Vitamin D is characterized as a regulator of homeostasis of bone and mineral metabolism, but it can also provide nonskeletal actions because vitamin D receptors have been found in various tissues including the brain, prostate, breast, colon, pancreas, and immune cells. Bone metabolism, modulation of the immune response, and regulation of cell proliferation and differentiation are all biological functions of vitamin D. Vitamin D may play an important role in modifying the risk of cardiometabolic outcomes, including diabetes mellitus (DM), hypertension, and cardiovascular disease. The incidence of type 2 DM is increasing worldwide and results from a lack of insulin or inadequate insulin secretion following increases in insulin resistance. Therefore, it has been proposed that vitamin D deficiency plays an important role in insulin resistance resulting in diabetes. The potential role of vitamin D deficiency in insulin resistance has been proposed to be associated with inherited gene polymorphisms including vitamin D-binding protein, vitamin D receptor, and vitamin D 1alpha-hydroxylase gene. Other roles have been proposed to involve immunoregulatory function by activating innate and adaptive immunity and cytokine release, activating inflammation by upregulation of nuclear factor κB and inducing tumor necrosis factor α, and other molecular actions to maintain glucose homeostasis and mediate insulin sensitivity by a low calcium status, obesity, or by elevating serum levels of parathyroid hormone. These effects of vitamin D deficiency, either acting in concert or alone, all serve to increase insulin resistance. Although there is evidence to support a relationship between vitamin D status and insulin resistance, the underlying mechanism requires further exploration. The purpose of this paper was to review the current information available concerning the role of vitamin D in insulin resistance.
1. Introduction
The incidence of type 2 diabetes mellitus (type 2 DM) is increasing at an alarming rate both nationally and worldwide. Defects in pancreatic β-cell function, insulin sensitivity, and systemic inflammation all contribute to the development of type 2 DM. Since insulin resistance is a risk factor for diabetes, understanding the role of various nutritional and other modifiable risk factors that may contribute to the pathogenesis of diabetes is important. Obesity and other lifestyle factors such as exercise, alcohol consumption, smoking, and certain dietary habits can also play an important role. Recently, a novel association between insulin resistance and vitamin D deficiency has been proposed. Vitamin D has in vitro and in vivo effects on pancreatic β-cells and insulin sensitivity. In this study, we place specific emphasis on the epidemiological evidence and possible mechanisms of these effects. In addition, we also review the therapeutic strategies involving vitamin D in the treatment of insulin resistance.
2. Synthesis and Metabolism of Vitamin D 2.1. Synthesis of 1,25-Hydroxyvitamin D
Vitamin D is obtained from exposure to sunlight, diet (fortified foods), and dietary supplements. When the skin is exposed to solar ultraviolet B radiation (wavelength, 290 to 315 nm), 7-dehydrocholesterol is converted to previtamin D3, which is rapidly converted to vitamin D3 (cholecalciferol) (Figure 1). Vitamin D from the skin and diet is transported in the blood by circulating vitamin D-binding protein (DBP, a specific binding protein for vitamin D and its metabolites in serum) to the liver. In the liver, vitamin D is metabolized by P 450 vitamin D-25-hydroxylase to 25-hydroxyvitamin D, which is the major circulating metabolite and used to determine a patient’s vitamin D status [1–5]. Almost all 25-hydroxyvitamin D is bound to circulating DBP and is filtered by the kidneys and reabsorbed by the proximal convoluted tubules. In the kidney, megalin and cubilin, members of the LDL receptor superfamily, play essential roles in endocytic internalization of 25-hydroxyvitamin D [6, 7]. In the proximal renal tubules, 25-hydroxyvitamin D is hydroxylased at the position of carbon 1 of the A-ring by the enzyme 25-hydroxyvitamin D3 1α-hydroxylase (CYP27B1) to its active form, 1,25-hydroxyvitamin D. This enzyme is also found in extrarenal sites including the placenta, monocytes and macrophages [8–11].
The synthesis and metabolism of vitamin D in the regulation of mineral homeostasis and nonskeletal functions. When under exposed to solar UVB (ultraviolet B), 7-dehydrocholesterol in the skin is converted to previtamin D3, which is immediately converted to vitamin D3. Vitamin D can also be obtained from dietary vitamin D2 and D3 incorporated into chylomicrons. Vitamin D in the circulation is bound to DBP (vitamin D-binding protein), which transports it to the liver where it is converted to 25-hydroxyvitamin D by vitamin D-25-hydroxylase. The biologically inactive 25-hydroxyvitamin D must be converted in the kidneys to active 1,25-hydroxyvitamin D by 1-OHase (25-hydroxyvitamin D3 1α-hydroxylase). Serum PTH (parathyroid hormone), low phosphorus/calcium, sex hormones, calcitonin, and prolactin can increase (⊕) the renal production of 1,25-hydroxyvitamin D. However, FGF-23 (fibroblast growth factor 23) and 1,25-hydroxyvitamin D have feedback functions to inhibit (⊝) 1-OHase. Finally, the active 1,25-hydroxyvitamin D can bind to VDR-RXR (vitamin D receptor-retinoic acid x-receptor complex) in the intestine, bone, and parathyroid glands and then exert the classical function of mineral homeostasis. In addition, it also has nonskeletal functions when bound to VDR-RXR in other organs (breast, colon, prostate, kidney, pancreas) or immune cells (macrophages/monocytes). FGFR: FGF-23 receptor; TRPV6: transient receptor potential cation channel, subfamily V, member 6; RANKL: receptor activator of nuclear factor-κB ligand; RANK: the receptor for RANKL on preosteoclasts.
2.2. Regulation of 1,25-Hydroxyvitamin D
The production of 1,25-hydroxyvitamin D is regulated by serum calcium and phosphorus levels, plasma parathyroid hormone (PTH) levels, and fibroblast growth factor 23 (FGF-23). Low serum calcium and phosphate levels result in enhanced activity of 1α-hydroxylase. PTH stimulates the transcription of 1α-hydroxylase and nuclear receptor 4A2 (NR4A2) is a key factor involved in the induction of 1α-hydroxylase transcription by PTH. 1,25-hydroxyvitamin D in turn suppresses PTH production at the level of transcription [12]. FGF-23 is a phosphaturic factor that promotes renal phosphate excretion by inactivating the sodium-phosphate cotransporter in the proximal tubule. 1,25-hydroxyvitamin D stimulates the production of FGF 23 in the bone, and an increased level of FGF-23 suppresses the expression of 1α-hydroxylase in the kidneys. FGF-23 requires a klotho (a multifunctional protein involved in phosphate and calcium homeostasis) as a cofactor for FGF signaling, and 1,25-hydroxyvitamin D upregulates klotho gene expression in the kidneys [12, 13].
2.3. Vitamin D Binding Protein (DBP) and Vitamin D Receptor (VDR)
Vitamin D signaling may occur by binding of circulating 1,25-hydroxyvitamin D to VDR in β-cells or by local production from the main circulating form, 25-hydroxyvitamin D. DBP (calbindin-D28 K), encoded by the Gc (group-specific component) gene, functions as a specific transporter of circulating vitamin D metabolites [14] and is essential for vitamin D endocytosis and metabolism [15]. DBP is a highly polymorphic single-chain serum glycoprotein synthesized and secreted by the liver that forms a complex with vitamin D ensuring that circulating vitamin D is delivered to target tissues [16]. Vitamin D exerts its actions in a variety of cell types through binding to the cytosolic/nuclear vitamin D receptor (VDR), which is a member of the steroid/thyroid hormone receptor family that functions as a transcriptional activator of many genes [17–19]. VDR is widely distributed in more than 38 types of tissue, where it clearly controls vital genes related to bone metabolism, oxidative damage, chronic diseases, and inflammation [20]. The VDR gene, located on chromosome 12q13.1, consists of 14 exons and has an extensive promoter region capable of generating multiple tissue-specific transcripts [21, 22]. Upon ligand binding, this nuclear hormone receptor in conjunction with its heterodimeric partner, the retinoid receptor (RXR), regulates gene transcription through vitamin D responsive elements (VDRE) in the promoter regions of vitamin D target genes, thereby modifying their expression [23]. In addition to cytosolic/nuclear VDR mediating transcriptional regulation, the possible existence of a vitamin D receptor localized to the plasma membrane VDR (mVDR) has been postulated recently [24]. Pancreatic β-cells express both the specific cytosolic/nuclear VDR and putative mVDR.
2.4. Extrarenal 1,25-Hydroxyvitamin D Production (Nonskeletal Functions)
Vitamin D is characterized as a regulator of homeostasis of bone and mineral metabolisms. In addition to its classical actions on mineral homeostasis, 1,25-dihydroxyvitamin D also has nonskeletal actions (Figure 1). It has been reported that the brain, prostate, breast, colon, and pancreas, as well as immune cells, have vitamin D receptors (VDR-RXR) and respond to this active form of vitamin D [4, 25–27]. More than 200 genes are controlled by 1,25-hydroxyvitamin D directly or indirectly to regulate cellular proliferation, differentiation, apoptosis, and angiogenesis [28]. For example, breast, colon, prostate, and other tissues express 25-hydroxyvitamin D3 1α-hydroxylase and produce 1,25-dihydroxyvitamin D which binds to VDR-RXR and then regulates a variety of genes that control proliferation, including p21 and p27, as well as genes that inhibit angiogenesis and induce differentiation and apoptosis. 1,25-dihydroxyvitamin D, an immunomodulator favoring the induction of regulatory T cells, can render dendritic cells tolerogenic with increased selective expression of immunoglobulin-like transcript 3 (ILT3) [29]. Meanwhile, 1,25-dihydroxyvitamin D inhibits rennin synthesis, and increases insulin production, myocardial contractility, the reproductive system, and hair growth [30–34]. Therefore, vitamin D may play an important role in modifying the risk of cardiometabolic outcomes, including type 2 DM, hypertension, and cardiovascular diseases.
3. Vitamin D Deficiency and Insulin Resistance3.1. Vitamin D Deficiency
Vitamin D deficiency has been linked to a wide field of health problems including several types of cancer and autoimmune and metabolic diseases such as type 1 DM and type 2 DM. More than 30–50% of all children and adults are at risk of vitamin D deficiency, defined as a serum 25-hydroxyvitamin D level below 50 nmol/L [35]. However, this cutoff value is significantly higher than the 25 nmol/L (10 ng/mL) [36]. The association of vitamin D status and cardiometabolic disorders (cardiovascular disease, diabetes, and metabolic syndrome) was reviewed recently in a meta-analysis of 28 independently published studies [37]. The findings showed a significant 55% reduction in the risk of diabetes (9 studies), a 33% reduction in the risk of cardiovascular diseases (16 studies), and a 51% reduction in metabolic syndrome (8 studies) associated with a high serum 25-dihydroxyvitamin D concentration [37].
3.2. Evidence Linking Vitamin D to Insulin Resistance and Diabetes
Several studies have indicated a relationship between vitamin D status and the risk of diabetes or glucose intolerance. Vitamin D has been proposed to play an important role and to be a risk factor in the development of insulin resistance and the pathogenesis of type 2 DM by affecting either insulin sensitivity or β-cell function, or both [31, 38, 39]. Type 1 DM has been also reported to be associated with vitamin D deficiency based on animal and human observational studies [19, 23, 40]. The prevalence of hypovitaminosis D was found to be higher in diabetic patients (24%; P<0.001) than in controls (16%) in one study [41]. Increasing evidence shows that vitamin D levels are also lower in patients with type 1 DM, especially at the onset [42].
3.3. Association between Vitamin D and Insulin Resistance
1,25-dihydroxyvitamin D plays an important role in glucose homeostasis via different mechanisms. It not only improves insulin sensitivity of the target cells (liver, skeletal muscle, and adipose tissue) but also enhances and improves β-cell function. In addition, 1,25-dihydroxyvitamin D protects β-cells from detrimental immune attacks, directly by its action on β-cells, but also indirectly by acting on different immune cells, including inflammatory macrophages, dendritic cells, and a variety of T cells. Macrophages, dendritic cells, T lymphocytes, and B lymphocytes can synthesize 1,25-dihydroxyvitamin D, all contributing to the regulation of local immune responses [43]. The potential role of vitamin D deficiency in insulin resistance is shown in Table 1.
Role of vitamin D deficiency in insulin resistance.
Role
References
Inherited gene polymorphisms
[44–68]
(1) Including DBP, VDR, and CYP1alpha gene polymorphisms
(2) Disturbance of vitamin D transport, action, and production
Immunoregulatory function
[69–83]
(1) Activating innate and adaptive immunity
(2) Enhancing dendritic cell maturation and macrophage differentiation, and cytokine release
(3) Enhancing T-cell proliferation
(4) Releases of IL-12, IL-2, INF-γ, and TNFα (destruction of the β-cell)
Inflammation
[84–90]
(1) Upregulation of NF-κB and inducing TNFα proinflammatory actions
(2) Downregulates IκB-α by decreasing mRNA stability and increasing IκB-α phosphorylation.
(3) Enhancing the expression of TLR2 and TLR4 protein and mRNA in human monocytes, reducing the release of cytokines
Other molecular actions of vitamin D to alter glucose homeostasis
[90–95]
(1) Low calcium status: hypocalcemia can lower glucose-stimulated insulin secretion in β-cell
(2) PTH level: elevating PTH reduces glucose uptake by liver, muscle and adipose cell
(3) Obesity: vitamin D deficiency can increase adiposity, and increasing sequestration of vitamin D in adipose tissue
DBP: vitamin D binding protein; VDR: vitamin D receptor; CYP1alpha: vitamin D 1alpha-hydroxylase; IL-12: interleukin-12; INF-γ: interferon-γ; TNF α: tumor necrosis factor α; NF-κB: nuclear factor κB; IκB-α: the inhibitor of NF-κB; TLR: Toll-like receptors; PTH: parathyroid hormone.
4. Role of Vitamin D Deficiency in Insulin Resistance4.1. Vitamin D Associated Gene Polymorphisms and Insulin Resistance
Gene polymorphisms of the DBP, VDR, or vitamin D 1alpha-hydroxylase (CYP1alpha) genes may affect insulin release and result in insulin resistant. In addition, these gene polymorphisms may disturb vitamin D production, transport, and action.
4.1.1. Gene Polymorphisms of the DBP Gene
Electrophoretic variants of DBP have been associated not only with diabetes, but also with prediabetic traits. Two frequent missense polymorphisms at codons 416 GAT → GAG (Asp → Glu) and 420 ACG → AAG (Thr → Lys) in exon 11 of the DBP gene are the genetic basis for the three common electrophoretic variants of DBP (Gc1F, Gc1S, and Gc2) and the resulting circulating phenotypes (Gc1F/Gc1F, Gc1F/Gc1S, Gc1S/Gc1S, Gc1F/Gc2, Gc1S/Gc2, and Gc2/Gc2) [44]. These variants of DBP are the serum carriers of vitamin D metabolites and have been associated with a higher risk of type 2 DM or prediabetic phenotypes in several studies [45–49]. However, some studies have shown that the genetic variants of the DBP gene are not associated with diabetes [50, 51].
4.1.2. Gene Polymorphisms of the VDR Gene
VDR functions as a transcription factor when bound to 1,25-dihydroxyvitamin D. VDRs are present in pancreatic β-cells and vitamin D is essential for normal insulin secretion [52]. Several VDR polymorphisms have been found since the early 1990s, including Apa1 [53], EcoRV, Bsm1 [54], Taq1 [55], Tru91 [56], Fok1 [57], and Cdx2 [58]. To date, three adjacent restriction fragment length polymorphisms for Bsm1, Apa1, and Taq1at the 3′ end of the VDR gene have been the most frequently studied [59]. VDR polymorphisms have been reported to be related to type 1 DM [60–62]. The Bsm1 polymorphism has been shown to be associated with type 1 DM in Indians living in the south of the country [60], and combinations of Bsm1/Apa1/Taq1 have been shown to influence susceptibility to type 1 DM in Germans [61]. In a Taiwanese population, the AA genotype of the Apa1 polymorphism was found to be associated with type 1 DM [62]. In type 1 DM, four well-known polymorphisms (Fok1, Apa1, Bsm1, and Taq1) in the VDR gene have been implicated in the susceptibility to type 1 DM, however the results to date have been inconclusive. A meta-analysis (57 case-control studies in 26 published studies) indicated that the Bsm1 polymorphism is associated with an increased risk of type 1 DM (BB+Bb versus bb: OR=1.30, 95% CI = 1.03−1.63), while the Fok1, Apa1, and Taq1 polymorphisms were not, especially in Asians [63]. The VDR genotype may affect insulin resistance, both with regards to insulin secretion (the Apa1 VDR polymorphism) and insulin resistance (the Bsm1 VDR polymorphism) [64].
In type 2 DM, the VDR gene polymorphism aa genotype was found to be associated with defective insulin secretion in Bangladeshi Asians, a population at increased risk of type 2 DM [65]. The associations of the Fok1, Apal, Bsm1 and Taq1 polymorphisms of the VDR gene with type 2 DM were also explored in a case-control study (308 type 2 DM patients and 240 control cases). In this study, no associations were found between the four polymorphisms examined and type 2 DM [66]. In another study, the distributions of alleles and genotypes of the four single-nucleotide polymorphisms in intron 8 (Bsm1, Tru91, Apal) and exon 9 (Taq1) of the VDR gene were similar in patients with type 2 DM (n=309) and controls (n=143) [67]. Therefore, the evidence supporting an association of VDR genotypes with the risk of diabetes is conflicting.
4.1.3. Gene Polymorphisms of the CYP1alpha Gene
Polymorphisms of the CYP1alpha gene involved in the metabolism of vitamin D may influence the susceptibility to type 2 DM. A study on the association of two markers, one in intron 6 and the other located upstream from the 5′ end of the CYP1alpha gene, with type 2 DM in a Polish population found no differences in the distributions of genotypes, haplotypes, and haplotype combinations between the groups. However, the T-C/T-T heterozygous haplotype combination was more prevalent in the subgroup of obese type 2 DM patients (BMI≥30) than in the controls (41.5% versus 28.6%, P=0.01), suggesting an association with the risk factors for diabetes and obesity [68].
4.2. Effects of Vitamin D on the Immune System and Insulin Resistance 4.2.1. Immunoregulatory Function of Vitamin D
Basic science and epidemiological studies indicate that vitamin D has importance not only for cardiovascular health, but also for the immune response. Vitamin D has been shown to have a role in the development and function of the immune system. In fact, inadequate vitamin D and other nutrients during the development of the immune system may play a critical role in the development of autoimmune diseases. Evidence from animal models and prospective studies of rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, and type 1 DM suggests that vitamin D has an important role as a modifiable environmental factor in autoimmune diseases [69–71].
4.2.2. Immunoregulatory Function of Vitamin D on Insulin Resistance
The immune system plays a central role in the destruction of β-cells [72]. The detection of VDR in almost all cells of the immune system, especially antigen-presenting cells (macrophages and dendritic cells) and activated T cells [73–75], led to the investigation of a potential role for vitamin D as an immunomodulator. In addition, activation of nuclear VDR is also known to modify transcription via several intracellular pathways and influence proliferation and differentiation of immune cells [76, 77]. The importance of vitamin D in immune regulation is highlighted by the facts that VDR is expressed in activated inflammatory cells, that T-cell proliferation is inhibited by 1,25-dihydroxyvitamin D, and that activated macrophages produce 1,25-dihydroxyvitamin D [74, 78]. Vitamin D signaling pathways regulate both innate and adaptive immunity, maintaining the associated inflammatory response within physiological limits.
The innate immune response involves the activation of Toll-like receptors(TLRs) on polymorphonuclear cells, monocytes, macrophages, and a number of epithelial cells [79]. 1,25-dihydroxyvitamin D primarily influences dendritic cell maturation and macrophage differentiation, and also reduces the release of cytokines [80]. The adaptive immune response is initiated by cells specializing in antigen presentation, including dendritic cells and macrophages, which are responsible for presenting antigens for specific recognition by T lymphocytes and B lymphocytes [81]. 1,25-dihydroxyvitamin D exerts an inhibitory effect on the adaptive immune system by modifying the capacity of antigen-presenting cells (APCs) to induce T lymphocyte activation, proliferation and cytokine secretion [82]. 1,25-dihydroxyvitamin D decreases the maturation of dendritic cells and also inhibits the release of interleukin-12 (IL-12) (stimulating T-helper 1 cell development), IL-2, interferon-γ (INF-γ), and tumor necrosis factor α (TNFα) (stimulators of inflammation), which involves the destruction of β-cells resulting in insulin resistance. Overall, 1,25-dihydroxyvitamin D directly modulates T-cell proliferation and cytokine production, decreases the development of T helper 1 (TH1) cells, inhibits TH17 cell development, and increases the production of Thelper 2 (TH2) cells and T regulatory cells [83]. These immunomodulatory effects of 1,25-dihydroxyvitamin D can lead to the protection of target tissues, such as β-cells.
4.3. Inflammation, Vitamin D, and Insulin Resistance
Chronic inflammation is involved in the development of insulin resistance, which increases the risk of type 2 DM. VDR is known to be expressed by macrophages and dendritic cells, suggesting that vitamin D plays an important role in the modulation of inflammatory responses [84]. Both cell types express the enzymes vitamin D-25-hydroxylase and 1α-hydroxylase and can produce 1,25-dihydroxyvitamin D [85]. Several studies have supported the role of vitamin D and 1,25-dihydroxyvitamin D as an anti-inflammatory agent. Macrophages are cells with a large capacity for cytokine production, in particular TNFα, which is one of the most important products released from these cells [78]. The transcriptional activation of the TNFα gene in macrophages is largely dependent on nuclear factor κB (NF-κB) dependent transcriptional activation [86]. In lipopolysaccharide-(LPS-) stimulated murine macrophages, 1,25-dihydroxyvitamin D upregulates IκB-α (the inhibitor of NF-κB) by increasing mRNA stability and decreasing IκB-α phosphorylation. Furthermore, increased IκB-α levels can reduce the nuclear translocation of NF-κB [87]. In addition, 1,25-dihydroxyvitamin D suppresses the expressions of TLR2 and TLR4 proteins and mRNA in human monocytes in a time- and dose-dependent fashion [88]. Recently, it has also been suggested that inflammation and activation of the innate immune system could be downregulated by hydroxyvitamin D by increased levels of inflammatory markers (TNFα, IL-6, IL-1, IL-8, cyclooxygenase-2, intercellular adhesion molecule-1, and B7-1) in monocytes from type 2 DM compared with monocytes from healthy controls [89]. In summary, 1,25-dihydroxyvitamin D inhibits the release of the pro-inflammatory cytokine TNFα and regulates the activity of NF-κB, [90] and suppresses the expressions of TLR2 and TLR4 proteins and mRNA in human monocytes, reducing the release of cytokines. Therefore, vitamin D may also function to reduce insulin resistance and the risk of diabetes by decreasing inflammatory responses.
4.4. Other Molecular Actions of Vitamin D to Alter Glucose Homeostasis
Several mechanisms have been proposed to explain the impact of vitamin D on insulin resistance including gene polymorphisms and the immunoregulatory function of vitamin D and inflammation as mentioned previously. The regulation of serum calcium via PTH and 1,25-dihydroxyvitamin D following changes in dietary calcium and obesity has been proposed to mediate the effects of vitamin D on insulin resistance.
4.4.1. Stimulation of Insulin Secretion by Vitamin D and Calcium
There is evidence that vitamin D may stimulate pancreatic insulin secretion directly. Vitamin D exerts its effects through nuclear vitamin D receptors [91]. The stimulatory effects of vitamin D on insulin secretion may only manifest when calcium levels are adequate. Insulin secretion is a calcium-dependent process, and therefore alterations in calcium flux can have adverse effects on β-cell secretary function. Glucose-stimulated insulin secretion has also been found to be lower in vitamin D-deficient rats when concurrent hypocalcemia has not been corrected [92].
4.4.2. Parathyroid Hormone (PTH)
PTH regulates the activity of renal 1α-hydroxylase to convert 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D. However, extra-renal 1α-hydroxylase, which may lead to the local production of 1,25-dihydroxyvitamin D under conditions of high vitamin D status [93], has also been identified in a variety of tissues including muscles and adipocytes [94]. PTH may mediate insulin resistance by reducing glucose uptake by liver, muscle and adipose cells. PTH treatment (16 h) was found to decrease insulin-stimulated glucose transport [90, 95] in an osteoblast-like cell type. Another study indicated that PTH decreased insulin-stimulated glucose uptake in rat adipocytes [96]. These studies suggest that PTH may elicit insulin resistance by reducing the number of glucose transporters (both GLUT1 and GLUT4) available in cell membranes to promote glucose uptake [90]. PTH has also been shown to suppress insulin release [97] and to promote insulin resistance in adipocytes [90]. Therefore, PTH may negatively affect insulin sensitivity through altering body composition and inhibiting insulin signaling.
4.4.3. Muscle and Obesity
Vitamin D and PTH have also been associated with a variety of other actions beyond their classical functions, including cell growth, differentiation and apoptosis. Both hormones have been shown to increase levels of intracellular calcium and other rapid signaling pathways in a variety of tissues including adipocytes and muscle cells. Vitamin D may reduce adiposity, thereby improving insulin sensitivity indirectly through improving muscle mass and the reduction in vitamin D status with increased adiposity [90]. In addition, obesity, increasing sequestration of vitamin D in adipose tissue, is also known to be associated with reduced vitamin D status [98].
5. Therapeutic Interventions on Insulin Resistance with Vitamin D5.1. Effect of Vitamin D on Insulin Resistance
Vitamin D may have a beneficial effect on improving pancreatic β-cell function, decreasing insulin resistance, and improving systemic inflammation [26].
5.1.1. Pancreatic β-cell Function
Several studies support a role of vitamin D in pancreatic β-cell function through direct and indirect effects. The direct effect is where vitamin D binds directly to the β-cell vitamin D receptor. The indirect effect may be via its important and well-recognized role in regulating extracellular calcium and calcium flux through β-cells [26].
5.1.2. Insulin Resistance
Vitamin D may have a beneficial effect on insulin action either directly, by stimulating the expression of insulin receptors and thereby enhancing insulin responsiveness for glucose transport [106], or indirectly via its role in regulating extracellular calcium and ensuring normal calcium influx through cell membranes and an adequate intracellular cytosolic calcium pool because calcium is essential for insulin-mediated intracellular processes in insulin-responsive tissues such as skeletal muscles and adipose tissues [107].
5.1.3. Inflammation
Systemic inflammation has been linked primarily to insulin resistance, but elevated cytokines may also play a role in β-cell dysfunction by triggering β-cell apoptosis. Vitamin D may improve insulin sensitivity and promote β-cell survival by directly modulating the generation and effects of cytokines. Vitamin D interacts with vitamin D response elements in the promoter region of cytokine genes to interfere with nuclear transcription factors implicated in cytokine generation, and its action and can downregulate activation of NFκB [108–110].
5.2. Evidence of Intervention with Vitamin D Supplementation
The mainstay management for vitamin D deficiency is vitamin D supplementation to prevent or ameliorate the disease. Several studies support that vitamin D supplementation may affect glucose homeostasis or improve insulin resistance [99–101, 105] (Table 2). Restoration of vitamin D levels was shown to ameliorate glucose tolerance in a study on one hypocalcemic woman with vitamin D deficiency [105]. A significant increase in serum calcium levels and a reduction in serum free fatty acid levels have been found after taking vitamin D supplementations [99]. Recently, a New Zealand study found that south Asian women with insulin resistance improved markedly after taking vitamin D supplements [111]. The optimal vitamin D concentrations for reducing insulin resistance have been shown to be 80 to 119 nmol/L, providing further evidence for an increase in the recommended adequate levels [43].
Effects of vitamin D supplementation in insulin resistance.
Study
Intervention
Subjects
Effect
Pittas et al. [26]
vitamin D (700 IU/d for 3 years) and calcium intake
314
Decreased insulin resistance
Inomata et al. [99]
1α(OH) vitamin D(400 IU/d for 3 wks)
14 noninsulin-dependent diabetes
(1) Increased insulin secretion(2) A reduction in serum free fatty acid levels
Gedik and Akalin [100]
1,25 (OH)2 vitamin D(2000 IU/d for 6 months)
4 patients with vitamin D deficiency
Increased insulin secretion
Borissova et al. [101]
1,25 (OH)2 vitamin D(1332 IU/d for 1 month)
10 females with type 2 diabetes
A decrease of 21.4% in insulin resistance
Orwoll et al. [102]
1,25 (OH)2 vitamin D (200 IU/d for 4 d)
20 patient with type 2 diabetes
No effect on insulin, glucose, c-peptide
Taylor and Wise [103]
1,25 (OH)2 vitamin D (300000 IU intramuscular)
3 Asians with type 2 diabetes
Increased insulin resistance
Ljunghall et al. [104]
1α(OH) vitamin D (30 IU/d for 3 months)
65 Caucasian men with impaired glucose tolerance
No difference in insulin resistance
Kumar et al. [105]
1,25 (OH)2 vitamin D ( 2000 IU/d for 1 month)
1 vitamin D deficient hypocalcemic woman
Increased glucose tolerance and β-cell function
Nevertheless, some studies have shown conflicting results of vitamin D supplementation for insulin resistance or improvement of type 2 DM [102–104] (Table 2). One report found that Asian patients with type 2 DM with vitamin D deficiency even had a worsening of glycemic control and an increase in insulin resistance [104]. These contrasting results suggest that the dose and method of supplementation, and the genetic background and baseline vitamin D status of individuals seem to be more important for the efficacy of vitamin D supplementations in insulin resistance.
6. Conclusion
Vitamin D is not only a regulator of bone and mineral metabolism, but also a potent immunomodulator linked to many major human diseases including glucose homeostasis and insulin resistance. Vitamin D deficiency has been shown to affect insulin secretion in both humans and animal models. Accumulating evidence suggests the role of vitamin D in the pathogenesis of insulin resistance including several vitamin-D-related gene polymorphisms and vitamin-D-related metabolic and immune pathways. Supplementations of vitamin D may provide for suitable management and act to ameliorate insulin resistance. Additionally, there is a need for randomized trials to evaluate the significant effects of vitamin D supplementations in insulin resistance.
Authors’ Contribution
C.-C. Sung and M.-T. Liao contributed equally to this work.
Conflict of Interests
There is no conflict of interests.
Acknowledgments
This work was supported by the National Science Council, Taiwan (NSC 100-2314-B-016-027), and Ministry of National Defense, Taiwan (I-4 and MAB101-60), to C.-C. Wu.
HolickM. F.Resurrection of vitamin D deficiency and rickets20061168206220722-s2.0-3374674173110.1172/JCI29449BouillonR.DeGrootL. J.JamesonJ. L.Vitamin D: from photosynthesis, metabolism, and action to clinical applicationseds2001Philadelphia, Pa, USAW.B. Saunders10091028DeLucaH. F.Overview of general physiologic features and functions of vitamin D2004806, supplement1689S1696SHolickM. F.Vitamin D deficiency2007357266281HruskaK. A.FavusM. J.Hyperphosphatemia and hypophosphatemia20066thWashington, DC, USAAmerican Society for Bone and Mineral Research233242ChristensenE. I.DevuystO.DomG.NielsenR.Van Der SmissenP.VerroustP.LeruthM.GugginoW. B.CourtoyP. J.Loss of chloride channel ClC-5 impairs endocytosis by defective trafficking of megalin and cubilin in kidney proximal tubules200310014847284772-s2.0-003815319610.1073/pnas.1432873100NykjaerA.DragunD.WaltherD.VorumH.JacobsenC.HerzJ.MelsenF.ChristensenE. I.WillnowT. E.An endocytic pathway essential for renal uptake and activation of the steroid 25-(OH) vitamin D319999645075152-s2.0-0033582543WeismanY.HarellA.EdelsteinS.1α,25-Dihydroxyvitamin D3 and 24,25-dihydroxyvitamin D3in vitro synthesis by human decidua and placenta197928157293173192-s2.0-0018673405GrayT. K.LesterG. E.LorencR. S.Evidence for extra-renal 1 α-hydroxylation of 25-hydroxyvitamin D3 in pregnancy19792044399131113132-s2.0-0018746180StoffelsK.OverberghL.BouillonR.MathieuC.Immune regulation of 1α-hydroxylase in murine peritoneal macrophages: unravelling the IFNγ pathway20071033–55675712-s2.0-3394722244910.1016/j.jsbmb.2006.12.091EstebanL.VidalM.DussoA.1α-Hydroxylase transactivation by γ-interferon in murine macrophages requires enhanced C/EBPβ expression and activation200489-901311372-s2.0-304263862410.1016/j.jsbmb.2004.03.092ChristakosS.AjibadeD. V.DhawanP.FechnerA. J.MadyL. J.Vitamin D: metabolism20103922432532-s2.0-7795394627410.1016/j.ecl.2010.02.002HenryH. L.Regulation of vitamin D metabolism20112545315412-s2.0-7865070555410.1016/j.beem.2011.05.003DaigerS. P.SchanfieldM. S.Cavalli SforzaL. L.Group specific component (Gc) proteins bind vitamin D and 25 hydroxyvitamin D1975726207620802-s2.0-0005645339NykjaerA.DragunD.WaltherD.VorumH.JacobsenC.HerzJ.MelsenF.ChristensenE. I.WillnowT. E.An endocytic pathway essential for renal uptake and activation of the steroid 25-(OH) vitamin D319999645075152-s2.0-0033582543ChunR. F.New perspectives on the vitamin D binding protein20123064454562-s2.0-8485992878210.1002/cbf.2835MathieuC.BadenhoopK.Vitamin D and type 1 diabetes mellitus: state of the art20051662612662-s2.0-2304443684910.1016/j.tem.2005.06.004ZellaJ. B.DeLucaH. F.Vitamin D and autoimmune diabetes20038822162222-s2.0-003730407310.1002/jcb.10347StrugnellS. A.DelucaH. F.The vitamin D receptor—structure and transcriptional activation199721532232282-s2.0-0030956080HausslerM. R.HausslerC. A.BartikL.WhitfieldG. K.HsiehJ. C.SlaterS.JurutkaP. W.Vitamin D receptor: molecular signaling and actions of nutritional ligands in disease prevention2008662S98S1122-s2.0-5264912174210.1111/j.1753-4887.2008.00093.xPalomerX.González-ClementeJ. M.Blanco-VacaF.MauricioD.Role of vitamin D in the pathogenesis of type 2 diabetes mellitus20081031851972-s2.0-3914913035610.1111/j.1463-1326.2007.00710.xUitterlindenA. G.FangY.Van MeursJ. B. J.PolsH. A. P.Van LeeuwenJ. P. T. M.Genetics and biology of vitamin D receptor polymorphisms200433821431562-s2.0-414314082010.1016/j.gene.2004.05.014JonesG.StrugnellS. A.DeLucaH. F.Current understanding of the molecular actions of vitamin D1998784119312312-s2.0-0031755168NemereI.SchwartzZ.PedrozoH.SylviaV. L.DeanD. D.BoyanB. D.Identification of a membrane receptor for 1,25-Dihydroxyvitamin D3 which mediates rapid activation of protein kinase C1998139135313592-s2.0-003166146010.1359/jbmr.1998.13.9.1353DussoA. S.BrownA. J.SlatopolskyE.Vitamin D20052891F8F282-s2.0-2084443189210.1152/ajprenal.00336.2004PittasA. G.LauJ.HuF. B.Dawson-HughesB.Review: the role of vitamin D and calcium in type 2 diabetes. A systematic review and meta-analysis2007926201720292-s2.0-3434726696310.1210/jc.2007-0298KendrickJ.TargherG.SmitsG.ChoncholM.25-Hydroxyvitamin D deficiency is independently associated with cardiovascular disease in the Third National Health and Nutrition Examination Survey200920512552602-s2.0-6734925481010.1016/j.atherosclerosis.2008.10.033NagpalS.NaS.RathnachalamR.Noncalcemic actions of vitamin D receptor ligands20052656626872-s2.0-2374443742110.1210/er.2004-0002PennaG.RoncariA.AmuchasteguiS.DanielK. C.BertiE.ColonnaM.AdoriniL.Expression of the inhibitory receptor ILT3 on dendritic cells is dispensable for induction of CD4+Foxp3+ regulatory T cells by 1,25-dihydroxyvitamin D3200510610349034972-s2.0-2774459560010.1182/blood-2005-05-2044LiY. C.Vitamin D regulation of the renin-angiotensin system20038823273312-s2.0-003730295410.1002/jcb.10343ChiuK. C.ChuA.GoV. L. W.SaadM. F.Hypovitaminosis D is associated with insulin resistance and β cell dysfunction20047958208252-s2.0-2442526414ZittermannA.Vitamin D and disease prevention with special reference to cardiovascular disease200692139482-s2.0-3374482061310.1016/j.pbiomolbio.2006.02.001LiY. C.PirroA. E.AmlingM.DellingG.BaronR.BronsonR.DemayM. B.Targeted ablation of the vitamin D receptor: an animal model of vitamin D-dependent rickets type II with alopecia19979418983198352-s2.0-0030610422PandaD. K.MiaoD.TremblayM. L.SiroisJ.FarookhiR.HendyG. N.GoltzmanD.Targeted ablation of the 25-hydroxyvitamin D 1α-hydroxylase enzyme: evidence for skeletal, reproductive, and immune dysfunction20019813749875032-s2.0-003591270710.1073/pnas.131029498HolickM. F.ChenT. C.Vitamin D deficiency: a worldwide problem with health consequences20088741080S1086S2-s2.0-42249090551RossA. C.MansonJ. E.AbramsS. A.AloiaJ. F.BrannonP. M.ClintonS. K.Durazo-ArvizuR. A.GallagherJ. C.GalloR. L.JonesG.KovacsC. S.MayneS. T.RosenC. J.ShapsesS. A.The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know201196153582-s2.0-7865088629110.1210/jc.2010-2704ParkerJ.HashmiO.DuttonD.MavrodarisA.StrangesS.KandalaN. B.ClarkeA.FrancoO. H.Levels of vitamin D and cardiometabolic disorders: systematic review and meta-analysis20106532252362-s2.0-7634908427310.1016/j.maturitas.2009.12.013DeleskogA.HildingA.BrismarK.HamstenA.EfendicS.OstensonC. G.Low serum 25-hydroxyvitamin D level predicts progression to type 2 diabetes in individuals with prediabetes but not with normal glucose tolerance20125516681678ForouhiN. G.YeZ.RickardA. P.KhawK. T.LubenR.LangenbergC.WarehamN. J.Circulating 25-hydroxyvitamin D concentration and the risk of type 2 diabetes: results from the European Prospective Investigation into Cancer (EPIC)-Norfolk cohort and updated meta-analysis of prospective studies2012558217321822-s2.0-8485955879310.1007/s00125-012-2544-yMathieuC.BadenhoopK.Vitamin D and type 1 diabetes mellitus: state of the art20051662612662-s2.0-2304443684910.1016/j.tem.2005.06.004TargherG.BertoliniL.PadovaniR.ZenariL.ScalaL.CigoliniM.ArcaroG.Serum 25-hydroxyvitamin D3 concentrations and carotid artery intima-media thickness among type 2 diabetic patients20066555935972-s2.0-3375004928810.1111/j.1365-2265.2006.02633.xBorkarV. V.DevidayalV. S.BhallaA. K.Low levels of vitamin D in North Indian children with newly diagnosed type 1 diabetes20101153453502-s2.0-7795524458410.1111/j.1399-5448.2009.00589.xTakiishiT.GysemansC.BouillonR.MathieuC.Vitamin D and diabetes20103924194462-s2.0-7795393285310.1016/j.ecl.2010.02.013BlantonD.HanZ.BierschenkL.Linga-ReddyM. V. P.WangH.Clare-SalzlerM.HallerM.SchatzD.MyhrC.SheJ.-X.WasserfallC.AtkinsonM.Reduced serum vitamin D-binding protein levels are associated with type 1 diabetes20116010256625702-s2.0-8005342197510.2337/db11-0576SzathmaryE. J.The effect of Gc genotype on fasting insulin level in Dogrib Indians19877543683722-s2.0-0023115010IyengarS.HammanR. F.MarshallJ. A.MajumderP. P.FerrellR. E.On the role of Vitamin D binding globulin in glucose homeostasis: results from the San Luis Valley Diabetes Study1989666916982-s2.0-0024852132BaierL. J.DobberfuhlA. M.PratleyR. E.HansonR. L.BogardusC.Variations in the vitamin D-binding protein (Gc locus) are associated with oral glucose tolerance in nondiabetic Pima Indians1998838299329962-s2.0-003175759010.1210/jc.83.8.2993HiraiM.SuzukiS.HinokioY.ChibaM.KasugaS.HiraiA.ToyotaT.Group specific component protein genotype is associated with NIDDM in Japan19984167427432-s2.0-003183947410.1007/s001250050980HiraiM.SuzukiS.HinokioY.HiraiA.ChibaM.AkaiH.SuzukiC.ToyotaT.Variations in vitamin D-binding protein (group-specific component protein) are associated with fasting plasma insulin levels in Japanese with normal glucose tolerance2000855195119532-s2.0-003445573710.1210/jc.85.5.1951YeW. Z.Dubois-LaforgueD.Bellanné-ChantelotC.TimsitJ.VelhoG.Variations in the vitamin D-binding protein (Gc locus) and risk of type 2 diabetes mellitus in French Caucasians20015033663692-s2.0-003508303810.1053/meta.2001.20172KlupaT.MaleckiM.HannaL.SieradzkaJ.FreyJ.WarramJ. H.SieradzkiJ.KrolewskiA. S.Amino acid variants of the vitamin D-binding protein and risk of diabetes in white Americans of European origin199914154904932-s2.0-0032721408NormanA. W.FrankelB. J.HeldtA. M.GrodskyG. M.Vitamin D deficiency inhibits pancreatic secretion of insulin198020944588238252-s2.0-0019302750FaracoJ. H.MorrisonN. A.BakerA.ShineJ.FrossardP. M.ApaI dimorphism at the human vitamin D receptor gene locus1989175, article 21502-s2.0-0024601892MorrisonN. A.YeomanR.KellyP. J.EismanJ. A.Contribution of trans-acting factor alleles to normal physiological variability: vitamin D receptor gene polymorphisms and circulating osteocalcin19928915666566692-s2.0-002676957210.1073/pnas.89.15.6665MorrisonN. A.Jian Cheng QiTokitaA.KellyP. J.CroftsL.NguyenT. V.SambrookP. N.EismanJ. A.Prediction of bone density from vitamin D receptor alleles199436764602842872-s2.0-2344446054210.1038/367284a0YeW. Z.ReisA. F.VelhoG.Identification of a novel Tru9 I polymorphism in the human vitamin D receptor gene200045156572-s2.0-0033984322GrossC.KrishnanA. V.MalloyP. J.EccleshallT. R.ZhaoX. Y.FeldmanD.The vitamin D receptor gene start codon polymorphism: a functional analysis of FokI variants19981311169116992-s2.0-003175121510.1359/jbmr.1998.13.11.1691AraiH.MiyamotoK. I.YoshidaM.YamamotoH.TaketaniY.MoritaK.KubotaM.YoshidaS.IkedaM.WatabeF.KanemasaY.TakedaE.The polymorphism in the caudal-related homeodomain protein Cdx-2 binding element in the human vitamin D receptor gene2001167125612642-s2.0-0034972427UitterlindenA. G.FangY.Van MeursJ. B. J.PolsH. A. P.Van LeeuwenJ. P. T. M.Genetics and biology of vitamin D receptor polymorphisms200433821431562-s2.0-414314082010.1016/j.gene.2004.05.014McDermottM. F.RamachandranA.OgunkoladeB. W.AgannaE.CurtisD.BoucherB. J.SnehalathaC.HitmanG. A.Allelic variation in the vitamin D receptor influences susceptibility to IDDM in Indian Asians19974089719752-s2.0-003083601310.1007/s001250050776PaniM. A.KnappM.DonnerH.BraunJ.BaurM. P.UsadelK. H.BadenhoopK.Vitamin D receptor allele combinations influence genetic susceptibility to 1 diabetes in Germans20004935045072-s2.0-0034101764ChangT. J.LeiH. H.YehJ. I.ChiuK. C.LeeK. C.ChenM. C.TaiT. Y.ChuangL. M.Vitamin D receptor gene polymorphisms influence susceptibility to type 1 diabetes mellitus in the Taiwanese population20005255755802-s2.0-003403897210.1046/j.1365-2265.2000.00985.xZhangJ.LiW.LiuJ.WuW.OuyangH.ZhangQ.WangY.LiuL.YangR.LiuX.MengQ.LuJ.Polymorphisms in the vitamin D receptor gene and type 1 diabetes mellitus risk: an update by meta-analysis201235511351422-s2.0-8486280832210.1016/j.mce.2012.02.003OhJ. Y.Barrett-ConnorE.Association between vitamin D receptor polymorphism and type 2 diabetes or metabolic syndrome in community-dwelling older adults: the Rancho Bernardo study20025133563592-s2.0-003612353610.1053/meta.2002.29969HitmanG. A.MannanN.McDermottM. F.AgannaE.OgnnkoladeB. W.HalesC. N.BoucherB. J.Vitamin D receptor gene polymorphisms influence insulin secretion in Bangladeshi Asians19984746886902-s2.0-003192271110.2337/diabetes.47.4.688MaleckiM. T.FreyJ.MoczulskiD.KlupaT.KozekE.SieradzkiJ.Vitamin D receptor gene polymorphisms and association with type 2 diabetes mellitus in a Polish population200311185055092-s2.0-034776368110.1055/s-2003-44711YeW. Z.ReisA. F.Dubois-LaforgueD.Bellanné-ChantelotC.TimsitJ.VelhoG.Vitamin D receptor gene polymorphisms are associated with obesity in type 2 diabetic subjects with early age of onset200114521811862-s2.0-0034894334MaleckiM. T.KlupaT.WolkowP.BochenskiJ.WanicK.SieradzkiJ.Association study of the vitamin D: 1Alpha-hydroxylase (CYP1alpha) gene and type 2 diabetes mellitus in a Polish population20032921191242-s2.0-0038633589GelfandJ. M.CreeB. A. C.McElroyJ.OksenbergJ.GreenR.MowryE. M.MillerJ. W.HauserS. L.GreenA. J.Vitamin D in African Americans with multiple sclerosis20117621182418302-s2.0-7995812465010.1212/WNL.0b013e31821cccf5KamenD. L.CooperG. S.BoualiH.ShaftmanS. R.HollisB. W.GilkesonG. S.Vitamin D deficiency in systemic lupus erythematosus2006521141172-s2.0-3114444629110.1016/j.autrev.2005.05.009RitterhouseL. L.CroweS. R.NiewoldT. B.KamenD. L.MacwanaS. R.RobertsV. C.DedekeA. B.HarleyJ. B.ScofieldR. H.GuthridgeJ. M.JamesJ. A.Vitamin D deficiency is associated with an increased autoimmune response in healthy individuals and in patients with systemic lupus erythematosus2011709156915742-s2.0-8005147529810.1136/ard.2010.148494MathieuC.BadenhoopK.Vitamin D and type 1 diabetes mellitus: state of the art20051662612662-s2.0-2304443684910.1016/j.tem.2005.06.004MathieuC.AdoriniL.The coming of age of 1,25-dihydroxyvitamin D3 analogs as immunomodulatory agents2002841741792-s2.0-003622062910.1016/S1471-4914(02)02294-3ProvvediniD. M.TsoukasC. D.DeftosL. J.ManolagasS. C.1,25-Dihydroxyvitamin D3 receptors in human leukocytes19832214616118111832-s2.0-0020517536VeldmanC. M.CantornaM. T.DeLucaH. F.Expression of 1,25-dihydroxyvitamin D3 receptor in the immune system200037423343382-s2.0-003465231410.1006/abbi.1999.1605DongX.LutzW.SchroederT. M.BachmanL. A.WestendorfJ. J.KumarR.GriffinM. D.Regulation of relB in dendritic cells by means of modulated association of vitamin D receptor and histone deacetylase 3 with the promoter20051024416007160122-s2.0-2764459853910.1073/pnas.0506516102MuthianG.RaikwarH. P.RajasinghJ.BrightJ. J.1,25 Dihydroxyvitamin-D3 modulates JAK-STAT pathway in IL-12/IFNγ axis leading to Th1 response in experimental allergic encephalomyelitis2006837129913092-s2.0-3364633913410.1002/jnr.20826LiuP. T.StengerS.LiH.WenzelL.TanB. H.KrutzikS. R.OchoaM. T.SchauberJ.WuK.MeinkenC.KamenD. L.WagnerM.BalsR.SteinmeyerA.ZügelU.GalloR. L.EisanbergD.HewisonM.HollisB. W.AdamsJ. S.BloomB. R.ModlinR. L.Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response20063115768177017732-s2.0-3364522441910.1126/science.1123933AbdelsadikA.TradA.Toll-like receptors on the fork roads between innate and adaptive immunity20117212118811932-s2.0-8195516191910.1016/j.humimm.2011.08.015HewisonM.Vitamin D and the immune system: new perspectives on an old theme20103923653792-s2.0-7795394334910.1016/j.ecl.2010.02.010BikleD. D.Vitamin D and immune function: understanding common pathways20097258632-s2.0-7034973468210.1007/s11914-009-0011-6BhallaA. K.AmentoE. P.SerogB.GlimcherL. H.1,25-dihydroxyvitamin D3 inhibits antigen-induced T cell activation19841334174817542-s2.0-0021213827SterlingK. A.EftekhariP.GirndtM.KimmelP. L.RajD. S.The immunoregulatory function of vitamin D: Implications in chronic kidney disease2012874034122-s2.0-8486288828010.1038/nrneph.2012.93ChagasC. E. A.BorgesM. C.MartiniL. A.RogeroM. M.Focus on vitamin D, inflammation and type 2 diabetes20124152672-s2.0-8485636226210.3390/nu4010052FritscheJ.MondalK.EhrnspergerA.AndreesenR.KreutzM.Regulation of 25-hydroxyvitamin D3-1α-hydroxylase and production of 1α,25-dihydroxyvitamin D3 by human dendritic cells20031029331433162-s2.0-014215243010.1182/blood-2002-11-3521BakerR. G.HaydenM. S.GhoshS.NF-κB, inflammation, and metabolic disease201113111222-s2.0-7865087836310.1016/j.cmet.2010.12.008Cohen-LahavM.ShanyS.TobvinD.ChaimovitzC.DouvdevaniA.Vitamin D decreases NFκB activity by increasing IκBα levels20062148898972-s2.0-3364528334110.1093/ndt/gfi254SadeghiK.WessnerB.LaggnerU.PloderM.TamandlD.FriedlJ.ZügelU.SteinmeyerA.PollakA.RothE.Boltz-NitulescuG.SpittlerA.Vitamin D3 down-regulates monocyte TLR expression and triggers hyporesponsiveness to pathogen-associated molecular patterns20063623613702-s2.0-3294446495910.1002/eji.200425995GiuliettiA.van EttenE.OverberghL.StoffelsK.BouillonR.MathieuC.Monocytes from type 2 diabetic patients have a pro-inflammatory profile. 1,25-Dihydroxyvitamin D3 works as anti-inflammatory200777147572-s2.0-3424715855510.1016/j.diabres.2006.10.007TeegardenD.DonkinS. S.Vitamin D: emerging new roles in insulin sensitivity200922182922-s2.0-6924921547310.1017/S0954422409389301TaiK.NeedA. G.HorowitzM.ChapmanI. M.Vitamin D, glucose, insulin, and insulin sensitivity20082432792852-s2.0-3874909772810.1016/j.nut.2007.11.006BeaulieuC.KestekianR.HavrankovaJ.Gascon-BarreM.Calcium is essential in normalizing intolerance to glucose that accompanies vitamin D depletion in vivo199342135432-s2.0-0027468996FlanaganJ. N.WangL.TangprichaV.ReichrathJ.ChenT. C.HolickM. F.Regulation of the 25-hydroxyvitamin D-1alpha-hydroxylase gene and its splice variant20031641571672-s2.0-0642336656ZehnderD.BlandR.WilliamsM. C.McninchR. W.HowieA. J.StewartP. M.HewisonM.Extrarenal expression of 25-hydroxyvitamin D3-1α-hydroxylase20018628888942-s2.0-003509288710.1210/jc.86.2.888ThomasD. M.RogersS. D.SleemanM. W.PasquiniG. M.BringhurstF. R.NgK. W.ZajacJ. D.BestJ. D.Modulation of glucose transport by parathyroid hormone and insulin in UMR 106-01, a clonal rat osteogenic sarcoma cell line19951422632752-s2.0-0028905388ReuschJ. E. B.BegumN.SussmanK. E.DrazninB.Regulation of GLUT-4 phosphorylation by intracellular calcium in adipocytes19911296326932732-s2.0-0025786598PernaA. F.FaddaG. Z.ZhouX. J.MassryS. G.Mechanisms of impaired insulin secretion after chronic excess of parathyroid hormone19902592F210F2162-s2.0-0025046464BlumM.DolnikowskiG.SeyoumE.HarrisS. S.BoothS. L.PetersonJ.SaltzmanE.Dawson-HughesB.Vitamin D3 in fat tissue200833190942-s2.0-4614909716910.1007/s12020-008-9051-4InomataS.KadowakiS.YamataniT.Effect of 1α(OH)-vitamin D3 on insulin secretion in diabetes mellitus1986131871922-s2.0-0022461934GedikO.AkalinS.Effects of vitamin D deficiency and repletion on insulin and glucagon secretion in man19862931421452-s2.0-0022640891BorissovaA. M.TankovaT.KirilovG.DakovskaL.KovachevaR.The effect of vitamin D3 on insulin secretion and peripheral insulin sensitivity in type 2 diabetic patients20035742582612-s2.0-0037527609OrwollE.RiddleM.PrinceM.Effects of vitamin D on insulin and glucagon secretion in non-insulin- dependent diabetes mellitus1994595108310872-s2.0-0028350615TaylorA. V. G.WiseP. H.Vitamin D replacement in Asians with diabetes may increase insulin resistance1998748723653662-s2.0-0031841229LjunghallS.LindL.LithellH.SkarforsE.SelinusI.SorensenO. H.WideL.Treatment with one-alpha-hydroxycholecalciferol in middle-aged men with impaired glucose tolerance. A prospective randomized double-blind study198722243613672-s2.0-0023546759KumarS.DaviesM.ZakariaY.MawerE. B.GordonC.OlukogaA. O.BoultonA. J. M.Improvement in glucose tolerance and beta-cell function in a patient with vitamin D deficiency during treatment with vitamin D1994708244404432-s2.0-0028342653MaestroB.CampiónJ.DávilaN.CalleC.Stimulation by 1,25-dihydroxyvitamin D3 of insulin receptor expression and insulin responsiveness for glucose transport in U-937 human promonocytic cells20004743833912-s2.0-0033823521WilliamsP. F.CatersonI. D.CooneyG. J.ZilkensR. R.TurtleJ. R.High affinity insulin binding and insulin receptor-effector coupling: modulation by Ca2+19901185475562-s2.0-002512376210.1016/0143-4160(90)90031-ORiachyR.VandewalleB.ConteJ. K.MoermanE.SacchettiP.LukowiakB.GmyrV.BouckenoogheT.DuboisM.PattouF.1,25-dihydroxyvitamin D3 protects RINm5F and human islet cells against cytokine-induced apoptosis: implication of the antiapoptotic protein A20200214312480948192-s2.0-003689214310.1210/en.2002-220449GysemansC. A.CardozoA. K.CallewaertH.GiuliettiA.HulshagenL.BouillonR.EizirikD. L.MathieuC.1,25-Dihydroxyvitamin D3 modulates expression of chemokines and cytokines in pancreatic islets: implications for prevention of diabetes in nonobese diabetic mice20051464195619642-s2.0-1544438032910.1210/en.2004-1322Van EttenE.MathieuC.Immunoregulation by 1,25-dihydroxyvitamin D3: basic concepts2005971-2931012-s2.0-2754449968610.1016/j.jsbmb.2005.06.002Von HurstP. R.StonehouseW.CoadJ.Vitamin D supplementation reduces insulin resistance in South Asian women living in New Zealand who are insulin resistant and vitamin D deficient-a randomised, placebo-controlled trial201010345495552-s2.0-7764921988410.1017/S0007114509992017