degrees ( 72 ) .
There seems to be a significant sum of grounds to propose that Vitamin D has a possible function in type 1 and type 2 diabetes, although a greater sum of grounds exists for type 2 diabetes. It would be difficult to disregard the grounds and the plausible mechanisms of vitamin D in diabetes.
Vitamin D has proved to hold an immunoregulatory consequence which may play a large function in vitamin D deficient babies who have the possible to develop type 1 diabetes. Given that vitamin D receptors are located in assorted immune cells and tissues that regulate immune tolerance and type 1 diabetes is an autoimmune goaded disease, in theory suggests that there is a likely function. Furthermore cohort surveies have shown that vitamin D deficient babies who were given equal supplementation of vitamin D had a lower hazard of developing type 1 diabetes compared to controls. Vitamin D is strongly recommended for turning kids in order to forestall them from developing conditions such as rachitiss but grounds exists that it should be implemented for the intent of forestalling autoimmune conditions such as type 1 diabetes excessively. Vitamin D can besides hold of import immune effects in type 2 diabetes as they have an increased sum of go arounding inflammatory cytokines which are thought to play a critical function in insulin opposition. Although mechanisms indicate that vitamin D supplementation should be given to patients with type 2 diabetes for this intent, there seems to be really small published informations look intoing the effects of vitamin D and redness in type 2 diabetes
Vitamin D receptor polymorphisms are linked with type 1 and type 2 diabetes but these are merely apparent in some populations and it is difficult to construe informations due to confounding conflicting consequences. However, farther research and better techniques need to be done before we can do confident readings.
As mentioned before most patients with type 2 diabetes have pancreatic beta cells with residuary capacity and vitamin D has proved to hold a direct consequence of increasing insulin secernment chiefly by raising intracellcular Ca degrees in the beta cells. Furthermore surveies in both human and carnal theoretical accounts have yielded promising consequences.
Although the direction of diabetes is focused on cut downing blood glucose degrees, most diabetic patients really die as a consequence of macrovascular complications which are non wholly glucose related. Diabetic patients with terrible vitamin D lack have a higher mortality and this may good be due to the function of vitamin D in cut downing blood force per unit area, redness and smooth musculus cell proliferation, which are characteristics of coronary artery disease.
In general, most experimental surveies that have been performed support the function of vitamin D in type 1 and type 2 diabetics but cross sectional and prospective surveies do non account for possible confounders. Further robust randomised controlled tests with a big sample sizes and grounds of optimum curative serum vitamin D concentrations are required before we can do a house illation. Nevertheless at that place seems to be much more grounds to propose that vitamin D does more good than injury for diabetics.