Type 1 (T1D) and type 2 (T2D) diabetes are considered multifactorial diseases in which both genetic predisposition and environmental factors participate in their development. Many cellular, preclinical, and observational studies support a role for vitamin D in the pathogenesis of both types of diabetes including: (1) T1D and T2D patients have a higher incidence of hypovitaminosis D; (2) pancreatic tissue (more specifically the insulinproducing b-cells) as well as numerous cell types of the immune system express the vitamin D receptor (VDR) and vitamin D-binding protein (DBP); and (3) some allelic variations in genes involved in vitamin D metabolism and VDR are associated with glucose (in)tolerance, insulin secretion, and sensitivity, as well as inflammation. Moreover, pharmacologic doses of 1,25-dihydroxyvitamin D (1,25(OH) 2 D), the active form of vitamin D, prevent insulitis and T1D in nonobese diabetic (NOD) mice and other models of T1D, possibly by immune modulation as well as by direct effects on b-cell function. In T2D, vitamin D supplementation can increase insulin sensitivity and decrease inflammation. This article reviews the role of vitamin D in the pathogenesis of T1D and T2D, focusing on the therapeutic potential for vitamin D in the prevention/intervention of T1D and T2D as well as its complications.
Diabetes mellitus is one of the most common endocrine diseases, characterized by an increase in plasma glucose. Different forms of diabetes with very distinct pathogenesis exist. Over time, diabetes can lead to blindness, kidney failure, and nerve damage. Diabetes is also an important factor in accelerating atherosclerosis, leading to stroke, coronary heart disease, and other large blood vessel diseases, all ultimately associated with increased mortality risks.
The most prevalent form of diabetes is type 2 diabetes (T2D), currently affecting more than 300 million people worldwide. T2D is characterized by the combination of insulin resistance and failing β-cell function. Type 1 diabetes (T1D), on the other hand, is an autoimmune disease in which the body’s own immune system mistakenly attacks and destroys the insulin-producing β cell in the pancreas. T1D typically occurs in young, lean individuals, but older patients can also be affected. This subgroup is referred to as latent autoimmune diabetes in adults (LADA). LADA is a slow, progressive form of T1D. Other forms of diabetes include gestational diabetes (GD), secondary diabetes due to pancreatic diseases or surgery, and genetic forms of diabetes.
Vitamin D is a secosteroid that is generated from 7-dehydrocholesterol in skin under the influence of UV light. Therefore, by definition, vitamin D cannot be considered a true vitamin but rather a prohormone, as the natural source of vitamin D in evolution of vertebrates and primates is photosynthesis in the skin. Indeed, the normal human diet is usually poor in vitamin D except for fatty fish. Regardless of the source of vitamin D, it needs to be hydroxylated twice to become biologically active. Vitamin D is first hydroxylated in the liver by 25-hydroxylases (25(OH)ase), consisting of cytochrome P450 (CYP) isoforms (the mitochondrial CYP27A1 and the microsomal CYP2R1 [the most critical enzyme], CYP3A4, and CYPJ3) into 25-hydroxyvitamin D (25(OH)D). The second hydroxylation occurs in the kidney, by 1α-hydroxylase (1α(OH)ase, CYP27B1), as this tissue is normally the only one capable of the secretion of its end product, 1,25(OH) 2 D, into the blood circulation. Vitamin D and its metabolites are bound to a carrier protein (vitamin D binding protein; DBP) when transported through the circulation. Another multifunctional hydroxylase, 24-hydroxylase (24(OH)ase, CYP24A1), catabolizes vitamin D metabolites. Vitamin D exerts its action via a nuclear receptor (vitamin D receptor; VDR), present in nearly all nucleated cells, but with the highest concentration in the epithelial cells of the gut. However, most of these enzymes and proteins essential for the action of vitamin D are also present in many tissues not related to bone and calcium metabolism, such as the immune system.
Over many years, links between vitamin D status and diabetes mellitus have been identified. As early as the 1980s, it was shown that vitamin D deficiency in rodents and rabbits inhibits pancreatic insulin secretion, indicating that vitamin D is essential for the function of the endocrine pancreas. Later, the connection between vitamin D and diabetes was reinforced by the discovery of the VDR and DBP in pancreatic tissue (more specifically in the insulin-producing β cells) and also in various cell types of the immune system. Thus, vitamin D has been proposed as a possible therapeutic agent in the prevention and treatment of T1D and T2D.
Type 1 diabetes
T1D is a chronic autoimmune disease that results from the immune-mediated destruction of pancreatic β cells, thus resulting in insulin deficiency. The autoimmune process most commonly initiates in childhood and progresses for a variable period of months and even years before it leads to hyperglycemia and, thus, diagnosis. By the time of diagnosis only 10% to 30% of functional β-cell mass remains. T1D is the second most common chronic disease in children, second only to asthma, and is considered as a complex genetic trait; not only do numerous genetic loci contribute to susceptibility, but environmental factors also play an important role in determining risk.
Vitamin D and Genetic Predisposition to T1D
In T1D the major genetic determinant is located in the major histocompatibility complex (MHC) region on chromosome 6p21, although multiple non-MHC genes also contribute to T1D disease susceptibility. Refining genetic mapping particularly of the non-MHC loci may improve the ability to predict the risk of T1D and facilitate the testing of more aggressive preventive therapies. In this context, associations of T1D with polymorphisms in the CYP27B1 gene on chromosome 12q13.1-q13.3 may be useful. It is hypothesized that presence of polymorphisms in the CYP27B1 gene may reduce the (local) expression of 1α(OH)ase and consequently the conversion of 25(OH)D to 1,25(OH) 2 D, leading to increased predisposition to T1D.
In the past, it has been shown that allelic variations in the VDR gene are an important determinant for the amount of VDR expressed, and which in turn may influence the immune-modulatory function of the VDR. Several authors have demonstrated that VDR polymorphisms are able to influence the immune response in either healthy individuals or T1D patients. In epidemiologic studies, clear associations between VDR polymorphisms and T1D have been reported in South Indian, German, and Taiwanese populations, but were not found in a large combined population sample of British, Portuguese, and Finnish origin. In a recent study it was shown that specific VDR polymorphisms interact with the predisposing HLA DRB1 allele through vitamin D response element present in the promoter region of the DRB1*0301 allele, which may be detrimental for the manifestation of T1D, particularly in the case of vitamin D deficiency in early childhood due to poor expression of DRB1 0301 in the thymus.
1,25(OH) 2 D is biologically inactivated through a series of events starting with 24-hydroxylation. The 24(OH)ase enzyme is encoded by the CYP24A1 gene located on chromosome 20q13.2-q13.3. At present, no associations between CYP24A1 gene polymorphisms and T1D have been found.
Vitamin D as an Environmental Risk Factor
T1D has been linked to a clear north-south gradient as well as to a deficiency in vitamin D concentrations. Indeed, the incidence of T1D is higher in countries of northern latitude, this trend being reversed in the southern hemisphere. Latitude itself is unlikely to be an independent risk factor for T1D onset. On the other hand, UV-B irradiation, which follows a north-south gradient, is known to convert 7-dehydrocholesterol to vitamin D in the skin, and has protective properties against autoimmunity. A more significant correlation of T1D has been observed with erythemal UV-B irradiation than with latitude. Recently, Mohr and colleagues assessed the T1D incidence data for children younger than 14 years during 1990 to 1994 in 51 regions worldwide. This investigation found that incidence rates of T1D approached zero in regions worldwide with high UV-B irradiance. Furthermore, seasonality of T1D onset is well known. Kahn and colleagues reported that spring births were associated with increased likelihood of T1D, which might reflect insufficient maternal/neonatal vitamin D levels during a critical fetal/neonatal programming period. Indeed, vitamin D has been shown to have a role in development and function of the immune system. In fact, inadequate vitamin D and other nutrients during immune system development (from gestation up to the second year of life) may play a critical role in the development of autoimmune diseases. Therefore, it is thought that restoration of vitamin D levels (either by supplementation with vitamin D or by administration of [less hypercalcemic analogues of] the active hormone 1,25(OH) 2 D) may reduce the risk of T1D. How vitamin D interferes with the pathogenesis of T1D is still not fully elucidated, though some possible mechanisms have been suggested ( Fig. 1 ).
Vitamin D as an Immune System Modulator
There is increasing evidence that active vitamin D (1,25(OH) 2 D) acts as a modulator of the immune system. One of the first indications for this role was the finding of VDR expression in a wide range of immune cells (eg, monocytes, activated lymphocytes). Also, activation of the nuclear VDR is known to modify transcription via several intracellular pathways and influence proliferation and differentiation of immune cells.
Antigen-presenting cells: dendritic cells
Dendritic cells (DCs), which are highly specialized antigen-presenting cells, are known to be important for the priming of CD4 + T cells. DCs act as sentinels in lymphoid and nonlymphoid organs, capturing and processing antigens; once the antigen is captured the DCs will mature, increasing the expression of costimulatory molecules. For activation of T cells, appropriate interaction between the T-cell receptor and antigen/MHC complex as well as costimulatory signals are necessary. However, when there is a disruption in these interactions, T cells become anergic. There is increasing evidence that by hampering the costimulatory capacity of DCs, a shift from immunogenicity to tolerance can be achieved. 1,25(OH) 2 D has dramatic effects on antigen presentation, whereby it reduces antigen presentation by suppressing the expression of MHC-II molecules as well as costimulatory molecules. Many studies have shown the immunosuppressive properties of 1,25(OH) 2 D 3 on DCs. For instance, in vitro exposure of the cultured immature DCs to 1,25(OH) 2 D 3 can inhibit their maturation, decrease their production of interleukin (IL)-12, and increase the production of IL-10, thus leading to an immune-modulatory DC. 1,25(OH) 2 D 3 not only inhibits maturation of DCs but also increases the apoptosis of mature DCs. Furthermore, coculture of 1,25(OH) 2 D 3 -treated DCs with autoreactive T-cell clones isolated from T1D patients inhibited T-cell proliferation and showed selective apoptosis of the autoreactive T cells. Extensive proteomic analysis of DCs treated with TX527, a 14-epivitamin D 3 analogue, showed that DCs are not merely locked in an immature state but adopt a tolerogenic phenotype with special migratory and endocytic properties compared with mature or immature DCs. Furthermore, these 1,25(OH) 2 D 3 -treated DCs may induce Treg cells and inhibit autoimmune diseases such as T1D. However, most of these studies do not exclude that 1,25(OH) 2 D 3 could have a direct action on T-cell modulation as well.
T lymphocytes
VDR expression was first described in activated T cells, and early work suggested that vitamin D exerted its immune-modulatory effects on these cells. In the 1980s, several studies reported that 1,25(OH) 2 D 3 could inhibit proliferation of mitogen-stimulated T-cell cultures. In 1987, Rigby and colleagues described that 1,25(OH) 2 D 3 treatment inhibited IL-2 and interferon (IFN)-γ production by human T cells. Others demonstrated inhibition of the aforementioned cytokines as well as IL-12, a known T-cell stimulating factor that is involved in the differentiation of naïve T cells into Th0 cells, which further develop into either Th1 cells or Th2 cells. In addition, an enhancement of Th2-related cytokines (IL-4, IL-5, and IL-10) was observed. As already mentioned, 1,25(OH) 2 D 3 can also induce Treg cells in vitro and in vivo.
Until recently, most of these studies were performed on peripheral blood mononuclear cells (PBMC) consisting of lymphocytes and monocytes. As such, direct effects of 1,25(OH) 2 D 3 on T cells could not be proven. Work by Jeffery and colleagues on isolated CD4 + cells demonstrated that 1,25(OH) 2 D 3 can directly modulate T-cell responses. 1,25(OH) 2 D 3 inhibited the production of IFN-γ, IL-17, and IL-21 inflammatory cytokines by CD4 + T cells, and induced development of Treg cells expressing CTLA-4 and FoxP3. T cells cultured in the presence of both 1,25(OH) 2 D 3 and IL-2 expressed the highest levels of CTLA-4 and FoxP3, and possessed the ability to suppress proliferation of resting CD4 + T cells. Of interest, a different study showed that exposure of the skin to the topical vitamin D analogue calcipotriol before immunization with ovalbumin (OVA) and CpG DNA as an immune-stimulatory adjuvant induces Treg cells that prevent consequent antigen-specific CD8 + T-cell proliferation and IFN-γ production.
B lymphocytes
Resting B lymphocytes normally do not express VDR. On activation, however, VDR expression has been reported. Administration of 1,25(OH) 2 D 3 decreases proliferation and immunoglobulin (Ig) production, and induces apoptosis. Although 1,25(OH) 2 D 3 has potent direct effects on B lymphocytes in vitro, indirect mediation by T cells and monocytes or macrophages has been suggested as its most important mechanism of action.
Cytokines
Active vitamin D has also been reported to down-regulate the production of several cytokines, in particular, inflammatory cytokines such as IL-2, IL-6, IL-12, IFN-γ, tumor necrosis factor (TNF)-α, and TNF-β, while enhancing anti-inflammatory cytokines such as IL-4, IL-10, and TGF-β. This finding is of great relevance for the pathogenesis of T1D, as especially IFN-γ and IL-12, which are markers of Th1 immune responses, are known to enhance inflammatory processes and participate in immune-mediated destruction of insulin-producing β cells. Recently, low-intensity chronic inflammation related to obesity has been linked to insulin resistance, the major cause of T2D. It is suggested that the relationship between vitamin D and low-intensity chronic inflammation and insulin resistance in T2D can be mediated in part by the immune-modulating properties of 1,25(OH) 2 D 3 .
Vitamin D and the β Cell
Exposure of pancreatic β cells to proinflammatory cytokines induces endoplasmic reticulum stress, leading to death by apoptosis. Treatment of β cells with 1,25(OH) 2 D has been reported to directly protect against β-cell death by reducing expression of MHC class I molecules, inducing expression of antiapoptotic A20 protein and decreasing expression of Fas. The latter is a transmembrane cell surface receptor, transducing an apoptotic death signal and contributing to the pathogenesis of several autoimmune diseases including T1D. Of note, in vitro treatment of pancreatic islets with 1,25(OH) 2 D 3 was also shown to decrease IL-1β and IL-15 cytokine as well as IP-10 chemokine (IFN-γ inducible protein 10) expression in pancreatic β cells, indicating that 1,25(OH) 2 D 3 treatment could reduce the migration and recruitment of effector T cells and macrophages to the islets.
Animal Models
The immune-modulatory properties of active vitamin D suggest that vitamin D (metabolites or analogues) could be potential therapeutic agents for the prevention or cure of T1D. Treatment of NOD mice, an animal model for T1D, with high doses of 1,25(OH) 2 D 3 (5 μg/kg/2 d) showed a decrease in insulitis and diabetes development. Decreased numbers of effector T cells, as well as induction of Treg cells, was shown to be the basis for this protection. Later, the authors demonstrated that the arrest of insulitis and block of T-cell infiltration into the pancreas by treatment of prediabetic NOD mice with 1,25(OH) 2 D 3 was associated with reduced chemokine production by islet cells. Treatment of prediabetic NOD mice with 1,25(OH) 2 D 3 increased deletion of T lymphocytes in the thymus, allowing activation-induced cell death (AICD)-sensitive T lymphocytes to reach the periphery. Culture of DCs and thymic T lymphocytes from 1,25(OH) 2 D 3 -treated animals separately, however, demonstrated that both cell types needed to be exposed to 1,25(OH) 2 D 3 to obtain the apoptosis-restorative effect. Moreover, transfer experiments demonstrated that T lymphocytes from 1,25(OH) 2 D 3 -treated NOD mice were not able to transfer diabetes into young irradiated NOD mice, in contrast to age-matched untreated mice. The latter indicates that 1,25(OH) 2 D 3 is able to directly modulate immune cell responses. The authors also found that 1,25(OH) 2 D 3 is a potent inducer of thymic DC differentiation in NOD mice, consisting in modulation toward a more pronounced lymphoid phenotype and up-regulation of CD86. Moreover, NOD DCs generated from bone marrow in the presence of in vitro 1,25(OH) 2 D 3 exhibit dedifferentiation features of tolerogenic DCs.
Unfortunately, the doses needed for disease prevention in NOD mice lead to hypercalcemia and bone decalcification. This issue can be (partially) solved by using structural analogues of 1,25(OH) 2 D 3 . In fact, administration of vitamin D 3 analogues, specifically selected for their enhanced immune effects and decreased calcemic effects, was shown to delay or even inhibit the development of insulitis and the onset of T1D in NOD mice. The proposed mechanism of action was a restoration of suppressor-cell functionality.
In the streptozotocin-induced diabetes model, which is an inflammation-driven model of diabetes, 1,25(OH) 2 D 3 also induced a reduction in the incidence of diabetes. In the case of overt diabetes, 1,25(OH) 2 D 3 has little effect in reverting the disease. It is possible that at this point the number of remaining β-cell mass is simply not sufficient to restore insulin needs. Therefore, an alternative option to insulin therapy is islet or β-cell transplantation. In that regard, it has been shown that overtly diabetic NOD mice that received syngeneic islets and were treated with KH1060 (a 20-epivitamin D 3 analogue) together with cyclosporine displayed a significant prolongation of islet graft survival compared with untreated controls. The authors also demonstrated that this analogue in combination with cyclosporine was able to prevent early graft failure and delay graft rejection of xenogeneic islets transplanted in spontaneously diabetic NOD mice. More recently, a combination therapy using TX527, a 14-epivitamin D 3 analogue, with cyclosporine or IFN-β also induced a significant delay in diabetes recurrence after syngeneic islet transplantation, with an increase of IL-10 expression in islet grafts. Work by Adorini in an allogeneic islet transplantation model also confirmed that 1,25(OH) 2 D 3 treatment in combination with mycophenolate mofetil was able to reduce graft rejection, possibly by inducing tolerogenic DCs and/or Treg cells. Taken together, 1,25(OH) 2 D 3 and its structural analogues display attractive anti-inflammatory properties that open new avenues for the primary, secondary, or tertiary prevention of T1D and other autoimmune diseases.
Nevertheless, despite all the work showing the beneficial effects of vitamin D in T1D prevention, data from VDR knockout mice show conflicting results. Zeitz and colleagues showed in their model that mice presented higher concentrations of blood glucose and lower levels of circulating insulin, whereas Mathieu and colleagues and Gysemans and colleagues did not observe major alterations in glucose tolerance or diabetes incidence in their VDR knockout mouse models. However, these contradictory data could result from the different genetic background of the mice or the control of serum calcium homeostasis, but could also point toward redundancy of vitamin D signaling pathways, and may suggest that compensatory mechanisms are taking place when VDR is completely abrogated from early life onwards.
Clinical Interventions
Large-scale trials evaluating the efficacy of vitamin D in the prevention of T1D are still lacking, but interesting data can be obtained from epidemiologic observations and small-scale trials.
Several retrospective studies found beneficial effects of supplementation with regular vitamin D in early life on the later lifetime risk of T1D. Hypponen and colleagues found a significantly reduced risk of T1D development in a birth-cohort study when high doses of vitamin D supplementation (up to 2000 IU/d) were given during infancy. In addition, 2 studies by Stene and colleagues showed that use of cod liver oil, which is rich in vitamin D, during the first year of life was associated with a lower risk of developing T1D later in life. Finally, the European Community–sponsored Concerted Action on the Epidemiology and Prevention of Diabetes showed a 33% reduction of T1D in children who received vitamin D supplementation early in life. A meta-analysis of data from 4 case-control studies and one cohort study revealed lately that the risk of T1D was significantly reduced (29% reduction) in infants who were supplemented with vitamin D as compared with those who were not supplemented (pooled odds ratio 0.71, 95% confidence interval [CI] 0.60–0.84). There was also some evidence of a dose-response effect, with those using higher amounts of vitamin D being at lower risk of developing T1D. Some studies were not able to show an association with a reduced T1D risk, but none of them were associated with an increased risk.
Vitamin D supplementation during pregnancy has also yielded contradictory results. In 2000, Stene and colleagues documented in a pilot case-control study that cod liver oil, taken by the mother during pregnancy, was associated with a lower risk of T1D in their offspring. In a larger case-control study, Stene and colleagues could not confirm their initial results and were unable to find an association between the use of cod liver oil or other vitamin D supplements during pregnancy and T1D risk. Nevertheless, Fronczak and colleagues reported lower levels of anti-islet cell autoantibodies in almost two-thirds of children whose mothers had higher vitamin D intake during the third trimester. Taking into account that T1D susceptibility has been linked to certain HLA genotypes, Wicklow and Taback intend to pursue a trial using 2000 IU of regular vitamin D per day in newborn babies with increased HLA-associated risk. So far they have shown in a few babies that this dose of supplementation seems safe, and did not cause alterations in serum and urine calcium measurements ( Table 1 ).
| Intervention | Subjects’ Characteristics | Study Results | Refs. |
|---|---|---|---|
| Vitamin D supplements (first year of life) | 1429 cases; 5026 controls Age <14 y | Risk T1D ↓ (OR = 0.83) age <5 y Risk T1D ↓ (OR = 0.81) age 5–9 y Risk T1D ↓ (OR = 0.47) age 10–14 y | |
| Cod liver oil (pregnancy) (first year of life) | 78 cases; 980 controls Pregnant women Offspring <15 y | Risk of T1D ↓ offspring (OR = 0.63) Risk of T1D ↓ cod-liver oil fed-infants (OR = 0.82) | |
| 2000 IU/d (first year of life) | 81 cases; 10,285 controls Age 1–31 y | Insulin and C-peptide ↑ Risk of T1D ↓ (RR = 0.22) | |
| Cod liver oil (first year of life) | 95 cases; 346 controls Age <15 y | Risk of T1D ↓ Supplementation during 7–12 mo (OR = 0.55) Supplementation during 0–6 mo (OR = 0.80) | |
| Vitamin D (food) (pregnancy) | Offspring Age <5 y | Insulin autoantibodies ↓ (OR = 0.49) | |
| 0.25 μg 1,25(OH) 2 D 3 every 2 d or 25 mg nicotinamide/kg/d (1 y) | 70 Recently diagnosed T1D Age >5 y | Insulin needs ↓ 1,25(OH) 2 D 3 -treated group at 3–6 mo | |
| Vitamin D supplements (lactation) | 159 cases; 318 controls Age 0–29 y | Risk of T1D ↓ (OR = 0.33) | |
| 0.5 μg 1α(OH)D 3 /d (1 y) | 35 LADA Adults | C-peptide ↑ β-Cell function ↑ | |
| 2000 IU vitamin D first year of life | 7 newborns HLA-associated T1D risk Age >1 y | Serum and urine calcium = |
Data on intervention with active vitamin D (1,25(OH) 2 D) starting when β-cell damage is already present are disappointing. A small intervention trial in which newly-onset diabetic children were given a small dose (0.25 μg) of 1,25(OH) 2 D or nicotinamide showed that although insulin requirements decreased in the group treated with 1,25(OH) 2 D, they had no improvement in C-peptide levels. LADA is considered to be a subtype of T1D, in which the clinical manifestation begins and progresses slowly in adulthood. As in T1D, patients with LADA exhibit the presence of autoantibodies to the islets, especially those against glutamic acid decarboxylase. Li and colleagues described results of a pilot study in which LADA patients were given a synthetic analogue of vitamin D 3 , 1α(OH)D 3 , in addition to insulin treatment. The patients who received the analogue exhibited a better ability to preserve β-cell function in comparison with patients treated with insulin alone (see Table 1 ).
Type 2 diabetes
T2D is a disorder that results from defects in both insulin secretion and insulin sensitivity, and accounts for 90% of all diabetes cases. The growing rate of T2D is worrisome, with in the United States alone an estimated 1 million new cases every year. Initially, patients counteract their increased insulin resistance and stabilize circulating glucose levels through increased insulin production by pancreatic β cells. As the disease progresses and functional alterations are accentuated, patients show decreased insulin secretion, and eventually they can also present loss of β-cell mass. The exact mechanisms involving T2D development are still unknown, but lifestyle (eg, obesity, sedentary lifestyle, and unhealthy eating habits) and genetic components (eg, PPARγ and CAPN10 genes, and a whole set of gene polymorphisms each with small contributing effects) seem to be involved. This disease is most prevalent in obese, sedentary individuals with a concomitant elevation in free fatty acids and proinflammatory cytokines, and relatives of T2D patients also have an increased probability of developing this disease.
Vitamin D and Lifestyle in T2D
The number one risk factor for T2D is obesity. However, weight loss is difficult to achieve and maintain in a long term. Identification of easily modifiable risk factors is, therefore, urgently needed for primary prevention of T2D. It is interesting that obesity is often related to hypovitaminosis D. Indeed, the absolute fat mass has an inverse relation with the serum 25(OH)D concentration and correlates positively with the serum parathyroid hormone (PTH) level. This relationship may be caused by the great capacity of adipose tissue of storing vitamin D, thus making it biologically unavailable. An increased PTH level and a decreased amount of serum 25(OH)D 3 as well as 1,25(OH) 2 D 3 can increase intracellular calcium in adipocytes, which then stimulates the lipogenesis and predisposes to further weight gain. Therefore, it is presently unclear whether (mild) vitamin D deficiency is contributing to or is the consequence of obesity.
Vitamin D deficiency has been associated with higher risks for metabolic syndrome and T2D. Population studies suggest that vitamin D (and calcium) may play a significant role in promoting β-cell function and insulin sensitivity, important issues in the pathogenesis of T2D. The National Health and Nutrition Examination Survey (NHANES), a large cross-sectional study, showed an inverse correlation between serum 25(OH)D and incidence of T2D and insulin resistance. In a prospective examination of the Medical Research Council Ely Study 1990 to 2000, an inverse relationship between 25(OH)D and glycemic status was found. Supporting these data, a positive correlation between plasma 25(OH)D and insulin sensitivity in healthy subjects subjected to glucose tolerance tests was also reported. On the other hand, prolonged treatment of osteomalacia with vitamin D can increase insulin secretion and improve glucose tolerance.
Vitamin D deficiency in obese patients has been linked to secondary hyperparathyroidism, which can contribute to T2D development, as elevated levels of PTH have been associated to glucose intolerance and cardiovascular complications. Current data suggest that T2D patients with vitamin D insufficiency have increased C-reactive protein, fibrinogen, and hemoglobin A1c compared with healthy controls, indicating that inflammation provoked by immune cells (eg, macrophages) are implicated in insulin resistance and T2D. The authors reported that administration of vitamin D ameliorates markers of systemic inflammation, which are typically found in T2D patients, thereby possibly improving β-cell survival.
Another intriguing observation is that insulin resistance in skeletal muscle has a positive correlation with T2D, for which a possible explanation has recently been proposed. Oh and colleagues observed that up-regulation of caveolin-1 (highly likely to be involved in nongenomic vitamin D signaling ) significantly improved insulin sensitivity and improved glucose uptake in the skeletal muscle. Therefore, it would be interesting to investigate whether vitamin D supplementation in the nonobese T2D mouse model would improve insulin sensitivity and whether this would be correlated to caveolin-1 expression.
Vitamin D and Genetic Predisposition to T2D
T2D is a polygenic disorder, but monogenic disorders closely related to T2D also exist. Monogenic forms of T2D are rare and include subtypes of maturity onset diabetes (MODY). The majority of proteins that are linked to MODY are transcription factors (such as HNF-4α, HNF-1α, IPF-1, HNF-1β, and NEUROD1). On the other hand, causative genes in the more common polygenic forms of T2D are harder to be identified. However, there are several indications that polymorphisms of the DBP and VDR are related to impaired glucose tolerance and obesity. Even though these correlations vary according to age, lifestyle, and ethnicity of the subjects, there seems to be a fair amount of evidence to support this theory.
The DBP protein (also known as group-specific component protein, or GC) located on chromosome 4q12 is a highly polymorphic serum protein, mainly produced in the liver, with 3 common alleles (Gc1F, Gc1S, and Gc2) and more than 120 rare variants. Few studies have examined DBP polymorphisms and the risk of vitamin D–related diseases. In this regard, the DPB protein has been linked to abnormalities in glucose metabolism and obesity-related traits in different populations. Hirai and colleagues evaluated the variations of the DBP gene (Gc1F, Gc1S, and Gc2) in Japanese individuals with normal glucose tolerance. These investigators demonstrated that people with Gc1S/Gc2 and Gc1S/Gc1S had significantly higher fasting plasma concentrations than those with Gc1F/Gc1F. The same group also reported that Japanese T2D patients had higher frequencies of the Gc1S/Gc2 genotype and lower frequencies of the Gc1F allele in comparison with control subjects. Other studies in Caucasian patients of American or European origin could not confirm the relation between genetic variants of the DBP gene and the susceptibility to T2D. It has been suggested that DBP polymorphisms can perhaps influence bioactive 25(OH)D levels through changes in the ratio of free/bound hormones, by a differential affinity, or through effects on concentrations of the DBP/25(OH)D complex that can be internalized by receptor-mediated endocytosis and activate the VDR pathway.
The VDR gene is located on chromosome 12q13.11 and consists of 11 exons. Most VDR polymorphisms are located at the 3′ untranslated region of the VDR gene, such as the BsmI, ApaI, and TaqI restriction fragment length polymorphisms. Several observational studies have reported associations between VDR polymorphisms and T2D, fasting glucose, glucose intolerance, insulin sensitivity, insulin secretion, and calcitriol levels. In the Rancho Bernardo study, polymorphism in ApaI, BsmI, and TaqI in older Caucasian men was verified. The investigators observed that the frequency of aa genotype of ApaI polymorphism was marginally higher in T2D patients. Also, fasting plasma glucose and prevalence of glucose intolerance were significantly higher in nondiabetic persons with aa genotype compared with those with AA genotype. Moreover, the bb genotype of BsmI polymorphism was associated with insulin resistance. Ortlepp and colleagues investigated the association of fasting glucose, low physical activity, and BsmI VDR polymorphism. In this study, males with low physical activity and gene carriers with the genotype BB had significantly higher levels of fasting glucose than gene carriers with the genotype Bb or bb. Of note, this effect was not seen in individuals with high physical activity. A recent study found that the BsmI polymorphism seems to influence body mass index (BMI; weight in kilograms divided by height in meters squared), whereas the FokI seems to affect insulin sensitivity and serum high-density lipoprotein cholesterol (cHDL) level. It was found that BB carriers tend to have higher BMI and waist circumference compared with the bb genotypes. Similarly, FF and Ff carriers had higher fasting insulin levels than the ff carriers, and lower cHDL levels in comparison with ff genotypes. Ye and colleagues also describe a correlation between BMI/obesity and VDR polymorphism. This study found that T2D patients who were diagnosed at 45 years or younger with T-allele of TaqI and the b-allele of BsmI had higher BMI. More recently, Dilmec and colleagues could not find a correlation between VDR polymorphisms (ie, ApaI and TaqI) and T2D risk in a study of 241 individuals (72 patients with T2DM and 169 healthy individuals). Regarding the matter of ethnicity, studies are inconclusive, as associations between VDR polymorphisms and the risk of T2D in different ethnic populations have produced variable results.
The pathophysiological mechanisms of these associations remain unexplained, but there seems to be a relation between the VDR genotype and certain traits of susceptibility to T2D. For instance, VDR polymorphisms are linked to obesity, and vitamin D itself has been reported to participate in adipocyte differentiation and metabolism. Moreover, polymorphisms of VDR might play a role in the pathogenesis of T2D by influencing the secretory capacity of β cells. The VDR genotype was associated with altered fasting glucose, confirming the importance of vitamin D in the modulation of insulin secretion (see next section).
Vitamin D and the β Cell
There is strong evidence that vitamin D is important for glucose homeostasis and that this could be mediated by its direct action on β-cell function. Several studies in animals and humans indicate a positive correlation between vitamin D deficiency and glucose intolerance as well as impaired insulin secretion. Further, this deficiency seems to have a specific effect on insulin and not on other islet hormones such as glucagon. For instance, experiments on glucose- and sulfonylurea-stimulated islets obtained from rats kept on a vitamin D–deficient diet showed impaired insulin secretion and glucose tolerance. These defects were partially corrected by vitamin D replenishment. However, whether these defects are directly caused by lack of vitamin D or indirectly by hypocalcemia is not clear.
More convincing data on the beneficial effects of vitamin D on insulin secretion were obtained in experiments demonstrating that synthesis and release of insulin by islets isolated from normal animals could be enhanced by glucose challenge in the presence of high doses of 1,25(OH) 2 D 3 . Stimulation of islets by 1,25(OH) 2 D 3 was shown to significantly increase the levels of cytosolic Ca 2+ , indicating that this could be a mechanism by which 1,25(OH) 2 D 3 is able to stimulate insulin secretion. Ca 2+ is known to be important for the exocytosis of insulin from the β cell and for β-cell glycolysis, which participates in translating circulating glucose levels. Moreover, vitamin D could regulate insulin secretion and synthesis by facilitating the conversion of proinsulin to insulin, which is known to be dependent on the cleavage by β-cell calcium-dependent endopeptidases. It is also possible that high intracellular Ca 2+ improves the binding of calmodulin to the insulin receptor substrate-1, thereby interfering with insulin-stimulated tyrosine phosphorylation and phosphoinositide-3 kinase activation. In this regard, PTH has been found to be inversely associated with insulin sensitivity. Another possible mechanism that has been suggested is that vitamin D could directly modulate β-cell growth and differentiation.
The effects of 1,25(OH) 2 D 3 and its analogues have been examined regarding binding to nuclear VDR and membrane VDR, through which they induce genomic and nongenomic responses, respectively. Among these studies, Sergeev and Rhoten have reported that the administration of 1,25(OH) 2 D 3 evoked oscillations of intracellular Ca 2+ in a pancreatic β-cell line within a few minutes. Later, Kajikawa and colleagues demonstrated that the 6-s- cis analogue, 1,25(OH) 2 lumisterol 3 , has a rapid insulinotropic effect, through nongenomic signal transduction via putative membrane VDR, which would be dependent on the augmentation of Ca 2+ influx through voltage-dependent Ca 2+ channels on the plasma membrane, being also linked to metabolic signals derived from glucose in pancreatic β cells.
As T2D has been recently associated with systemic inflammation, which is linked primarily to insulin resistance, vitamin D may also improve insulin sensitivity and β-cell function by directly modulating the generation and effects of inflammatory cytokines, as discussed previously.
Animal Studies
Experimental studies in animal models also suggest a role for vitamin D in the pathogenesis of T2D. Animal studies reveal that vitamin D deficiency is associated with impaired insulin sensitivity, while insulin secretion increases through vitamin D supplementation.
Chang-Quan and colleagues reported that T2D was associated with an abnormal vitamin D metabolism that was characterized by deficiency in 1,25(OH) 2 D and was related to renal injury. In the ob/ob mouse model, treatment with 1α(OH)D improved hyperglycemia, hyperinsulinemia, and fat tissue responsiveness to hormones. Anderson and Rowling demonstrated in Zucker Diabetic Fatty rats that vitamin D status was compromised due to poor vitamin D reabsorption in the kidney.
Considering that obesity seems to be an important risk factor to T2D, it was investigated whether vitamin D 3 had a beneficial effect on blood glucose in obese SHR and Wistar rats. Although vitamin D 3 supplementation in SHR rats did not alter the blood glucose levels in all rats, 40% of those rats had a reduction in glucose by 60%. In Wistar rats, a significant reduction in glucose levels in all animals supplemented with vitamin D 3 was found. In addition, feeding of cod liver oil to streptozotocin-induced diabetic rats partially improved their blood glucose levels as well as their cardiovascular and metabolic abnormalities. In another study, vitamin D 3 supplementation of spontaneously hypertensive rats normalized the membrane potential and contractility of aorta.
Clinical Interventions
In view of the cellular, preclinical data and observational studies in man, it seems reasonable to consider that vitamin D status influences the incidence of T2D and that vitamin D supplementation could prevent or ameliorate the disease, at least in cases of (mild) vitamin D deficiency. Despite this, trials in patients have yielded conflicting results ( Table 2 ).
| Intervention | Subjects’ Characteristics | Study Results | Refs. |
|---|---|---|---|
| 2000 IU vitamin D 3 /d (2 y), n = 25 0.25 μg 1α(OH)D 3 /d (2 y), n = 23 >0.25 μg 1,25(OH) 2 D 3 /d (1 y), n = 40 | n = 238 Postmenopausal women Age 45–54 y | Fasting glucose levels = | |
| 2 μg 1α(OH)D 3 /d (3 wk) | 7 cases; 7 controls T2D Japanese patients Age ∼54 y | Insulin secretion ↑ Free fatty acid ↓ | |
| 2000 IU vitamin D 3 /d (6 mo) | 4 cases; 10 controls Vitamin D deficient subjects Age ∼32 y | Insulin secretion ↑ | |
| 0.75 μg 1α(OH)D 3 /d (3 mo) | 65 Caucasian vitamin D sufficient men with impaired glucose tolerance Age 61–65 y | Glucose levels = Insulin secretion = Body weight ↓ Urinary calcium ↑ | |
| 2000 IU vitamin D/d (1 mo) | 1 Vitamin D deficient hypocalcemic woman Age ∼65 y | Glucose tolerance ↑ β-Cell function ↑ | |
| Single IV injection of 100,000 IU vitamin D 3 | 22 Vitamin D deficient subjects Age ∼45 y | Insulin and C-peptide ↑ | |
| 500 mg Ca 2+ and/or 0.5 μg 1,25(OH) 2 D 3 /d (21 d) | 17 Uremic men and women Age ∼50 y | First-phase insulin secretion and insulin sensitivity ↑ | |
| Oral 1 μg 1,25(OH) 2 D 3 /d (4 d) | 20 T2D men and women Age ∼60 y | Insulin secretion and C-peptide ↑ Urinary calcium ↑ in patients with short duration of diabetes | |
| 1.5 μg 1,25(OH) 2 D 3 /d (7 d) | 18 Healthy young men Age ∼26 y | PTH concentration ↓ Urinary calcium ↑ | |
| Single IM injection 300,000 IU vitamin D 2 | 3 T2D men and women | Insulin resistance ↑ | |
| 1332 IU vitamin D 3 /d (1 mo) | 10 T2D women Age ∼54 y | First-phase insulin secretion ↑ | |
| Vitamin D and/or calcium supplementation | 4843 cases; 1,576,114 controls Female nurses Age ∼46 y | 23% ↓ risk of T2D when vitamin D consumption/d is ≥800 IU compared with <200 IU/d | |
| 500 mg calcium and 700 IU vitamin D 3 /d (3 y) | 314 Nondiabetic Caucasians Age ∼71 y | Rise glycemia and insulin resistance ↓ in patients with impaired fasting glucose levels | |
| 1000 mg Calcium and 400 IU vitamin D 3 /d (6 y) | 2291 cases; 31,660 controls Postmenopausal women Age 50–79 y | Insulin or glucose levels = Diabetes incidence = | |
| 3 doses of 120,000 IU vitamin D 3 /fortnight (6 wk) | 1000 healthy, centrally obese males Age ≥35 y | Insulin secretion = Insulin sensitivity ↑ |
Vitamin D 3 supplementation of vitamin D–deficient T2D patients tended to reduce insulin requirements and lower serum triglycerides. Boucher and colleagues showed transient improvement of insulin secretion and C-peptide levels in at-risk patients treated with intramuscular vitamin D. In support to these findings, a small study in which a group of T2D women received 1332 IU of vitamin D 3 daily for 1 month showed an improvement on first-phase insulin secretion and a trend toward decreased insulin resistance. Moreover, the Nurses’ Health Study, which included 1,580,957 women over a period of more than 20 years with no history of diabetes, cardiovascular disease, or cancer at baseline, showed that a combined daily intake of greater than 1200 mg calcium and greater than 800 IU vitamin D was associated with a 33% lower risk of T2D compared with an intake of less than 600 mg and 400 IU calcium and vitamin D. In 2008, 2 nested case-control studies, collected by the Finnish Mobile Clinic from 1973 to 1980, were pooled for analysis. These results supported the hypothesis that high vitamin D status provides protection against T2D. Recently, a New Zealand study found that South Asian women with insulin resistance improved markedly after taking vitamin D supplements. Optimal vitamin D concentrations for reducing insulin resistance were shown to be 80 to 119 nmol/L, providing further evidence for an increase in the recommended adequate levels.
On the other hand, some studies show no effect of vitamin D supplementation and improvement of T2D. For instance, the Women’s Health Initiative, in which low-dose calcium and 400 IU/d of vitamin D supplementation were given, did not show protection against diabetes. It was recently reported that daily oral administration of 800 IU (20 μg) vitamin D 3 alone or in association with 1000 mg calcium to older people also failed to prevent T2D. In one study, Asian T2D patients with vitamin D deficiency even had a worsening of their condition through increased insulin resistance and deterioration of glycemic control. Another point to note is that, in general, no benefits in glucose tolerance have been seen with vitamin D supplementation in patients who are not vitamin D deficient. Of importance is that some of these studies reported elevation in calcium urinary excretion in vitamin D–supplemented individuals. The contradictory results of vitamin D supplementation in T2D suggest that dose and method of supplementation, as well as the genetic background and baseline vitamin D status of individuals, appear to be important for the efficacy of vitamin D supplementation against development of T2D.
Type 2 diabetes
T2D is a disorder that results from defects in both insulin secretion and insulin sensitivity, and accounts for 90% of all diabetes cases. The growing rate of T2D is worrisome, with in the United States alone an estimated 1 million new cases every year. Initially, patients counteract their increased insulin resistance and stabilize circulating glucose levels through increased insulin production by pancreatic β cells. As the disease progresses and functional alterations are accentuated, patients show decreased insulin secretion, and eventually they can also present loss of β-cell mass. The exact mechanisms involving T2D development are still unknown, but lifestyle (eg, obesity, sedentary lifestyle, and unhealthy eating habits) and genetic components (eg, PPARγ and CAPN10 genes, and a whole set of gene polymorphisms each with small contributing effects) seem to be involved. This disease is most prevalent in obese, sedentary individuals with a concomitant elevation in free fatty acids and proinflammatory cytokines, and relatives of T2D patients also have an increased probability of developing this disease.
Vitamin D and Lifestyle in T2D
The number one risk factor for T2D is obesity. However, weight loss is difficult to achieve and maintain in a long term. Identification of easily modifiable risk factors is, therefore, urgently needed for primary prevention of T2D. It is interesting that obesity is often related to hypovitaminosis D. Indeed, the absolute fat mass has an inverse relation with the serum 25(OH)D concentration and correlates positively with the serum parathyroid hormone (PTH) level. This relationship may be caused by the great capacity of adipose tissue of storing vitamin D, thus making it biologically unavailable. An increased PTH level and a decreased amount of serum 25(OH)D 3 as well as 1,25(OH) 2 D 3 can increase intracellular calcium in adipocytes, which then stimulates the lipogenesis and predisposes to further weight gain. Therefore, it is presently unclear whether (mild) vitamin D deficiency is contributing to or is the consequence of obesity.
Vitamin D deficiency has been associated with higher risks for metabolic syndrome and T2D. Population studies suggest that vitamin D (and calcium) may play a significant role in promoting β-cell function and insulin sensitivity, important issues in the pathogenesis of T2D. The National Health and Nutrition Examination Survey (NHANES), a large cross-sectional study, showed an inverse correlation between serum 25(OH)D and incidence of T2D and insulin resistance. In a prospective examination of the Medical Research Council Ely Study 1990 to 2000, an inverse relationship between 25(OH)D and glycemic status was found. Supporting these data, a positive correlation between plasma 25(OH)D and insulin sensitivity in healthy subjects subjected to glucose tolerance tests was also reported. On the other hand, prolonged treatment of osteomalacia with vitamin D can increase insulin secretion and improve glucose tolerance.
Vitamin D deficiency in obese patients has been linked to secondary hyperparathyroidism, which can contribute to T2D development, as elevated levels of PTH have been associated to glucose intolerance and cardiovascular complications. Current data suggest that T2D patients with vitamin D insufficiency have increased C-reactive protein, fibrinogen, and hemoglobin A1c compared with healthy controls, indicating that inflammation provoked by immune cells (eg, macrophages) are implicated in insulin resistance and T2D. The authors reported that administration of vitamin D ameliorates markers of systemic inflammation, which are typically found in T2D patients, thereby possibly improving β-cell survival.
Another intriguing observation is that insulin resistance in skeletal muscle has a positive correlation with T2D, for which a possible explanation has recently been proposed. Oh and colleagues observed that up-regulation of caveolin-1 (highly likely to be involved in nongenomic vitamin D signaling ) significantly improved insulin sensitivity and improved glucose uptake in the skeletal muscle. Therefore, it would be interesting to investigate whether vitamin D supplementation in the nonobese T2D mouse model would improve insulin sensitivity and whether this would be correlated to caveolin-1 expression.
Vitamin D and Genetic Predisposition to T2D
T2D is a polygenic disorder, but monogenic disorders closely related to T2D also exist. Monogenic forms of T2D are rare and include subtypes of maturity onset diabetes (MODY). The majority of proteins that are linked to MODY are transcription factors (such as HNF-4α, HNF-1α, IPF-1, HNF-1β, and NEUROD1). On the other hand, causative genes in the more common polygenic forms of T2D are harder to be identified. However, there are several indications that polymorphisms of the DBP and VDR are related to impaired glucose tolerance and obesity. Even though these correlations vary according to age, lifestyle, and ethnicity of the subjects, there seems to be a fair amount of evidence to support this theory.
The DBP protein (also known as group-specific component protein, or GC) located on chromosome 4q12 is a highly polymorphic serum protein, mainly produced in the liver, with 3 common alleles (Gc1F, Gc1S, and Gc2) and more than 120 rare variants. Few studies have examined DBP polymorphisms and the risk of vitamin D–related diseases. In this regard, the DPB protein has been linked to abnormalities in glucose metabolism and obesity-related traits in different populations. Hirai and colleagues evaluated the variations of the DBP gene (Gc1F, Gc1S, and Gc2) in Japanese individuals with normal glucose tolerance. These investigators demonstrated that people with Gc1S/Gc2 and Gc1S/Gc1S had significantly higher fasting plasma concentrations than those with Gc1F/Gc1F. The same group also reported that Japanese T2D patients had higher frequencies of the Gc1S/Gc2 genotype and lower frequencies of the Gc1F allele in comparison with control subjects. Other studies in Caucasian patients of American or European origin could not confirm the relation between genetic variants of the DBP gene and the susceptibility to T2D. It has been suggested that DBP polymorphisms can perhaps influence bioactive 25(OH)D levels through changes in the ratio of free/bound hormones, by a differential affinity, or through effects on concentrations of the DBP/25(OH)D complex that can be internalized by receptor-mediated endocytosis and activate the VDR pathway.
The VDR gene is located on chromosome 12q13.11 and consists of 11 exons. Most VDR polymorphisms are located at the 3′ untranslated region of the VDR gene, such as the BsmI, ApaI, and TaqI restriction fragment length polymorphisms. Several observational studies have reported associations between VDR polymorphisms and T2D, fasting glucose, glucose intolerance, insulin sensitivity, insulin secretion, and calcitriol levels. In the Rancho Bernardo study, polymorphism in ApaI, BsmI, and TaqI in older Caucasian men was verified. The investigators observed that the frequency of aa genotype of ApaI polymorphism was marginally higher in T2D patients. Also, fasting plasma glucose and prevalence of glucose intolerance were significantly higher in nondiabetic persons with aa genotype compared with those with AA genotype. Moreover, the bb genotype of BsmI polymorphism was associated with insulin resistance. Ortlepp and colleagues investigated the association of fasting glucose, low physical activity, and BsmI VDR polymorphism. In this study, males with low physical activity and gene carriers with the genotype BB had significantly higher levels of fasting glucose than gene carriers with the genotype Bb or bb. Of note, this effect was not seen in individuals with high physical activity. A recent study found that the BsmI polymorphism seems to influence body mass index (BMI; weight in kilograms divided by height in meters squared), whereas the FokI seems to affect insulin sensitivity and serum high-density lipoprotein cholesterol (cHDL) level. It was found that BB carriers tend to have higher BMI and waist circumference compared with the bb genotypes. Similarly, FF and Ff carriers had higher fasting insulin levels than the ff carriers, and lower cHDL levels in comparison with ff genotypes. Ye and colleagues also describe a correlation between BMI/obesity and VDR polymorphism. This study found that T2D patients who were diagnosed at 45 years or younger with T-allele of TaqI and the b-allele of BsmI had higher BMI. More recently, Dilmec and colleagues could not find a correlation between VDR polymorphisms (ie, ApaI and TaqI) and T2D risk in a study of 241 individuals (72 patients with T2DM and 169 healthy individuals). Regarding the matter of ethnicity, studies are inconclusive, as associations between VDR polymorphisms and the risk of T2D in different ethnic populations have produced variable results.
The pathophysiological mechanisms of these associations remain unexplained, but there seems to be a relation between the VDR genotype and certain traits of susceptibility to T2D. For instance, VDR polymorphisms are linked to obesity, and vitamin D itself has been reported to participate in adipocyte differentiation and metabolism. Moreover, polymorphisms of VDR might play a role in the pathogenesis of T2D by influencing the secretory capacity of β cells. The VDR genotype was associated with altered fasting glucose, confirming the importance of vitamin D in the modulation of insulin secretion (see next section).
Vitamin D and the β Cell
There is strong evidence that vitamin D is important for glucose homeostasis and that this could be mediated by its direct action on β-cell function. Several studies in animals and humans indicate a positive correlation between vitamin D deficiency and glucose intolerance as well as impaired insulin secretion. Further, this deficiency seems to have a specific effect on insulin and not on other islet hormones such as glucagon. For instance, experiments on glucose- and sulfonylurea-stimulated islets obtained from rats kept on a vitamin D–deficient diet showed impaired insulin secretion and glucose tolerance. These defects were partially corrected by vitamin D replenishment. However, whether these defects are directly caused by lack of vitamin D or indirectly by hypocalcemia is not clear.
More convincing data on the beneficial effects of vitamin D on insulin secretion were obtained in experiments demonstrating that synthesis and release of insulin by islets isolated from normal animals could be enhanced by glucose challenge in the presence of high doses of 1,25(OH) 2 D 3 . Stimulation of islets by 1,25(OH) 2 D 3 was shown to significantly increase the levels of cytosolic Ca 2+ , indicating that this could be a mechanism by which 1,25(OH) 2 D 3 is able to stimulate insulin secretion. Ca 2+ is known to be important for the exocytosis of insulin from the β cell and for β-cell glycolysis, which participates in translating circulating glucose levels. Moreover, vitamin D could regulate insulin secretion and synthesis by facilitating the conversion of proinsulin to insulin, which is known to be dependent on the cleavage by β-cell calcium-dependent endopeptidases. It is also possible that high intracellular Ca 2+ improves the binding of calmodulin to the insulin receptor substrate-1, thereby interfering with insulin-stimulated tyrosine phosphorylation and phosphoinositide-3 kinase activation. In this regard, PTH has been found to be inversely associated with insulin sensitivity. Another possible mechanism that has been suggested is that vitamin D could directly modulate β-cell growth and differentiation.
The effects of 1,25(OH) 2 D 3 and its analogues have been examined regarding binding to nuclear VDR and membrane VDR, through which they induce genomic and nongenomic responses, respectively. Among these studies, Sergeev and Rhoten have reported that the administration of 1,25(OH) 2 D 3 evoked oscillations of intracellular Ca 2+ in a pancreatic β-cell line within a few minutes. Later, Kajikawa and colleagues demonstrated that the 6-s- cis analogue, 1,25(OH) 2 lumisterol 3 , has a rapid insulinotropic effect, through nongenomic signal transduction via putative membrane VDR, which would be dependent on the augmentation of Ca 2+ influx through voltage-dependent Ca 2+ channels on the plasma membrane, being also linked to metabolic signals derived from glucose in pancreatic β cells.
As T2D has been recently associated with systemic inflammation, which is linked primarily to insulin resistance, vitamin D may also improve insulin sensitivity and β-cell function by directly modulating the generation and effects of inflammatory cytokines, as discussed previously.
Animal Studies
Experimental studies in animal models also suggest a role for vitamin D in the pathogenesis of T2D. Animal studies reveal that vitamin D deficiency is associated with impaired insulin sensitivity, while insulin secretion increases through vitamin D supplementation.
Chang-Quan and colleagues reported that T2D was associated with an abnormal vitamin D metabolism that was characterized by deficiency in 1,25(OH) 2 D and was related to renal injury. In the ob/ob mouse model, treatment with 1α(OH)D improved hyperglycemia, hyperinsulinemia, and fat tissue responsiveness to hormones. Anderson and Rowling demonstrated in Zucker Diabetic Fatty rats that vitamin D status was compromised due to poor vitamin D reabsorption in the kidney.
Considering that obesity seems to be an important risk factor to T2D, it was investigated whether vitamin D 3 had a beneficial effect on blood glucose in obese SHR and Wistar rats. Although vitamin D 3 supplementation in SHR rats did not alter the blood glucose levels in all rats, 40% of those rats had a reduction in glucose by 60%. In Wistar rats, a significant reduction in glucose levels in all animals supplemented with vitamin D 3 was found. In addition, feeding of cod liver oil to streptozotocin-induced diabetic rats partially improved their blood glucose levels as well as their cardiovascular and metabolic abnormalities. In another study, vitamin D 3 supplementation of spontaneously hypertensive rats normalized the membrane potential and contractility of aorta.
Clinical Interventions
In view of the cellular, preclinical data and observational studies in man, it seems reasonable to consider that vitamin D status influences the incidence of T2D and that vitamin D supplementation could prevent or ameliorate the disease, at least in cases of (mild) vitamin D deficiency. Despite this, trials in patients have yielded conflicting results ( Table 2 ).
Related posts:
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
