Vitamin D deficiency has been linked to the onset of diabetes. This review summarizes the role of Vitamin D in maintaining the normal release of insulin by the pancreatic beta cells (β-cells). Diabetes is initiated by the onset of insulin resistance. The β-cells can overcome this resistance by releasing more insulin, thus preventing hyperglycaemia. However, as this hyperactivity increases, the β-cells experience excessive Ca2+ and reactive oxygen species (ROS) signalling that results in cell death and the onset of diabetes. Vitamin D deficiency contributes to both the initial insulin resistance and the subsequent onset of diabetes caused by β-cell death. Vitamin D acts to reduce inflammation, which is a major process in inducing insulin resistance. Vitamin D maintains the normal resting levels of both Ca2+ and ROS that are elevated in the β-cells during diabetes. Vitamin D also has a very significant role in maintaining the epigenome. Epigenetic alterations are a feature of diabetes by which many diabetes-related genes are inactivated by hypermethylation. Vitamin D acts to prevent such hypermethylation by increasing the expression of the DNA demethylases that prevent hypermethylation of multiple gene promoter regions of many diabetes-related genes. What is remarkable is just how many cellular processes are maintained by Vitamin D. When Vitamin D is deficient, many of these processes begin to decline and this sets the stage for the onset of diseases such as diabetes.

Introduction

Diabetes, which is characterized by an elevation in blood glucose, is becoming increasingly common. One reason for this is the increasing prevalence of obesity. A likely link between obesity and diabetes is the deficiency of Vitamin D that occurs in obesity. The aim of this review is to explore why Vitamin D deficiency is such a strong risk factor for diabetes. This review will begin by describing how Vitamin D deficiency may be the link between obesity and diabetes. Vitamin D seems to act to maintain many of the sequential events that enable the beta cells (β-cells) located in the pancreatic islets of Langerhans to release the insulin necessary to control blood levels of glucose. The decline in insulin levels begins with the onset of insulin resistance.

The β-cells are capable of increasing the amount of insulin being released in order to counteract the reduced effectiveness of insulin action. However, as the elevation of glucose continues to rise, this glucotoxicity increases the hyperactivity further and this overwhelms the β-cells that begin to die. The resulting decline in the release of insulin results in the excessive elevation of blood glucose that characterizes diabetes. In this review, this sequence of events will be described in more detail so as to illustrate why Vitamin D deficiency is such a strong risk factor for diabetes.

Vitamin D deficiency and diabetes

There is increasing evidence that Vitamin D deficiency may contribute to the onset of diabetes [19]. This is supported by the finding that polymorphisms of the Vitamin D receptor (VDR) have been linked to diabetes [10]. There are indications that Vitamin D supplementation may prevent the onset of type 2 diabetes (T2D) [9,11].

It will be argued later that Vitamin D acts to control many of the processes that initiate the onset of diabetes such as the formation of Ca2+ and reactive oxygen species (ROS). In effect, Vitamin D controls the expression of those genes that function to ensure that the levels of Ca2+ and ROS are maintained at their normal low physiological levels [82,83,137140,168]. Another important action of Vitamin D is to maintain the normal mitochondrial control of cellular bioenergetics [104]. Vitamin D also plays a role by reducing inflammation that helps to control the insulin resistance that is a major contributor to diabetes [62]. These multiple actions of Vitamin D will be discussed in more detail in the following sections. One of the major causes of diabetes is obesity.

Obesity, Vitamin D and diabetes

There is a close association between obesity and Vitamin D deficiency [1219]. Through its ability to promote energy expenditure by increasing fatty acid (FA) oxidation and mitochondrial metabolism, Vitamin D can reduce the onset of weight gain in mice [20]. Many reasons have been put forward to explain the reduced levels of Vitamin D in obesity [19,21]. Perhaps, the most significant is that Vitamin D in the serum is reduced because it enters into the large fat depots located in the adipose tissue. There may also be ‘volumetric dilution’ as a result of the large body size in obesity. To understand how Vitamin D may act to reduce diabetes, it is instructive to explore the link between obesity and diabetes.

The initial phase of diabetes is driven by insulin resistance in those organs (adipose tissue, skeletal muscle and liver) that respond to insulin to control glucose and lipid metabolism [22,23]. Initially, the pancreatic islet β-cells can overcome this resistance by releasing more insulin, thus preventing hyperglycaemia [24]. With time, this hyperactivity causes β-cell dysfunction that results in cell death and the onset of T2D caused by a marked decline in insulin secretion [25]. There is increasing evidence to support the fact that Vitamin D deficiency can contribute to both the initial insulin resistance and the subsequent onset of diabetes caused by β-cell death as described below.

Vitamin D and insulin resistance

The low levels of Vitamin D in obesity may contribute to the onset of diabetes, because it functions to regulate many of the processes that are altered during the onset of both insulin resistance and the subsequent decline in β-cells that results in diabetes [2628]. Under normal conditions, Vitamin D has many actions to control both gene transcription and cell signalling pathways to alleviate the onset of insulin resistance especially in adipose tissue [21]. It can act through a non-genomic pathway to control lipogenesis and lipolysis [29]. However, most of its actions seem to be mediated through genomic mechanisms. One of these actions is to inhibit adipocyte differentiation during adipogenesis by maintaining the Wnt/β-catenin signalling pathway [21,30] and the mitogen-activated protein kinase signalling pathway [31]. Vitamin D also acts to inhibit apoptosis by reducing the expression of the mitochondrial uncoupling protein 2 (UCP2) [32,33].

The diabetes that develops during obesity is driven by the onset of insulin resistance [9,22,3436], which results in a decline in the ability of insulin to reduce the output of glucose from the liver and to increase the uptake of glucose into muscle and adipose cells [37]. This onset of insulin resistance seems to depend on an increase in dietary fat such as FAs, which occurs in obesity [35,38,39]. These FAs and associated metabolites, such as acyl-CoAs, ceramides and diacylglycerol, act on various protein kinases, such as Jun kinase (JNK), protein kinase C and nuclear factor-κB (NF-κB) kinase-β [IκB kinase-β (IKK-β)], that reduce insulin signalling by phosphorylating the insulin receptor substrate (IRS) [40]. Vitamin D plays a significant role in maintaining the insulin signalling pathway, because one of its actions is to increase the expression of the insulin receptor [41,42]. A deficiency in Vitamin D would result in a decline in the insulin receptor, thus contributing to the onset of insulin resistance. An increase in Ca2+ concentration, which also occurs during Vitamin D deficiency, may also contribute to insulin resistance by decreasing the activity of the glucose transporter-4 (GLUT4) [4345].

Another serious consequence of obesity is a marked alteration in the secretion of adipokines (leptin, adiponectin and resistin), which are important hormones that contribute to glucose and lipid homeostasis [4648]. A decline in the release of leptin and adiponectin reduces the regulation of various metabolic pathways and contributes to the onset of insulin resistance. On the other hand, obesity is associated with an elevation of resistin, which contributes to the marked elevation in inflammation that contributes to insulin resistance [4951]. These adipokines are important hormones that contribute to glucose and lipid homeostasis. For example, adiponectin has both an anti-inflammatory function and it also acts to sensitize the action of insulin [52]. Vitamin D has an important role in regulating the secretion of these adipokines. Vitamin D also acts to regulate energy homeostasis by regulating the formation of leptin [47]. One of the actions of leptin is to reduce appetite by acting on the hypothalamus [53], and it also regulates lipid metabolism by stimulating lipolysis while inhibiting lipogenesis [54,55].

The inflammation that is associated with obesity also contributes to the onset of insulin resistance [23,36,5662]. Much of the inflammation is driven by the adipose macrophages, which accumulate in the white adipose tissue [35]. This inflammation results in the formation of cytokines, such as interleukin-6 and tumour necrosis factor α, that play a major role in the development of insulin resistance [22,35,62]. One of the actions of these cytokines is to stimulate both the Jun N-terminal kinase 1 (JNK1) and IKK-β/NF-κB pathways. These kinases then phosphorylate IRS-1, resulting in a reduction in insulin signalling [40,63].

This inflammation, which is a major process in inducing insulin resistance [21], is reduced by Vitamin D [62]. There is increasing evidence to show that Vitamin D acts by reducing the release of chemokines and cytokines that drive inflammation, and it also reduces monocyte chemotaxis [6467].

Another significant activator of insulin resistance is an increase in the formation of ROS [23,6878]. There are indications that this oxidative stress may arise through the increase in the free FAs that act on the mitochondria to increase the formation of ROS (Figure 1) [79,80]. The increase in ROS then acts to reduce the activity of the insulin signalling pathway [35,78]. Vitamin D plays an important role in reducing adipocyte ROS formation [81]. This action of Vitamin D in regulating ROS levels depends on its ability to control the expression of cellular antioxidants as part of its role to maintain phenotypic stability of cell signalling pathways [82,83]. The increase in ROS may also arise through a decline in mitochondrial function that is another consequence of Vitamin D deficiency as described later.

Vitamin D acts to prevent diabetes by maintaining low levels of Ca2+ and ROS.

Figure 1.
Vitamin D acts to prevent diabetes by maintaining low levels of Ca2+ and ROS.

The UV in sunlight acts on the skin to initiate the formation of Vitamin D3 (cholecalciferol) through the photolysis of 7-dehydrocholesterol. The Vitamin D3 enters the blood and is transferred to the liver where a hydroxyl group is added to the C-25 position by a vitamin D-25 hydroxylase (encoded by the CYP27A1 gene) to form 25-hydroxyvitamin D3 [25(OH)D3], which is the immediate precursor for active Vitamin D. This 25(OH)D3 is carried in the blood to enter multiple cell types where a 25(OH)D3–1α-hydroxylase (encoded by the CYP27B1 gene) adds another hydroxyl group to the 1 position to form the active 1,25(OH)2D3, which enters the nucleus to bind to the VDR that binds to the Vitamin D response element (VDRE) to activate expression of a large number of genes. The onset of diabetes is associated with increased levels of both Ca2+ and ROS, which are normally regulated by Vitamin D, which acts to maintain low resting levels of both Ca2+ and ROS. Vitamin D increases expression of antioxidants that reduce levels of ROS, and it maintains low Ca2+ levels by increasing expression of the plasma membrane Ca2+-ATPase (PMCA) and the NCX1, which extrude Ca2+, and the Ca2+ buffer calbindin. Vitamin D also reduces the expression of the L-type CaV1.2 and CaV1.3 Ca2+ channels. One of the main functions of Vitamin D is to maintain the expression of the DNA demethylases, such as JMJD1A and JMJD3 as well as LSD1 and LSD2, that act to prevent the hypermethylation of promoter regions that is responsible for reducing gene transcription.

Figure 1.
Vitamin D acts to prevent diabetes by maintaining low levels of Ca2+ and ROS.

The UV in sunlight acts on the skin to initiate the formation of Vitamin D3 (cholecalciferol) through the photolysis of 7-dehydrocholesterol. The Vitamin D3 enters the blood and is transferred to the liver where a hydroxyl group is added to the C-25 position by a vitamin D-25 hydroxylase (encoded by the CYP27A1 gene) to form 25-hydroxyvitamin D3 [25(OH)D3], which is the immediate precursor for active Vitamin D. This 25(OH)D3 is carried in the blood to enter multiple cell types where a 25(OH)D3–1α-hydroxylase (encoded by the CYP27B1 gene) adds another hydroxyl group to the 1 position to form the active 1,25(OH)2D3, which enters the nucleus to bind to the VDR that binds to the Vitamin D response element (VDRE) to activate expression of a large number of genes. The onset of diabetes is associated with increased levels of both Ca2+ and ROS, which are normally regulated by Vitamin D, which acts to maintain low resting levels of both Ca2+ and ROS. Vitamin D increases expression of antioxidants that reduce levels of ROS, and it maintains low Ca2+ levels by increasing expression of the plasma membrane Ca2+-ATPase (PMCA) and the NCX1, which extrude Ca2+, and the Ca2+ buffer calbindin. Vitamin D also reduces the expression of the L-type CaV1.2 and CaV1.3 Ca2+ channels. One of the main functions of Vitamin D is to maintain the expression of the DNA demethylases, such as JMJD1A and JMJD3 as well as LSD1 and LSD2, that act to prevent the hypermethylation of promoter regions that is responsible for reducing gene transcription.

Vitamin D also plays a prominent role in regulating the epigenetic modifications that are a feature of diabetes [84,85]. In individuals who are obese, there is an increase in DNA methylation, which is a risk factor for developing diabetes [86]. Vitamin D acts by preventing the hypermethylation of gene promotors such as those that regulate many diabetes-related genes. Such epigenetic alterations that result in a decline in the expression of key signalling proteins are a feature of diabetes. Some of this hypermethylation is induced by an increase in ROS formation [87], which is a feature of diabetes, as described above. For example, Prdx2 and SCARA3 are two of the genes that are inactivated by hypermethylation, and this contributes to the increase in ROS because they encode proteins that act normally to reduce ROS [85]. The role of Vitamin D in reducing ROS levels is one way that it acts to prevent hypermethylation. In addition, one of the main functions of Vitamin D is to maintain the expression of the DNA demethylases, such as Jumonji domain-containing protein 1A and 3 (JMJD1A and JMJD3) and lysine-specific demethylase 1 and 2 (LSD1 and LSD2), which act to prevent the hypermethylation of multiple gene promoter regions (Figure 1) [88].

Vitamin D and mitochondrial respiration

There is increasing evidence that mitochondrial dysfunction is a feature of many pathologies such as depression and skeletal muscle fatigue [8999]. One of the main functions of Vitamin D is to maintain the activity of the mitochondrial respiratory chain [100]. Vitamin D also regulates the expression of uncoupling protein 1 (UCP1), which is located on the inner mitochondrial membrane where it acts to control thermogenesis [21]. During Vitamin D deficiency, mitochondrial respiration declines due to a reduction in the nuclear mRNA molecules and proteins that contribute to mitochondrial respiration [101,102]. In particular, the formation of ATP declines because there is a reduction in the expression of complex I of the electron transport chain. This decline in the electron transport chain also results in an increase in the formation of ROS that induces oxidative stress, which is a feature of diabetes [72,103]. One of the main actions of Vitamin D is to maintain the normal mitochondrial control of cellular bioenergetics [104]. The Ca2+ buffering role of the mitochondria is also compromised, resulting in an increase in the intracellular level of Ca2+, which is a feature of β-cell dysfunction in diabetes. Such a decline in mitochondrial function caused by Vitamin D deficiency may be particularly significant for diabetes. The decline in mitochondrial bioenergetics caused by reduced respiration results in a change in mitochondrial oxidative phosphorylation, thereby decreasing the formation of ATP and increasing the generation of ROS.

Mitochondrial function is regulated by Vitamin D through two actions. First, it acts through the VDR in the nucleus to increase the expression of many of the components responsible for mitochondrial function (Figure 1) [101,102]. Secondly, the VDR enters the mitochondrion where it may act directly to regulate mitochondrial function, but it is not clear exactly what it does within the mitochondria. The VDR, which is located in the mitochondria [105], enters through the permeability transition pore [106].

This important role of Vitamin D in maintaining normal mitochondrial function may account for the link between Vitamin D deficiency and diabetes. The elevation of ROS and the reduction in ATP formation will have a major impact on Ca2+ homeostasis that may account for the decline of insulin release by the pancreatic β-cells. The formation of ROS facilitates the release of Ca2+ from the endoplasmic reticulum (ER) by the inositol 1,4,5-trisphosphate receptors (InsP3Rs) and the ryanodine receptors (RYRs), whereas the decline in ATP will reduce the ability of the Ca2+ pumps on the plasma membrane and the ER to extrude Ca2+ from the cytoplasm of cells. Both these effects will induce an abnormal elevation in Ca2+ levels in the β-cells and will contribute to the onset of diabetes as described below.

Insulin secretion by β-cells from the pancreatic islets of Langerhans

To understand how Vitamin D deficiency results in a dysregulation of β-cell function, it is necessary to understand how these β-cells respond normally to elevations of glucose. An elevation of glucose in the plasma acts on the pancreatic β-cells to induce the release of insulin [107,108]. The glucose, which acts by entering the β-cells via the GLUT2, is rapidly phosphorylated to form glucose-6-phosphate (G-6-P) by hexokinase IV [107]. The G-6-P is then converted into fructose-6-phosphate and then into fructose-2,6-P2 (F-2,6-P2) by phosphofructose kinase-2. The F-2,6-P2 then enters the glycolytic and tricarboxylic acid cycles, resulting in an elevation in ATP. The increase in ATP then acts to inhibit the ATP-sensitive K+ (KATP) channel, which results in membrane depolarization that then activates the L-type voltage-operated channels to generate the localized Ca2+ pulses that trigger the release of insulin [109]. This pulsatile elevation of intracellular Ca2+ is presented as a slow oscillation with a periodicity of 4–6 min that induces the periodic release of insulin [109112]. On the crest of these slow spikes, there are faster spikes with periodicities of 10–20 s.

The secretion of insulin is also sensitive to other factors such as acetylcholine (ACh), which is released by the α-cells of the human islet [113], which enhances the response of β-cells to glucose [114]. These other stimuli, such as ACh and free fatty acids (FFAs), can contribute to this glucose-induced primary Ca2+ signal. The ACh acts by stimulating the M3 muscarinic receptor to activate the InsP3/Ca2+ pathway [114116]. This mobilization of internal Ca2+ seems to prime the cell to generate stronger Ca2+ transients that trigger the release of insulin [113]. In addition to this stimulatory signal, the cholinergic signalling pathway can also act indirectly to reduce insulin secretion [117]. Support for cholinergic stimulation playing a role in insulin secretion has emerged from studies on Pima Indians where genetic variations in the M3 receptor have been linked to early-onset T2D [118]. In mice, mutation of the Itpr1 gene that encodes the InsP3R1 channel, which releases Ca2+ from the ER, has been linked to diabetes [119]. The significance of the InsP3/Ca2+ pathway is also supported by the observation that there is a depletion in the levels of inositol in diabetes [120]. The ability of Li+ to control bipolar disorder may depend on its ability to reduce inositol levels, which reduces the activity of the InsP3/Ca2+ pathway [121]. The FFAs also potentiate glucose-induced insulin secretion by acting through the InsP3/Ca2+ pathway that is stimulated by the G-protein-coupled receptor 40 (GPR40) receptor [122]. The InsP3/Ca2+ pathway appears to act synergistically with glucose to control the release of insulin [123,124].

This role of Ca2+ in regulating insulin secretion is carefully regulated. However, when the β-cells are hyperactivated to counteract the insulin resistance described earlier, the increase in Ca2+ is elevated well above normal and particularly when there is a decline in the level of Vitamin D, which acts normally to maintain Ca2+ homeostasis as described below.

Vitamin D, β-cell inactivation and diabetes

One of the causes of diabetes [both type 1 diabetes (T1D) and T2D] is a decline in the secretion of insulin by the β-cells. This decline in β-cell function can result from many mechanisms [107]. In the case of T1D, autoimmunity seems to be a major factor in inducing a decline in β-cells. A decline in the level of Vitamin D may contribute to the onset of this immune response [125,126]. Vitamin D acts to reduce the inflammatory mechanisms responsible for T1D [2,4,127,128].

As a result of the insulin resistance described earlier, there is an increase in the blood level of glucose (hyperglycaemia) that is one of the causes of T2D that induces a decline in insulin secretion [24,129131]. There are indications that this decline in β-cell function may result from excessive Ca2+ signalling [132]. The overstimulation causes an increase in the resting level of Ca2+ and it also alters the regular Ca2+ oscillations that drive the secretion of insulin [133,134]. Vitamin D may contribute to the alteration in Ca2+ signalling, because it normally acts to reduce the expression of the L-type Ca2+ channels (Figure 1) [135,136]. During Vitamin D deficiency, there will be an increased expression of these channels that will enhance the Ca2+ signals in β-cells. With regard to Ca2+ homeostasis, Vitamin D also acts by increasing the expression of those components that act to maintain low resting levels of Ca2+, such as the buffers calbindin D-9k, calbindin D-28k and parvalbumin, the Ca2+ pumps, the sodium/calcium exchanger (NCX) and the plasma membrane Ca2+-ATPase 1b (PMCA1b; Figure 1) [137140]. This excessive Ca2+ signalling induces apoptosis and the subsequent cell death of the β-cell [25,141145].

The deleterious effects of glucotoxicity may also be mediated by chronic oxidative stress [23,71,76,107,130,131,146153]. A detailed description of ROS production and how it contributes to the onset of diabetes has been described by Newsholme et al. [23] and Gerber and Rutter [153]. As described earlier, Vitamin D deficiency results in a decline in mitochondrial respiration, resulting in an increase in ROS formation. An increase in ROS is particularly deleterious for β-cells, because they have low levels of ROS-detoxifying enzyme when compared with other cell types [71,76,130,154157]. For example, there is a decline in the level of the antioxidant glutathione (GSH) [158]. A reduction in B-cell lymphoma 2 (Bcl-2) levels will also result in an increase in InsP3-induced Ca2+ release because the activity of the InsP3 receptor is normally suppressed by Bcl-2 [159].

One of the effects of this oxidative stress is to inhibit transcription of the insulin gene [146,148]. Another important action of the ROS, which are increased during oxidative stress, is to enhance Ca2+ signalling. The increase in ROS enhances the release of Ca2+ from the ER by sensitizing both the InsP3Rs [160163] and the RYRs (Figure 1) [164,165]. These two Ca2+ release channels located on the ER have been implicated in β-cell death [166]. ROS can also inhibit the PMCA Ca2+ pump in the plasma membrane that will further increase intracellular Ca2+ levels [167]. All this evidence that a decline in β-cell function may depend on an increase in both Ca2+ and ROS may help to explain why Vitamin D deficiency is a risk factor for diabetes, as described earlier. Maintaining low resting levels of both Ca2+ and ROS is one of the primary functions of Vitamin D (Figure 1) [82,83,168].

Vitamin D working together with Klotho and Nrf2 can regulate the expression of many of the antioxidant systems that reduce oxidative stress by removing ROS and also by reversing the oxidative changes that occur during excessive ROS signalling. It reduces the expression of the NADPH oxidase (NOX) that generates ROS [169] while up-regulating the superoxide dismutase that rapidly converts superoxide (O2·) into hydrogen peroxide (H2O2) [170]. Vitamin D also increases the expression of glucose-6-phosphate dehydrogenase (G6PD), glutamate cysteine ligase and glutathione reductase to increase the formation of the major redox buffer GSH [171173]. Up-regulating the expression of the glutathione peroxidase drives the conversion of H2O2 into water [170]. This ability of Vitamin D to maintain normal resting levels of both Ca2+ and ROS may explain why Vitamin D deficiency has been linked to the onset of diabetes. When Vitamin D levels decline, there will be an increase in both Ca2+ and ROS levels, both of which have been linked to the changes that occur in the β-cells that result in a decline in their cell mass and the onset of diabetes.

Conclusion

Diabetes is initiated by the onset of insulin resistance. The pancreatic islet β-cells can overcome this resistance by releasing more insulin, thus preventing hyperglycaemia. However, as this hyperactivity increases, the β-cells experience excessive Ca2+ and ROS signalling that results in cell death and the onset of T2D caused by a marked decline in insulin secretion. Vitamin D deficiency contributes to both the initial insulin resistance and the subsequent onset of diabetes caused by β-cell death.

Vitamin D acts to maintain a large number of cellular processes and this acts to reduce the onset of diabetes. For example, it maintains the Wnt/β-catenin signalling pathway that inhibits adipocyte differentiation during adipogenesis. It also prevents apoptosis by reducing the expression of the mitochondrial UCP2. With regard to insulin resistance, it acts to maintain the insulin signalling pathway by increasing the expression of the insulin receptor. Vitamin D has an important role in regulating the secretion of the adipokines that play an important role in maintaining both glucose and lipid homeostasis. By regulating the formation of leptin, which reduces appetite, it reduces the ingestion of excessive metabolites. Vitamin D also acts to reduce inflammation, which is a major process in inducing insulin resistance.

One of the main functions of Vitamin D is to maintain normal mitochondrial activity. In particular, it helps to maintain physiological electron flow in the respiratory chain, thereby preventing the formation of ROS, which reduces the activity of the insulin signalling pathway. It also reduces ROS by controlling expression of cellular antioxidants as part of its role in maintaining phenotypic stability of cell signalling pathways. This important role of Vitamin D in maintaining normal mitochondrial function may account for the link between Vitamin D deficiency and diabetes. The elevation of ROS and the reduction in ATP formation will have a major impact on Ca2+ homeostasis that may account for the death of the pancreatic β-cells, which results in the decline of insulin release.

Vitamin D has a very significant role in maintaining the epigenome. Epigenetic alterations are a feature of diabetes by which many diabetes-related genes are inactivated by hypermethylation. Vitamin D acts to prevent such hypermethylation by increasing the expression of the DNA demethylases that act to prevent the hypermethylation of multiple gene promoter regions of many diabetes-related genes.

What is remarkable is just how many cellular processes are maintained by Vitamin D. When Vitamin D is deficient, many of these processes begin to decline and this sets the stage for the onset of diseases such as diabetes.

Abbreviations

     
  • ACh

    acetylcholine

  •  
  • β-cells

    beta cells

  •  
  • Bcl-2

    B-cell lymphoma 2

  •  
  • ER

    endoplasmic reticulum

  •  
  • F-2,6-P2

    fructose-2,6-P2

  •  
  • FA

    fatty acid

  •  
  • FFAs

    free fatty acids

  •  
  • G-6-P

    glucose-6-phosphate

  •  
  • G6PD

    glucose-6-phosphate dehydrogenase

  •  
  • GLUT

    glucose transporter

  •  
  • GPR40

    G-protein-coupled receptor 40

  •  
  • GSH

    glutathione

  •  
  • IKK-β

    IκB kinase-β

  •  
  • InsP3R

    inositol 1,4,5-trisphosphate receptors

  •  
  • IRS

    insulin receptor substrate

  •  
  • JMJD1A and JMJD3

    Jumonji domain-containing protein 1A and 3

  •  
  • LSD1 and LSD2

    lysine-specific demethylase 1 and 2

  •  
  • NCX

    sodium/calcium exchanger

  •  
  • NF-κB

    nuclear factor-κB

  •  
  • NOX

    NADPH oxidase

  •  
  • PMCA

    plasma membrane Ca2+-ATPase

  •  
  • ROS

    reactive oxygen species

  •  
  • RYR

    ryanodine receptor

  •  
  • T1D

    type 1 diabetes

  •  
  • T2D

    type 2 diabetes

  •  
  • UCP1

    uncoupling protein 1

  •  
  • UCP2

    uncoupling protein 2

  •  
  • VDR

    Vitamin D receptor.

Competing Interests

The Author declares that there are no competing interests associated with this manuscript.

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