Vitamin D deficiency and diabetes - Biochemical Journal

Biochemical Journal (2017) 474 1321–1332 DOI: 10.1042/BCJ20170042

Review Article

Vitamin D deficiency and diabetes Michael J. Berridge The Babraham Institute, Babraham, Cambridge CB22 3AT, U.K. Correspondence: Michael J. Berridge ([email protected])

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 Received: 13 January 2017 Revised: 10 February 2017 Accepted: 13 February 2017 Version of Record published: 24 March 2017

There is increasing evidence that Vitamin D deficiency may contribute to the onset of diabetes [1–9]. 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

© 2017 The Author(s); published by Portland Press Limited on behalf of the Biochemical Society

1321

Biochemical Journal (2017) 474 1321–1332 DOI: 10.1042/BCJ20170042

maintained at their normal low physiological levels [82,83,137–140,168]. 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 [12–19]. 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 [26–28]. 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 [9,22,34–36], 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) [43–45]. 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 [46–48]. 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 [49–51]. 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].

1322

© 2017 The Author(s); published by Portland Press Limited on behalf of the Biochemical Society

Biochemical Journal (2017) 474 1321–1332 DOI: 10.1042/BCJ20170042

The inflammation that is associated with obesity also contributes to the onset of insulin resistance [23,36,56– 62]. 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 [64–67]. Another significant activator of insulin resistance is an increase in the formation of ROS [23,68–78]. 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

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.

© 2017 The Author(s); published by Portland Press Limited on behalf of the Biochemical Society

1323

Biochemical Journal (2017) 474 1321–1332 DOI: 10.1042/BCJ20170042

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 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 [89–99]. 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].

1324

© 2017 The Author(s); published by Portland Press Limited on behalf of the Biochemical Society

Biochemical Journal (2017) 474 1321–1332 DOI: 10.1042/BCJ20170042

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 [109–112]. 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 [114–116]. 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 [24,129–131]. 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) [137–140]. This excessive Ca2+ signalling induces apoptosis and the subsequent cell death of the β-cell [25,141–145]. The deleterious effects of glucotoxicity may also be mediated by chronic oxidative stress [23,71,76,107,130,131,146–153]. 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 [71,76,130,154–157]. 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].

© 2017 The Author(s); published by Portland Press Limited on behalf of the Biochemical Society

1325

Biochemical Journal (2017) 474 1321–1332 DOI: 10.1042/BCJ20170042

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 [160–163] 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 (O−· 2 ) 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 [171–173]. 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

1326

© 2017 The Author(s); published by Portland Press Limited on behalf of the Biochemical Society

Biochemical Journal (2017) 474 1321–1332 DOI: 10.1042/BCJ20170042

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.

References 1 2 3 4 5 6 7 8 9 10

11 12 13 14 15 16 17 18 19 20 21 22 23 24 25

Scragg, R., Sowers, M. and Bell, C. (2004) Serum 25-hydroxyvitamin D, diabetes, and ethnicity in the Third National Health and Nutrition Examination Survey. Diabetes Care 27, 2813–2818 doi:10.2337/diacare.27.12.2813 Mathieu, C., Gysemans, C., Giulietti, A. and Bouillon, R. (2005) Vitamin D and diabetes. Diabetologia 48, 1247–1257 doi:10.1007/ s00125-005-1802-7 Palomer, X., González-Clemente, J.M., Blanco-Vaca, F. and Mauricio, D. (2008) Role of vitamin D in the pathogenesis of type 2 diabetes mellitus. Diabetes Obes. Metab. 10, 185–197 doi:10.1111/j.1463-1326.2007.00710.x Takiishi, T., Gysemans, C., Bouillon, R. and Mathieu, C. (2010) Vitamin D and diabetes. Endocrinol. Metab. Clin. North Am. 39, 419–446 doi:10.1016/ j.ecl.2010.02.013 Mitri, J., Muraru, M.D. and Pittas, A.G. (2011) Vitamin D and type 2 diabetes: a systematic review. Eur. J. Clin. Nutr. 65, 1005–1015 doi:10.1038/ ejcn.2011.118 Wacker, M. and Holick, M.F. (2013) Vitamin D — effects on skeletal and extraskeletal health and the need for supplementation. Nutrients 5, 111–148 doi:10.3390/nu5010111 Lips, P., Eekhoff, M., van Schoor, N., Oosterwerff, M., de Jongh, R., Krul-Poel, Y. et al. (2016) Vitamin D and type 2 diabetes. J. Steroid Biochem. Mol. Biol. pii: S0960-0760(16)30338-7. doi:10.1016/j.jsbmb.2016.11.021 Alam, U., Arul-Devah, V., Javed, S. and Malik, R.A. (2016) Vitamin D and diabetic complications: true or false prophet? Diabetes Ther. 7, 11–26 doi:10.1007/s13300-016-0159-x Wimalawansa, S.J. (2016) Associations of vitamin D with insulin resistance, obesity, type 2 diabetes, and metabolic syndrome. J. Steroid Biochem. Mol. Biol. pii: S0960-0760(16)30253-9. doi:10.1016/j.jsbmb.2016.09.017 Sentinelli, F., Bertoccini, L., Barchetta, I., Capoccia, D., Incani, M., Pani, M.G. et al. (2016) The vitamin D receptor (VDR) gene rs11568820 variant is associated with type 2 diabetes and impaired insulin secretion in Italian adult subjects, and associates with increased cardio-metabolic risk in children. Nutr. Metab. Cardiovasc. Dis. 26, 407–413 doi:10.1016/j.numecd.2016.02.004 Sergeev, I.N. (2016) 1,25-Dihydroxyvitamin D3 and type 2 diabetes: Ca2+-dependent molecular mechanisms and the role of vitamin D status. Horm. Mol. Biol. Clin. Invest. 26, 61–65 doi:10.1515/hmbci-2015-0069 Smotkin-Tangorra, M., Purushothaman, R., Gupta, A., Nejati, G., Anhalt, H. and Ten, S. (2007) Prevalence of vitamin D insufficiency in obese children and adolescents. J. Pediatr. Endocrinol. Metab. 20, 817–823 doi:10.1515/JPEM.2007.20.7.817 Kumar, J., Muntner, P., Kaskel, F.J., Hailpern, S.M. and Melamed, M.L. (2009) Prevalence and associations of 25-hydroxyvitamin D deficiency in US children: NHANES 2001-2004. Pediatrics 124, e362–e370 doi:10.1542/peds.2009-0051 Oliveira, R.M., Novaes, J.F., Azeredo, L.M., Cândido, A.P. and Leite, I.C. (2014) Association of vitamin D insufficiency with adiposity and metabolic disorders in Brazilian adolescents. Public Health Nutr. 17, 787–794 doi:10.1017/S1368980013001225 Harel, Z., Flanagan, P., Forcier, M. and Harel, D. (2011) Low vitamin D status among obese adolescents: prevalence and response to treatment. J. Adolesc. Health 48, 448–452 doi:10.1016/j.jadohealth.2011.01.011 Vimaleswaran, K.S., Berry, D.J., Lu, C., Tikkanen, E., Pilz, S., Hiraki, L.T. et al. (2013) Causal relationship between obesity and vitamin D status: bi-directional Mendelian randomization analysis of multiple cohorts. PLoS Med. 10, e1001383 doi:10.1371/journal.pmed.1001383 Turer, C.B., Lin, H. and Flores, G. (2013) Prevalence of vitamin D deficiency among overweight and obese US children. Pediatrics 131, e152–e161 doi:10.1542/peds.2012-1711 Pereira-Santos, M., Costa, P.R.F., Assis, A.M.O., Santos, C.A.S.T. and Santos, D.B. (2015) Obesity and vitamin D deficiency: a systematic review and meta-analysis. Obes. Rev. 16, 341–349 doi:10.1111/obr.12239 De Souza Silva, J.S., Pereira, S.E., Saboya Sobrinho, C.J. and Ramalho, A. (2016) Obesity, related diseases and their relationship with vitamin D deficiency in adolescents. Nutr. Hosp. 33, 856–864 doi:10.20960/nh.381 Marcotorchino, J., Tourniaire, F., Astier, J., Karkeni, E., Canault, M., Amiot, M.-J. et al. (2014) Vitamin D protects against diet-induced obesity by enhancing fatty acid oxidation. J. Nutr. Biochem. 25, 1077–1083 doi:10.1016/j.jnutbio.2014.05.010 Abbas, M.A. (2017) Physiological functions of vitamin D in adipose tissue. J. Steroid Biochem. Mol. Biol. 165(Pt B), 369–381 doi:10.1016/j.jsbmb. 2016.08.004 Kahn, S.E., Hull, R.L. and Utzschneider, K.M. (2006) Mechanisms linking obesity to insulin resistance and type 2 diabetes. Nature 444, 840–846 doi:10.1038/nature05482 Newsholme, P., Cruzat, V.F., Keane, K.N., Carlessi, R. and de Bittencourt, Jr, P.I.H. (2016) Molecular mechanisms of ROS production and oxidative stress in diabetes. Biochem. J. 473, 4527–4550 doi:10.1042/BCJ20160503C Leahy, J.L. (2005) Pathogenesis of type 2 diabetes mellitus. Arch. Med. Res. 36, 197–209 doi:10.1016/j.arcmed.2005.01.003 Butler, A.E., Janson, J., Bonner-Weir, S., Ritzel, R., Rizza, R.A. and Butler, P.C. (2003) β-cell deficit and increased β-cell apoptosis in humans with type 2 diabetes. Diabetes 52, 102–110 doi:10.2337/diabetes.52.1.102

© 2017 The Author(s); published by Portland Press Limited on behalf of the Biochemical Society

1327

Biochemical Journal (2017) 474 1321–1332 DOI: 10.1042/BCJ20170042

26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

1328

Chiu, K.C., Chu, A., Go, V.L. and Saad, M.F. (2004) Hypovitaminosis D is associated with insulin resistance and beta cell dysfunction. Am. J. Clin. Nutr. 79, 820–825 PMID:15113720 Mezza, T., Muscogiuri, G., Sorice, G.P., Prioletta, A., Salomone, E., Pontecorvi, A. et al. (2012) Vitamin D deficiency: a new risk factor for type 2 diabetes? Ann. Nutr. Metab. 61, 337–348 doi:10.1159/000342771 Pilz, S., Kienreich, K., Rutters, F., de Jongh, R., van Ballegooijen, A.J., Grübler, M. et al. (2013) Role of vitamin D in the development of insulin resistance and type 2 diabetes. Curr. Diab. Rep. 13, 261–270 doi:10.1007/s11892-012-0358-4 Shi, H., Norman, A.W., Okamura, W.H., Sen, A. and Zemel, M.B. (2001) 1α,25-Dihydroxyvitamin D3 modulates human adipocyte metabolism via nongenomic action. FASEB J. 15, 2751–2753 doi:10.1096/fj.01-0584fje Lee, H., Bae, S. and Yoon, Y. (2012) Anti-adipogenic effects of 1,25-dihydroxyvitamin D3 are mediated by the maintenance of the wingless-type MMTV integration site/β-catenin pathway. Int. J. Mol. Med. 30, 1219–1224 doi:10.3892/ijmm.2012.1101 Sakuma, S., Fujisawa, J., Sumida, M., Tanigawa, M., Inoda, R., Sujihera, T. et al. (2012) The involvement of mitogen-activated protein kinases in the 1α,25-dihydroxy-cholecalciferol-induced inhibition of adipocyte differentiation in vitro. J. Nutr. Sci. Vitaminol. 58, 1–8 doi:10.3177/jnsv.58.1 Shi, H., Norman, A.W., Okamura, W.H., Sen, A. and Zemel, M.B. (2002) 1α,25-Dihydroxyvitamin D3 inhibits uncoupling protein 2 expression in human adipocytes. FASEB J. 16, 1808–1810 doi:10.1096/fj.02-0255fje Sun, X. and Zemel, M.B. (2004) Role of uncoupling protein 2 (UCP2) expression and 1α, 25-dihydroxyvitamin D3 in modulating adipocyte apoptosis. FASEB J. 18, 1430–1432 doi:10.1096/fj.04-1971fje Reaven, G.M. (1988) Role of insulin resistance in human disease. Diabetes 37, 1595–1607 doi:10.2337/diab.37.12.1595 Qatanani, M. and Lazar, M.A. (2007) Mechanisms of obesity-associated insulin resistance: many choices on the menu. Genes Dev. 21, 1443–1455 doi:10.1101/gad.1550907 Goossens, G.H. (2008) The role of adipose tissue dysfunction in the pathogenesis of obesity-related insulin resistance. Physiol. Behav. 94, 206–218 doi:10.1016/j.physbeh.2007.10.010 Saltiel, A.R. and Kahn, C.R. (2001) Insulin signalling and the regulation of glucose and lipid metabolism. Nature 414, 799–806 doi:10.1038/414799a Savage, D.B., Petersen, K.F. and Shulman, G.I. (2007) Disordered lipid metabolism and the pathogenesis of insulin resistance. Physiol. Rev. 87, 507–520 doi:10.1152/physrev.00024.2006 Lackey, D.E., Lazaro, R.G., Li, P., Johnson, A., Hernandez-Carretero, A., Weber, N. et al. (2016) The role of dietary fat in obesity-induced insulin resistance. Am. J. Physiol. Endocrinol. Metab. 311, E989–E997 doi:10.1152/ajpendo.00323.2016 Petersen, K.F. and Shulman, G.I. (2006) Etiology of insulin resistance. Am. J. Med. 119(Suppl. 1), S10–S16 doi:10.1016/j.amjmed.2006.01.009 Maestro, B., Campión, J., Dávila, N. and Calle, C. (2000) Stimulation by 1,25-dihydroxyvitamin D3 of insulin receptor expression and insulin responsiveness for glucose transport in U-937 human promonocytic cells. Endocr. J. 47, 383–391 doi:10.1507/endocrj.47.383 Maestro, B., Molero, S., Bajo, S., Dávila, N. and Calle, C. (2002) Transcriptional activation of the human insulin receptor gene by 1,25-dihydroxyvitamin D(3). Cell Biochem. Funct. 20, 227–232 doi:10.1002/cbf.951 Draznin, B., Sussman, K.E., Eckel, R.H., Kao, M., Yost, T. and Sherman, N.A. (1988) Possible role of cytosolic free calcium concentrations in mediating insulin resistance of obesity and hyperinsulinemia. J. Clin. Invest. 82, 1848–1852 doi:10.1172/JCI113801 Draznin, B., Lewis, D., Houlder, N., Sherman, N., Adamo, M., Garvey, W.T. et al. (1989) Mechanism of insulin resistance induced by sustained levels of cytosolic free calcium in rat adipocytes. Endocrinology 125, 2341–2349 doi:10.1210/endo-125-5-2341 Reusch, J.E.-B., Begum, N., Sussman, K.E. and Draznin, B. (1991) Regulation of GLUT-4 phosphorylation by intracellular calcium in adipocytes. Endocrinology 129, 3269–3273 doi:10.1210/endo-129-6-3269 Kershaw, E.E. and Flier, J.S. (2004) Adipose tissue as an endocrine organ. J. Clin. Endocrinol. Metab. 89, 2548–2556 doi:10.1210/jc.2004-0395 Kong, J., Chen, Y., Zhu, G., Zhao, Q. and Li, Y.C. (2013) 1,25-Dihydroxyvitamin D3 upregulates leptin expression in mouse adipose tissue. J. Endocrinol. 216, 265–271 doi:10.1530/JOE-12-0344 Walker, G.E., Ricotti, R., Roccio, M., Moia, S., Bellone, S., Prodam, F. et al. (2014) Pediatric obesity and vitamin D deficiency: a proteomic approach identifies multimeric adiponectin as a key link between these conditions. PLoS ONE 9, e83685 doi:10.1371/journal.pone.0083685 Rajala, M.W., Obici, S., Scherer, P.E., and Rossetti, L. (2003) Adipose-derived resistin and gut-derived resistin-like molecule-β selectively impair insulin action on glucose production. J. Clin. Invest. 111, 225–230 doi:10.1172/JCI16521 Rangwala, S.M., Rich, A.S., Rhoades, B., Shapiro, J.S., Obici, S., Rossetti, L. et al. (2004) Abnormal glucose homeostasis due to chronic hyperresistinemia. Diabetes 53, 1937–1941 doi:10.2337/diabetes.53.8.1937 Qi, Y., Nie, Z., Lee, Y.-S., Singhal, N.S., Scherer, P.E., Lazar, M.A. et al. (2006) Loss of resistin improves glucose homeostasis in leptin deficiency. Diabetes 55, 3083–3090 doi:10.2337/db05-0615 Chandran, M., Phillips, S.A., Ciaraldi, T. and Henry, R.R. (2003) Adiponectin: more than just another fat cell hormone? Diabetes Care 26, 2442–2450 doi:10.2337/diacare.26.8.2442 Schwartz, M.W., Woods, S.C., Porte, Jr, D., Seeley, R.J. and Baskin, D.G. (2000) Central nervous system control of food intake. Nature 404, 661–671 doi:10.1038/35007534 Frühbeck, G., Aguado, M. and Martınez, J.A. (1997) In vitro lipolytic effect of leptin on mouse adipocytes: evidence for a possible autocrine/paracrine role of leptin. Biochem. Biophys. Res. Commun. 240, 590–594 doi:10.1006/bbrc.1997.7716 Frühbeck, G., Aguado, M., Gómez-Ambrosi, J. and Martínez, J.A. (1998) Lipolytic effect of in vivo leptin administration on adipocytes of lean and Ob/Ob mice, but not db/db mice. Biochem. Biophys. Res. Commun. 250, 99–102 doi:10.1006/bbrc.1998.9277 Hotamisligil, G.S., Arner, P., Caro, J.F., Atkinson, R.L. and Spiegelman, B.M. (1995) Increased adipose tissue expression of tumor necrosis factor-α in human obesity and insulin resistance. J. Clin. Invest. 95, 2409–2415 doi:10.1172/JCI117936 Xu, H., Barnes, G.T., Yang, Q., Tan, G., Yang, D., Chou, C.J. et al. (2003) Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. J. Clin. Invest. 112, 1821–1830 doi:10.1172/JCI200319451 Weisberg, S.P., McCann, D., Desai, M., Rosenbaum, M., Leibel, R.L., and Ferrante, Jr, A.W. (2003) Obesity is associated with macrophage accumulation in adipose tissue. J. Clin. Invest. 112, 1796–1808 doi:10.1172/JCI200319246 Wellen, K.E. and Hotamisligil, G.S. (2005) Inflammation, stress, and diabetes. J. Clin. Invest. 115, 1111–1119 doi:10.1172/JCI200525102 Shoelson, S.E., Lee, J. and Goldfine, A.B. (2006) Inflammation and insulin resistance. J. Clin. Invest. 116, 1793–1801 doi:10.1172/JCI29069

© 2017 The Author(s); published by Portland Press Limited on behalf of the Biochemical Society

Biochemical Journal (2017) 474 1321–1332 DOI: 10.1042/BCJ20170042

61 62 63 64 65 66 67 68

69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94

Donath, M.Y. and Shoelson, S.E. (2011) Type 2 diabetes as an inflammatory disease. Nat. Rev. Immunol. 11, 98–107 doi:10.1038/nri2925 Wimalawansa, S.J. (2016) Vitamin D deficiency is a surrogate marker for visceral fat content, metabolic syndrome, type 2 diabetes, and future metabolic complications. J. Diabetes Metab. Disord. Control 3, 00059 doi:10.15406/jdmdc.2016.03.00059 Cai, D., Yuan, M., Frantz, D.F., Melendez, P.A., Hansen, L., Lee, J. et al. (2005) Local and systemic insulin resistance from hepatic activation of IKKβ and NF-κB. Nat. Med. 11, 183–190 doi:10.1038/nm1166 Marcotorchino, J., Gouranton, E., Romier, B., Tourniaire, F., Astier, J., Malezet, C. et al. (2012) Vitamin D reduces the inflammatory response and restores glucose uptake in adipocytes. Mol. Nutr. Food Res. 56, 1771–1782 doi:10.1002/mnfr.201200383 Ding, C., Wilding, J.P.H., Bing, C. and Randeva, H.S. (2013) 1,25-Dihydroxyvitamin D3 protects against macrophage-induced activation of NFκB and MAPK signalling and chemokine release in human adipocytes. PLoS ONE 8, e61707 doi:10.1371/journal.pone.0061707 Gao, D., Trayhurn, P. and Bing, C. (2013) 1,25-Dihydroxyvitamin D3 inhibits the cytokine-induced secretion of MCP-1 and reduces monocyte recruitment by human preadipocytes. Int. J. Obes. 37, 357–365 doi:10.1038/ijo.2012.53 Lorente-Cebrián, S., Eriksson, A., Dunlop, T., Mejhert, N., Dahlman, I., Aström, G. et al. (2012) Differential effects of 1α,25-dihydroxycholecalciferol on MCP-1 and adiponectin production in human White adipocytes. Eur. J. Nutr. 51, 335–342 doi:10.1007/s00394-011-0218-z Rösen, P., Nawroth, P.P., King, G., Möller, W., Tritschler, H.-J. and Packer, L. (2001) The role of oxidative stress in the onset and progression of diabetes and its complications: a summary of a Congress series sponsored by UNESCO-MCBN, the American Diabetes Association and the German Diabetes Society. Diabetes Metab. Res. Rev. 17, 189–212 doi:10.1002/dmrr.196 Evans, J.L., Goldfine, I.D., Maddux, B.A., and Grodsky, G.M. (2002) Oxidative stress and stress-activated signaling pathways: a unifying hypothesis of type 2 diabetes. Endocr. Rev. 23, 599–622 doi:10.1210/er.2001-0039 Haber, C.A., Lam, T.K.T., Yu, Z., Gupta, N., Goh, T., Bogdanovic, E. et al. (2003) N-acetylcysteine and taurine prevent hyperglycemia-induced insulin resistance in vivo: possible role of oxidative stress. Am. J. Physiol. Endocrinol. Metab. 285, E744–E753 doi:10.1152/ajpendo.00355.2002 Robertson, R.P., Harmon, J., Tran, P.O., Tanaka, Y. and Takahashi, H. (2003) Glucose toxicity in β-cells: type 2 diabetes, good radicals gone bad, and the glutathione connection. Diabetes 52, 581–587 doi:10.2337/diabetes.52.3.581 Brownlee, M. (2005) The pathobiology of diabetic complications: a unifying mechanism. Diabetes 54, 1615–1625 doi:10.2337/diabetes.54.6.1615 Houstis, N., Rosen, E.D., and Lander, E.S. (2006) Reactive oxygen species have a causal role in multiple forms of insulin resistance. Nature 440, 944–948 doi:10.1038/nature04634 Fridlyand, L.E. and Philipson, L.H. (2006) Reactive species and early manifestation of insulin resistance in type 2 diabetes. Diabetes Obes. Metab. 8, 136–145 doi:10.1111/j.1463-1326.2005.00496.x Wright, E., Scism-Bacon, J.L. and Glass, L.C. (2006) Oxidative stress in type 2 diabetes: the role of fasting and postprandial glycaemia. Int. J. Clin. Pract. 60, 308–314 doi:10.1111/j.1368-5031.2006.00825.x Robertson, R.P., Zhou, H., Zhang, T. and Harmon, J.S. (2007) Chronic oxidative stress as a mechanism for glucose toxicity of the beta cell in type 2 diabetes. Cell Biochem. Biophys. 48, 139–146 doi:10.1007/s12013-007-0026-5 Manucha, W., Ritchie, B. and Ferder, L. (2015) Hypertension and insulin resistance: implications of mitochondrial dysfunction. Curr. Hypertens. Rep. 17, 504 doi:10.1007/s11906-014-0504-2 Verdile, G., Keane, K.N., Cruzat, V.F., Medic, S., Sabale, M., Rowles, J. et al. (2015) Inflammation and oxidative stress: the molecular connectivity between insulin resistance, obesity, and Alzheimer’s disease. Mediators Inflamm. 2015, 17 doi:10.1155/2015/105828 Carlsson, C., Håkan Borg, L.A. and Welsh, N. (1999) Sodium palmitate induces partial mitochondrial uncoupling and reactive oxygen species in rat pancreatic islets in vitro. Endocrinology 140, 3422–3428 doi:10.1210/endo.140.8.6908 Rao, M.S. and Reddy, J.K. (2001) Peroxisomal β-oxidation and steatohepatitis. Semin. Liver Dis. 21, 43–56 doi:10.1055/s-2001-12928 Sun, X. and Zemel, M.B. (2007) 1α,25-Dihydroxyvitamin D3 modulation of adipocyte reactive oxygen species production. Obesity 15, 1944–1953 doi:10.1038/oby.2007.232 Berridge, M.J. (2015) Vitamin D: a custodian of cell signalling stability in health and disease. Biochem. Soc.Trans. 43, 349–358 doi:10.1042/ BST20140279 Berridge, M.J. (2015) Vitamin D cell signalling in health and disease. Biochem. Biophys. Res. Commun. 460, 53–71 doi:10.1016/j.bbrc.2015.01.008 Alam, F., Islam, M., Gan, S., Mohamed, M. and Sasongko, T. (2016) DNA methylation: an epigenetic insight into type 2 diabetes mellitus. Curr. Pharm. Des. 22, 4398–4419 doi:10.2174/1381612822666160527111152 Karachanak-Yankova, S., Dimova, R., Nikolova, D., Nesheva, D., Koprinarova, M., Maslyankov, S. et al. (2015) Epigenetic alterations in patients with type 2 diabetes mellitus. Balkan J. Med. Genet. 18, 15–24 doi:10.1515/bjmg-2015-0081 Wahl, S., Drong, A., Lehne, B., Loh, M., Scott, W.R., Kunze, S. et al. (2017) Epigenome-wide association study of body mass index, and adverse outcomes of adiposity. Nature 541, 81–86 doi:10.1038/nature20784 Baccarelli, A. and Bollati, V. (2009) Epigenetics and environmental chemicals. Curr. Opin. Pediatr. 21, 243–251 doi:10.1097/MOP.0b013e32832925cc Pereira, F., Barbáchano, A., Singh, P.K., Campbell, M.J., Muñoz, A. and Larriba, M.J. (2012) Vitamin D has wide regulatory effects on histone demethylase genes. Cell Cycle 11, 1081–1089 doi:10.4161/cc.11.6.19508 Kato, T. (2007) Mitochondrial dysfunction as the molecular basis of bipolar disorder: therapeutic implications. CNS Drugs 21, 1–11 doi:10.2165/ 00023210-200721010-00001 Andreazza, A.C., Shao, L., Wang, J.-F. and Young, L.T. (2010) Mitochondrial complex I activity and oxidative damage to mitochondrial proteins in the prefrontal cortex of patients with bipolar disorder. Arch. Gen. Psychiatry 67, 360–368 doi:10.1001/archgenpsychiatry.2010.22 Jou, S.H., Chiu, N.Y. and Liu, C.S. (2009) Mitochondrial dysfunction and psychiatric disorders. Chang. Gung. Med. J. 32, 370–379 PMID:19664343 Clay, H.B., Sillivan, S. and Konradi, C. (2011) Mitochondrial dysfunction and pathology in bipolar disorder and schizophrenia. Int. J. Dev. Neurosci. 29, 311–324 doi:10.1016/j.ijdevneu.2010.08.007 Andreazza, A.C., Wang, J.-F., Salmasi, F., Shao, L. and Young, L.T. (2013) Specific subcellular changes in oxidative stress in prefrontal cortex from patients with bipolar disorder. J. Neurochem. 127, 552–561 doi:10.1111/jnc.12316 Callaly, E., Walder, K., Morris, G., Maes, M., Debnath, M. and Berk, M. (2015) Mitochondrial dysfunction in the pathophysiology of bipolar disorder: effects of pharmacotherapy. Mini. Rev. Med. Chem. 15, 355–365 doi:10.2174/1389557515666150324122026

© 2017 The Author(s); published by Portland Press Limited on behalf of the Biochemical Society

1329

Biochemical Journal (2017) 474 1321–1332 DOI: 10.1042/BCJ20170042

95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124

125

126

1330

Morris, G. and Berk, M. (2015) The many roads to mitochondrial dysfunction in neuroimmune and neuropsychiatric disorders. BMC Med. 13, 68 doi:10. 1186/s12916-015-0310-y Bansal, Y. and Kuhad, A. (2016) Mitochondrial dysfunction in depression. Curr. Neuropharmacol. 14, 610–618 doi:10.2174/ 1570159X14666160229114755 Bouillon, R. and Verstuyf, A. (2013) Vitamin, D, mitochondria, and muscle. J. Clin. Endocrinol. Metab. 98, 961–963 doi:10.1210/jc.2013-1352 Sinha, A., Hollingsworth, K.G., Ball, S. and Cheetham, T. (2013) Improving the vitamin D status of vitamin D deficient adults is associated with improved mitochondrial oxidative function in skeletal muscle. J. Clin. Endocrinol. Metab. 98, E509–E513 doi:10.1210/jc.2012-3592 Ryan, Z.C., Craig, T.A., Folmes, C.D., Wang, X., Lanza, I.R., Schaible, N.S. et al. (2016) 1α,25-Dihydroxyvitamin D3 regulates mitochondrial oxygen consumption and dynamics in human skeletal muscle cells. J. Biol. Chem. 291, 1514–1528 doi:10.1074/jbc.M115.684399 Consiglio, M., Viano, M., Casarin, S., Castagnoli, C., Pescarmona, G. and Silvagno, F. (2015) Mitochondrial and lipogenic effects of vitamin D on differentiating and proliferating human keratinocytes. Exp. Dermatol. 24, 748–753 doi:10.1111/exd.12761 Scaini, G., Rezin, G.T., Carvalho, A.F., Streck, E.L., Berk, M. and Quevedo, J. (2016) Mitochondrial dysfunction in bipolar disorder: evidence, pathophysiology and translational implications. Neurosci. Biobehav. Rev. 68, 694–713 doi:10.1016/j.neubiorev.2016.06.040 Kim, H.K., Andreazza, A.C., Yeung, P.Y., Isaacs-Trepanier, C. and Young, L.T. (2014) Oxidation and nitration in dopaminergic areas of the prefrontal cortex from patients with bipolar disorder and schizophrenia. J. Psychiatry Neurosci. 39, 276–285 doi:10.1503/jpn.130155 Lowell, B.B., and Shulman, G.I. (2005) Mitochondrial dysfunction and type 2 diabetes. Science 307, 384–387 doi:10.1126/science.1104343 Calton, E.K., Keane, K.N. and Soares, M.J. (2015) The potential regulatory role of vitamin D in the bioenergetics of inflammation. Curr. Opin. Clin. Nutr. Metab. Care 18, 367–373 doi:10.1097/MCO.0000000000000186 Silvagno, F., De Vivo, E., Attanasio, A., Gallo, V., Mazzucco, G. and Pescarmona, G. (2010) Mitochondrial localization of vitamin D receptor in human platelets and differentiated megakaryocytes. PLoS ONE 5, e8670 doi:10.1371/journal.pone.0008670 Silvagno, F., Consiglio, M., Foglizzo, V., Destefanis, M. and Pescarmona, G. (2013) Mitochondrial translocation of vitamin D receptor is mediated by the permeability transition pore in human keratinocyte cell line. PLoS ONE 8, e54716 doi:10.1371/journal.pone.0054716 Fu, Z., Gilbert, E.R. and Liu, D. (2013) Regulation of insulin synthesis and secretion and pancreatic beta-cell dysfunction in diabetes. Curr. Diabetes Rev. 9, 25–53 doi:10.2174/157339913804143225 Nicholls, D.G. (2016) The pancreatic β-cell: a bioenergetic perspective. Physiol. Rev. 96, 1385–1447 doi:10.1152/physrev.00009.2016 Gilon, P., Chae, H.-Y., Rutter, G.A. and Ravier, M.A. (2014) Calcium signaling in pancreatic β-cells in health and in type 2 diabetes. Cell Calcium 56, 340–361 doi:10.1016/j.ceca.2014.09.001 Grapengiesser, E., Gylfe, E. and Hellman, B. (1988) Glucose-induced oscillations of cytoplasmic Ca2+ in the pancreatic β-cell. Biochem. Biophys. Res. Commun. 151, 1299–1304 doi:10.1016/S0006-291X(88)80503-5 Henquin, J.C., Jonas, J.C. and Gilon, P. (1998) Functional significance of Ca2+ oscillations in pancreatic beta cells. Diabete. Metab. 24, 30–36 PMID:9534006 Soria, B. and Martin, F. (1998) Cytosolic calcium oscillations and insulin release in pancreatic islets of Langerhans. Diabetes Metab. 24, 37–40 PMID:9534007 Rodriguez-Diaz, R., Dando, R., Jacques-Silva, M.C., Fachado, A., Molina, J., Abdulreda, M.H. et al. (2011) Alpha cells secrete acetylcholine as a non-neuronal paracrine signal priming beta cell function in humans. Nat. Med. 17, 888–892 doi:10.1038/nm.2371 Barker, C.J., Leibiger, I.B. and Berggren, P.-O. (2013) The pancreatic islet as a signaling hub. Adv. Biol. Regul. 53, 156–163 doi:10.1016/j.jbior.2012. 09.011 Gilon, P. and Henquin, J.-C. (2001) Mechanisms and physiological significance of the cholinergic control of pancreatic β-cell function. Endocr. Rev. 22, 565–604 doi:10.1210/edrv.22.5.0440 Barker, C.J. and Berggren, P.-O. (2013) New horizons in cellular regulation by inositol polyphosphates: insights from the pancreatic β-cell. Pharmacol. Rev. 65, 641–669 doi:10.1124/pr.112.006775 Molina, J., Rodriguez-Diaz, R., Fachado, A., Jacques-Silva, M.C., Berggren, P.-O. and Caicedo, A. (2014) Control of insulin secretion by cholinergic signaling in the human pancreatic islet. Diabetes 63, 2714–2726 doi:10.2337/db13-1371 Guo, Y., Traurig, M., Ma, L., Kobes, S., Harper, I., Infante, A.M. et al. (2006) CHRM3 gene variation is associated with decreased acute insulin secretion and increased risk for early-onset type 2 diabetes in Pima Indians. Diabetes 55, 3625–3629 doi:10.2337/db06-0379 Ye, R., Ni, M., Wang, M., Luo, S., Zhu, G., Chow, R.H. et al. (2011) Inositol 1,4,5-trisphosphate receptor 1 mutation perturbs glucose homeostasis and enhances susceptibility to diet-induced diabetes. J. Endocrinol. 210, 209–217 doi:10.1530/JOE-11-0012 Greene, D.A., Lattimer-Greene, S., and Sima, A.A. (1989) Pathogenesis of diabetic neuropathy: role of altered phosphoinositide metabolism. Crit. Rev. Neurobiol. 5, 143–219 PMID:2561904 Berridge, M.J., Downes, C.P. and Hanley, M.R. (1989) Neural and developmental actions of lithium: a unifying hypothesis. Cell 59, 411–419 doi:10. 1016/0092-8674(89)90026-3 Mancini, A.D. and Poitout, V. (2013) The fatty acid receptor FFA1/GPR40 a decade later: how much do we know? Trends Endocrinol. Metab. 24, 398–407 doi:10.1016/j.tem.2013.03.003 Gautam, D., Han, S.-J., Hamdan, F.F., Jeon, J., Li, B., Li, J.H. et al. (2006) A critical role for β cell M3 muscarinic acetylcholine receptors in regulating insulin release and blood glucose homeostasis in vivo. Cell Metab. 3, 449–461 doi:10.1016/j.cmet.2006.04.009 Srivastava, M., Atwater, I., Glasman, M., Leighton, X., Goping, G., Caohuy, H. et al. (1999) Defects in inositol 1,4,5-trisphosphate receptor expression, Ca2+ signaling, and insulin secretion in the anx7(+/−) knockout mouse. Proc. Natl Acad. Sci. U.S.A. 96, 13783–13788 doi:10.1073/pnas.96.24. 13783 Littorin, B., Blom, P., Schölin, A., Arnqvist, H.J., Blohmé, G., Bolinder, J. et al. (2006) Lower levels of plasma 25-hydroxyvitamin D among young adults at diagnosis of autoimmune type 1 diabetes compared with control subjects: results from the nationwide Diabetes Incidence Study in Sweden (DISS). Diabetologia 49, 2847–2852 doi:10.1007/s00125-006-0426-x Sung, C.-C., Liao, M.-T., Lu, K.-C. and Wu, C.-C. (2012) Role of vitamin D in insulin resistance. J. Biomed. Biotechnol. 2012, 11 doi:10.1155/2012/ 634195

© 2017 The Author(s); published by Portland Press Limited on behalf of the Biochemical Society

Biochemical Journal (2017) 474 1321–1332 DOI: 10.1042/BCJ20170042

127 Hyppönen, E., Läärä, E., Reunanen, A., Järvelin, M.-R. and Virtanen, S.M. (2001) Intake of vitamin D and risk of type 1 diabetes: a birth-cohort study. Lancet 358, 1500–1503 doi:10.1016/S0140-6736(01)06580-1 128 Ysmail-Dahlouk, L., Nouari, W. and Aribi, M. (2016) 1,25-Dihydroxyvitamin D3 down-modulates the production of proinflammatory cytokines and nitric oxide and enhances the phosphorylation of monocyte-expressed STAT6 at the recent-onset type 1 diabetes. Immunol. Lett. 179, 122–130 doi:10.1016/ j.imlet.2016.10.002 129 Khaldi, M.Z., Guiot, Y., Gilon, P., Henquin, J.C. and Jonas, J.C. (2004) Increased glucose sensitivity of both triggering and amplifying pathways of insulin secretion in rat islets cultured for 1 wk in high glucose. Am. J. Physiol. Endocrinol. Metab. 287, E207–E217 doi:10.1152/ajpendo.00426.2003 130 Prentki, M. and Nolan, C.J. (2006) Islet β-cell failure in type 2 diabetes. J. Clin. Invest. 116, 1802–1812 doi:10.1172/JCI29103 131 Bensellam, M., Laybutt, D.R. and Jonas, J.-C. (2012) The molecular mechanisms of pancreatic β-cell glucotoxicity: recent findings and future research directions. Mol. Cell. Endocrinol. 364, 1–27 doi:10.1016/j.mce.2012.08.003 132 Guerrero-Hernandez, A. and Verkhratsky, A. (2014) Calcium signalling in diabetes. Cell Calcium 56, 297–301 doi:10.1016/j.ceca.2014.08.009 133 Bjorklund, A., Lansner, A., and Grill, V.E. (2000) Glucose-induced [Ca2+]i abnormalities in human pancreatic islets: important role of overstimulation. Diabetes 49, 1840–1848 doi:10.2337/diabetes.49.11.1840 134 Grill, V. and Björklund, A. (2001) Overstimulation and beta-cell function. Diabetes 50(Suppl 1), S122–S124 doi:10.2337/diabetes.50.2007.S122 135 Brewer, L.D., Thibault, V., Chen, K.C., Langub, M.C., Landfield, P.W. and Porter, N.M. (2001) Vitamin D hormone confers neuroprotection in parallel with downregulation of L-type Ca2+ channel expression in hippocampal neurons. J. Neurosci. 21, 98–108 PMID:11150325 136 Gezen-Ak, D., Dursun, E. Yilmazer, S. and van der Brug, M. (2011) The effects of vitamin D receptor silencing on the expression of LVSCC-A1C and LVSCC-A1D and the release of NGF in cortical neurons. PLoS ONE 6, e17553 doi:10.1371/journal.pone.0017553 137 de Viragh, P.A., Haglid, K.G. and Celio, M.R. (1989) Parvalbumin increases in the caudate putamen of rats with vitamin D hypervitaminosis. Proc. Natl Acad. Sci. U.S.A. 86, 3887–3890 doi:10.1073/pnas.86.10.3887 138 Bouillon, R., Carmeliet, G., Verlinden, L., van Etten, E., Verstuyf, A., Luderer, H.F. et al. (2008) Vitamin D and human health: lessons from vitamin D receptor null mice. Endocrine Rev. 29, 726–776 doi:10.1210/er.2008-0004 139 Wasserman, R.H. (2004) Vitamin D and the dual processes of intestinal calcium absorption. J. Nutr. 134, 3137–3139 PMID:15514288 140 Haussler, M.R., Whitfield, G.K., Kaneko, I., Haussler, C.A., Hsieh, D., Hsieh, J.-C. et al. (2013) Molecular mechanisms of vitamin D action. Calcif. Tissue Int. 92, 77–98 doi:10.1007/s00223-012-9619-0 141 Efanova, I.B., Zaitsev, S.V., Zhivotovsky, B., Köhler, M., Efendic,́ S., Orrenius, S. et al. (1998) Glucose and tolbutamide induce apoptosis in pancreatic beta-cells. A process dependent on intracellular Ca2+ concentration. J. Biol. Chem. 273, 33501–33507 doi:10.1074/jbc.273.50.33501 142 Pick, A., Clark, J., Kubstrup, C., Levisetti, M., Pugh, W., Bonner-Weir, S. et al. (1998) Role of apoptosis in failure of β-cell mass compensation for insulin resistance and β-cell defects in the male Zucker diabetes fatty rat. Diabetes 47, 358–364 doi:10.2337/diabetes.47.3.358 143 Donath, M.Y., Gross, D.J., Cerasi, E. and Kaiser, N. (1999) Hyperglycemia-induced beta-cell apoptosis in pancreatic islets of Psammomys obesus during development of diabetes. Diabetes 48, 738–744 doi:10.2337/diabetes.48.4.738 144 Wang, L., Bhattacharjee, A., Zuo, Z., Hu, F., Honkanen, R.E., Berggren, P.-O. et al. (1999) A low voltage-activated Ca2+ current mediates cytokine-induced pancreatic β-cell death. Endocrinology 140, 1200–1204 doi:10.1210/endo.140.3.6556 145 Rhodes, C.J. (2005) Type 2 diabetes — a matter of β-cell life and death? Science 307, 380–384 doi:10.1126/science.1104345 146 Matsuoka, T.A., Kajimoto, Y., Watada, H., Kaneto, H., Kishimoto, M., Umayahara, Y. et al. (1997) Glycation-dependent, reactive oxygen species mediated suppression of the insulin gene promoter activity in HIT cells. J. Clin. Invest. 99, 144–150 doi:10.1172/JCI119126 147 Ihara, Y., Toyokuni, S., Uchida, K., Odaka, H., Tanaka, T., Ikeda, H. et al. (1999) Hyperglycemia causes oxidative stress in pancreatic beta-cells of GK rats, a model of type 2 diabetes. Diabetes 48, 927–932 doi:10.2337/diabetes.48.4.927 148 Tanaka, Y., Gleason, C.E., Tran, P.O.T., Harmon, J.S. and Robertson, R.P. (1999) Prevention of glucose toxicity in HIT-T15 cells and Zucker diabetic fatty rats by antioxidants. Proc. Natl Acad. Sci. U.S.A. 96, 10857–10862 doi:10.1073/pnas.96.19.10857 149 Poitout, V. and Robertson, R.P. (2002) Minireview: secondary β-cell failure in type 2 diabetes — a convergence of glucotoxicity and lipotoxicity. Endocrinology 143, 339–342 doi:10.1210/endo.143.2.8623 150 Tanaka, Y., Tran, P.O.T., Harmon, J. and Robertson, R.P. (2002) A role for glutathione peroxidase in protecting pancreatic β cells against oxidative stress in a model of glucose toxicity. Proc. Natl Acad. Sci. U.S.A. 99, 12363–12368 doi:10.1073/pnas.192445199 151 Robertson, R.P. (2004) Chronic oxidative stress as a central mechanism for glucose toxicity in pancreatic islet beta cells in diabetes. J. Biol. Chem. 279, 42351–42354 doi:10.1074/jbc.R400019200 152 Fujimoto, S., Mukai, E. and Inagaki, N. (2011) Role of endogenous ROS production in impaired metabolism-secretion coupling of diabetic pancreatic β cells. Prog. Biophys. Mol. Biol. 107, 304–310 doi:10.1016/j.pbiomolbio.2011.07.013 153 Gerber, P.A. and Rutter, G.A. (2016) The role of oxidative stress and hypoxia in pancreatic beta-cell dysfunction in diabetes mellitus. Antioxid. Redox Signal. doi:10.1089/ars.2016.6755 154 Grankvist, K., Marklund, S.L. and Täljedal, I.B. (1981) CuZn-superoxide dismutase, Mn-superoxide dismutase, catalase and glutathione peroxidase in pancreatic islets and other tissues in the mouse. Biochem. J. 199, 393–398 doi:10.1042/bj1990393 155 Prentki, M. (1996) New insights into pancreatic β-cell metabolic signaling in insulin secretion. Eur. J. Endocrinol. 134, 272–286 doi:10.1530/eje.0. 1340272 156 Evans, J.L., Goldfine, I.D., Maddux, B.A. and Grodsky, G.M. (2003) Are oxidative stress-activated signaling pathways mediators of insulin resistance and β-cell dysfunction? Diabetes 52, 1–8 doi:10.2337/diabetes.52.1.1 157 Newsholme, P., Haber, E.P., Hirabara, S.M., Rebelato, E.L.O., Procopio, J., Morgan, D. et al. (2007) Diabetes associated cell stress and dysfunction: role of mitochondrial and non-mitochondrial ROS production and activity. J. Physiol. 583, 9–24 doi:10.1113/jphysiol.2007.135871 158 Calabrese, V., Cornelius, C., Leso, V., Trovato-Salinaro, A., Ventimiglia, B., Cavallaro, M. et al. (2012) Oxidative stress, glutathione status, sirtuin and cellular stress response in type 2 diabetes. Biochim. Biophys. Acta Mol. Basis Dis. 1822, 729–736 doi:10.1016/j.bbadis.2011.12.003 159 Distelhorst, C.W. and Bootman, M.D. (2011) Bcl-2 interaction with the inositol 1,4,5-trisphosphate receptor: role in Ca2+ signaling and disease. Cell Calcium 50, 234–241 doi:10.1016/j.ceca.2011.05.011 160 Missiaen, L., Taylor, C.W. and Berridge, M.J. (1991) Spontaneous calcium release from inositol trisphosphate-sensitive calcium stores. Nature 352, 241–244 doi:10.1038/352241a0

© 2017 The Author(s); published by Portland Press Limited on behalf of the Biochemical Society

1331

Biochemical Journal (2017) 474 1321–1332 DOI: 10.1042/BCJ20170042

161 Bootman, M.D., Taylor, C.W. and Berridge, M.J. (1992) The thiol reagent, thimerosal, evokes Ca2+ spikes in HeLa cells by sensitizing the inositol 1,4,5-trisphosphate receptor. J. Biol. Chem. 267, 25113–25119 162 Bird, G.S., Burgess, G.M. and Putney, Jr, J.W. (1993) Sulfhydryl reagents and cAMP-dependent kinase increase the sensitivity of the inositol 1,4,5-trisphosphate receptor in hepatocytes. J. Biol. Chem. 268, 17917–17923 163 Bánsághi, S., Golenár, T., Madesh, M., Csordás, G., RamachandraRao, S., Sharma, K. et al. (2014) Isoform- and species-specific control of inositol 1,4,5-trisphosphate (IP3) receptors by reactive oxygen species. J. Biol. Chem. 289, 8170–8181 doi:10.1074/jbc.M113.504159 164 Terentyev, D., Györke, I., Belevych, A.E., Terentyeva, R., Sridhar, A., Nishijima, Y. et al. (2008) Redox modification of ryanodine receptors contributes to sarcoplasmic reticulum Ca2+ leak in chronic heart failure. Circ. Res. 103, 1466–1472 doi:10.1161/CIRCRESAHA.108.184457 165 Donoso, P., Sanchez, G., Bull, R. and Hidalgo, C. (2011) Modulation of cardiac ryanodine receptor activity by ROS and RNS. Front. Biosci. 16, 553–567 doi:10.2741/3705 166 Luciani, D.S., Gwiazda, K.S., Yang, T.-L.B., Kalynyak, T.B., Bychkivska, Y., Frey, M.H.Z. et al. (2009) Roles of IP3R and RyR Ca2+ channels in endoplasmic reticulum stress and β-cell death. Diabetes 58, 422–432 doi:10.2337/db07-1762 167 Lock, J.T., Sinkins, W.G. and Schilling, W.P. (2011) Effect of protein S-glutathionylation on Ca2+ homeostasis in cultured aortic endothelial cells. Am. J. Physiol. Heart Circ. Physiol. 300, H493–H506 doi:10.1152/ajpheart.01073.2010 168 Mazahery, H., Camargo, Jr, C.A., Conlon, C., Beck, K.L., Kruger, M.C. and von Hurst, P.R. (2016) Vitamin D and autism spectrum disorder: a literature review. Nutrients 8, 236 doi:10.3390/nu8040236 169 Dong, J.H., Wong, S.L., Lau, C.W., Lee, H.K., Ng, C.F., Zhang, L.H. et al. (2012) Calcitriol protects renovascular function in hypertension by downregulating angiotensin II type 1 receptors and reducing oxidative stress. Eur. Heart J. 33, 2980–2990 doi:10.1093/eurheartj/ehr459 170 Briones, T.L. and Darwish, H. (2014) Decrease in age-related tau hyperphosphorylation and cognitive improvement following vitamin D supplementation are associated with modulation of brain energy metabolism and redox state. Neuroscience 262, 143–155 doi:10.1016/j.neuroscience.2013.12.064 171 Garcion, E., Sindji, L., Leblondel, G., Brachet, P. and Darcy, F. (1999) 1,25-Dihydroxyvitamin D3 regulates the synthesis of gamma-glutamyl transpeptidase and glutathione levels in rat primary astrocytes. J. Neurochem. 73, 859–866 doi:10.1046/j.1471-4159.1999.0730859.x 172 Bao, B.-Y., Ting, H.-J., Hsu, J.-W. and Lee, Y.-F. (2008) Protective role of 1α, 25-dihydroxyvitamin D3 against oxidative stress in nonmalignant human prostate epithelial cells. Int. J. Cancer 122, 2699–2706 doi:10.1002/ijc.23460 173 Jain, S.K. and Micinski, D. (2013) Vitamin D upregulates glutamate cysteine ligase and glutathione reductase, and GSH formation, and decreases ROS and MCP-1 and IL-8 secretion in high-glucose exposed U937 monocytes. Biochem. Biophys. Res. Commun. 437, 7–11 doi:10.1016/j.bbrc.2013.06.004

1332

© 2017 The Author(s); published by Portland Press Limited on behalf of the Biochemical Society