1,25-Dihydroxyvitamin D₃ and type 2 diabetes: Ca²⁺-dependent molecular mechanisms and the role of vitamin D status

Introduction

Vitamin D₃ is a precursor the secosteroid hormone 1,25-dihydroxyvitamin D₃ (1,25(OH)₂D₃). 1,25(OH)₂D₃ acts through the genomic and nongenomic steroid hormone mechanisms in a number of cell types [1–5]. Moreover, paracrine and autocrine modes of action of 1,25(OH)₂D₃ appear to be important in several cell types, including pancreatic β-cells [1, 2, 4]. Vitamin D is considered important for maintaining good health throughout the life and preventing diseases; however, the causality of these claims has not been mechanistically or probabilistically substantiated [4, 6].

1,25(OH)₂D₃ plays an important role in regulation of cellular Ca²⁺ signaling, which mediates a number of cellular responses and processes [7–11]. Ca²⁺ signals triggered by 1,25(OH)₂D₃ have been implicated in regulation of insulin secretion from pancreatic β-cells [12], while vitamin D status has been linked to type 2 diabetes (T2D) in observational studies [13–20]. Vitamin D deficiency and insufficiency appear to be associated with the increased risk of T2D; however, causality of these associations remains unproven [3, 5, 14, 20].

The purpose of this mini-review is to discuss the role of 1,25(OH)₂D₃ in regulation of insulin secretion from pancreatic β-cells, with emphasis on signaling pathways that involve the vitamin D-dependent regulators, initiators, and effectors activated via 1,25(OH)₂D₃-induced cellular Ca²⁺ signaling. The potential links of vitamin D status to prevention of T2D and diabetes-related disorders are also briefly discussed. Understanding the mechanism of 1,25(OH)₂D₃ in regulation of cellular Ca²⁺ signaling in pancreatic β-cells and the role of vitamin D hormonal and nutritional status in T2D is important because it may lead to discovery of the novel therapeutic and preventive modalities for this disease.

1,25(OH)₂D₃-induced cellular Ca²⁺ signaling and insulin secretion

There is convincing evidence that 1,25(OH)₂D₃ can regulate insulin secretion from pancreatic β-cells [12, 21–24]. The central signaling messenger that triggers insulin release is a rapid increase in concentration of intracellular (cytosolic) free Ca²⁺ ([Ca²⁺]_i), which results from interactions between nutrient secretagogues with hormones and neurotransmitters [24, 25]. Effects of 1,25(OH)₂D₃ on Ca²⁺ influx from the extracellular space and Ca²⁺ mobilization from the intracellular stores result in an increase in [Ca²⁺]_iin pancreatic β-cells. We showed that 1,25(OH)₂D₃ induces rapid (within 5–10 s), synchronous, sinusoidal [Ca²⁺]_ioscillations in pancreatic β-cells in vitro, which are independent on glucose [12, 21]. The mechanism of these oscillations involves 1,25(OH)₂D₃-dependent activation of Ca²⁺ channels in the plasma membrane and the endoplasmic reticulum (ER) membrane. 1,25(OH)₂D₃ stimulates Ca²⁺ influx through both voltage-dependent Ca²⁺ channels (VDCCs) and voltage-insensitive Ca²⁺ channels (VICCs) in the plasma membrane as well as Ca²⁺ mobilization from the ER stores through the ryanodine receptor/Ca²⁺ release channel (RYR), but not through the inositol 1,4,5-trisphosphate receptor/Ca²⁺ release channel (IP₃R). The regulatory effects of 1,25(OH)₂D₃ on intracellular Ca²⁺ in pancreatic β-cells appear to be linked to the membrane vitamin D receptor (VDR) associated with the plasma membrane and the ER membrane [26–31].

1,25(OH)₂D₃-evoked Ca²⁺ oscillations pattern oscillatory, pulsatile insulin release from pancreatic β-cells, and the amplitude and frequency of the Ca²⁺ oscillations and the insulin release oscillations are proportional to 1,25(OH)₂D₃ concentration, but are independent of glucose concentration [12, 21, 22]. The physiological significance of 1,25(OH)₂D₃-induduced Ca²⁺ oscillations in pancreatic β-cells may lay in supporting insulin secretion at a steady-state glucose concentration in blood, e.g. during fasting [12, 32]. In this context, the effects of 1,25(OH)₂D₃ on the cellular Ca²⁺ signaling and insulin secretion in pancreatic β-cells imply a potential role for the hormone and the vitamin D nutritional status in prevention and treatment of T2D. On the other hand, some of the risk factors for development of T2D are also determinants of vitamin D status [3, 5, 33].

It is important to note that 1,25(OH)₂D₃ can induce the apoptotic Ca²⁺ signal (a sustained, prolong, globalized increase in [Ca²⁺]_inot reaching cytotoxic levels) in several cell types (e.g. adipocytes) [4, 7–9]. However, in the secretory pancreatic β-cells 1,25(OH)₂D₃ triggers the transient and localized Ca²⁺ signals in the form of Ca²⁺ oscillations; moreover, the apoptotic machinery executing Ca²⁺-mediated apoptosis is not present in these cells, while intracellular Ca²⁺ buffers (vitamin D-dependent calbindins) rapidly terminate a sustained increase in [Ca²⁺]_i[12, 21, 34, 35]. It is also important to emphasize here that the mechanistic role of 1,25(OH)₂D₃ in regulation of Ca²⁺ signaling in and insulin secretion from pancreatic β-cells have not been demonstrated yet in animal studies and human intervention trials.

Vitamin D and diet-induced obesity model of pre-type 2 diabetes

A high fat diet-induced obesity (DIO) mouse model of pre-T2D is characterized by obese phenotype, elevated blood glucose and impaired glucose tolerance, and the development of adiposity and, eventually, T2D [5, 36]. Mice fed a high fat diet with the increased vitamin D₃ content demonstrated a decreased weight of adipose tissue and improved blood markers related to adiposity, T2D, and vitamin D status [36]. The fasting plasma glucose and insulin concentrations in these mice were significantly decreased, approaching levels found in the normal-weight, non-obese control, whereas concentration of adiponectin (an insulin sensitizing adipokine) demonstrated an increasing trend. DIO in mice was accompanied by low vitamin D status (a decreased plasma concentration of the transport form of vitamin D₃, 25-hydroxyvitamin D₃ (25(OH)D₃) and a decrease in plasma concentration of the hormone 1,25(OH)₂D₃. High vitamin D₃ intake induced a significant increase in the plasma concentrations of 25(OH)D₃ and 1,25(OH)₂D₃, indicating high vitamin D nutritional status and normal vitamin D hormonal status. Moreover, high vitamin D₃ intake increased mineral (Ca and P) content in the bone of DIO mice via regulatory effects mediated by 1,25(OH)₂D₃-parathyroid hormone (PTH) axis (an increase in 1,25(OH)₂D₃ and Ca concentration and a decrease in PTH concentration in blood) [37]. These findings demonstrate that high vitamin D intake can effectively decrease blood glucose and insulin in DIO/pre-T2D and that the hormonal mechanism of this effect involves 1,25(OH)₂D₃. These findings also imply that increased vitamin D intake may contribute to the prevention of T2D and bone disorders associated with T2D and obesity.

Vitamin D receptor and Ca²⁺ signaling in pancreatic β-cells

Inactivation of the nuclear vitamin D receptor (VDR) in VDR knockout mice has provided insights into the role of the 1,25(OH)₂D₃-mediated genomic signaling pathways in health and disease, including T2D [38, 39]. VDR-deficient mice exhibit phenotype similar to the vitamin D-dependent rickets type II in humans, but not the T2D phenotype [40, 41]. However, the VDR can be a determinant of insulin secretory capacity [42], probably, via regulating expression of Ca²⁺-binding proteins (vitamin D-dependent calbindins) in pancreatic β-cells. Alterations in the expression of Ca²⁺ channels, Ca²⁺ receptors, and Ca²⁺ binding proteins (e.g. in intestine and skin) due to VDR deficiency have been also reported [43]. These findings suggest the potential involvement of the genomic vitamin D signaling pathways mediated by the nuclear VDR in functioning of pancreatic β-cells, e.g. insulin production and expression of the cellular secretory machinery, while not excluding the role of 1,25(OH)₂D₃-induced rapid Ca²⁺ signals in insulin secretion. It is important to emphasize that the genomic disruption in VDR-deficient mice does not manifest in the development of T2D, possibly, because nongenomic Ca²⁺ signaling mediated by the membrane VDR appears to be uncoupled from genomic vitamin D signaling mediated by the nuclear VDR [3–5].

Vitamin D status and type 2 diabetes

Epidemiologic evidence has emerged suggesting the role of vitamin D in T2D, including observational studies that demonstrated the association between vitamin D status, insulin secretion and development of, or resistance to T2D [3, 13, 15, 44]. In these studies, a statistically significant inverse correlation suggesting that a low vitamin D status (concentration of 25(OH)D in blood) is associated with impaired insulin secretion and development of T2D has been reported. However, randomized controlled trials, particularly recently published studies, did not provide conclusive causal or mechanistic insights into whether or how vitamin D might prevent T2D [14–20]. Confounding effects could explain the association between vitamin D status and T2D in a non-casual or reverse-casual way [3, 5, 13]. It is also necessary to emphasize that the circulating concentration of the hormone 1,25(OH)₂D₃ in blood is homeostatically maintained at the precise “normal” level within a broad range of concentrations of 25(OH)D₃, which allows 1,25(OH)₂D₃ to mediate the genomic and nongenomic cellular responses and to perform its physiological functions in a fashion similar to that of other steroid hormones [4, 5]. For example, as discussed above, it has been demonstrated in a mouse model of DIO that normalization (an increase) in concentration of 1,25(OH)₂D₃ can prevent an increase of body fat and normalize glucose, insulin, and adiponectin levels in blood [3, 36, 37]. The rational design of vitamin D analogs selectively interacting with the membrane VDR and capable of regulating Ca²⁺ signaling in pancreatic β-cells could lead to a more positive clinical outcome in T2D [45]. Although the Ca²⁺-dependent mechanism of 1,25(OH)₂D₃ in pancreatic β-cells appears to be plausible, the causality for effects of 1,25(OH)₂D₃ on insulin secretion and the potential role of vitamin D status in prevention of T2D need to be established.

Summary and outlook

The studies reviewed have identified the mechanisms of Ca²⁺ regulatory effects of the hormone 1,25(OH)₂D₃ in pancreatic β-cells. 1,25(OH)₂D₃ regulates insulin secretion from pancreatic β-cells by inducing Ca²⁺ oscillations that pattern insulin release. The mechanism of Ca²⁺ oscillations involves Ca²⁺ influx through VDCCs and VICCs as well as Ca²⁺ release from the ER stores through RYRs (Figure 1).

Figure 1:

1,25(OH)₂D₃ regulates intracellular Ca²⁺ and insulin secretion in pancreatic β-cells.

This cartoon provides a schematic representation of the mechanisms and sites of action of 1,25(OH)₂D₃ in induction of the Ca²⁺ signal in and Ca²⁺-mediated insulin secretion from pancreatic β-cells. The cartoon is largely based on author’s studies employing in vitro models of insulin-secreting pancreatic β-cells. 1,25(OH)₂D₃ regulates Ca²⁺ entry from the extracellular space, Ca²⁺ mobilization from the intracellular stores, and intracellular Ca²⁺ buffering. Ca²⁺ enters the cell through both voltage-dependent Ca²⁺ channels (VDCCs; rapid, high permeability pathway) and voltage-insensitive Ca²⁺ channels (VICCs; slow, low permeability pathway). 1,25(OH)₂D₃ rapidly and in a concentration-dependent fashion triggers synchronous Ca²⁺ oscillations via activation of VDCCs and Ca²⁺ release via ryanodine receptors/Ca²⁺ release channels (RYRs). Ca²⁺ oscillations induce pulses of insulin secretion by exocytosis. The plasma membrane and ER ATP-ases restore the resting [Ca²⁺]_i in the cell. Vitamin D receptors (VDRs) are expressed in pancreatic β-cells; they can be found associated with the plasma membrane and the ER membrane as well as in the nuclear and cytosolic compartments. Pancreatic β-cells resist induction of apoptosis with 1,25(OH)₂D₃ due to their high cytosolic Ca²⁺ buffering capacity, non-sustained nature of the 1,25(OH)₂D₃-induced increase in [Ca²⁺]_i(Ca²⁺ oscillations) and, probably, a partial lack of the Ca²⁺-dependent apoptotic machinery (e.g. caspase-12).

The role of 1,25(OH)₂D₃ in Ca²⁺ signaling in pancreatic β-cells can be exploited in the discovery and development of vitamin D analogs effective in regulation of Ca²⁺-mediated insulin secretion. Moreover, association of low vitamin D status with T2D may indicate a role for vitamin D in this disease. Pre-clinical studies and randomized control trials will be necessary to confirm the validity of the 1,25(OH)₂D₃/Ca²⁺-dependent mechanisms and molecular targets in the insulin secretion and production pathways as well as the role of vitamin D in the prevention of, and vitamin D analogs in the hormone therapy for, T2D.

Highlights

The hormone 1,25(OH)₂D₃ targets Ca²⁺ signaling pathways in pancreatic β-cells.

1,25(OH)₂D₃ induces synchronous Ca²⁺ oscillations in pancreatic β-cells, which pattern pulsatile insulin secretion from these cells.

Vitamin D analogs regulating Ca²⁺ signaling in pancreatic β-cells can be developed for the hormone therapy of T2D.

The role of 1,25(OH)₂D₃ in Ca²⁺-mediated insulin secretion from pancreatic β-cells may support the recommendation to maintain optimal or high vitamin D status as a mechanistically plausible approach for reducing the risk of developing type 2 diabetes.