ReviewCalcium signaling in pancreatic β-cells in health and in Type 2 diabetes
Graphical abstract
Introduction
Under normal conditions, the rise in glycaemia that occurs upon food intake in mammals is limited by the action of insulin, the most important hypoglycemic hormone of the body. The actions of insulin thus oppose those of several hyperglycemic hormones, including glucagon, catecholamine, glucocorticoids and growth hormone. A deficit in insulin production or action leads to diabetes mellitus a major and growing health problem which affects ∼8% of adult population worldwide (http://www.idf.org/diabetesatlas/data-visualisations). There are two main types of diabetes. Type 1 diabetes (T1D) is characterized by an absolute deficit in insulin because of autoimmune-mediated β-cell destruction, whereas Type 2 diabetes (T2D) results from the inability of β-cells to compensate for insulin resistance, and subsequent β-cell “decompensation” [1]. T2D is almost 20 times more frequent than T1D.
The islets of Langerhans are small structures dispersed in the exocrine pancreas and constitute the endocrine part of the gland. They essentially contain four major cell types: β-, α-, δ- and PP-cells, which secrete insulin, glucagon, somatostatin and pancreatic polypeptide, respectively. The distribution and abundance of each cell type is species-dependent. Mouse and rat islets are composed of a central core of β-cells representing ∼75% of the cells and an outer layer of other endocrine cells including ∼20% of α-cells, <10% of δ-cells and 1–5% of PP-cells. In humans, the proportion of β-cells is lower (∼55%) while that of α-cells is higher (∼40%) than in mice [2], [3], [4], [5], [6]. Moreover, β-, α- and δ-cells are found in both the periphery and the center of the islet [2]. All cell types interact with each other by paracrine signals. Thus, glucagon stimulates insulin release whereas somatostatin inhibits the secretion of all the other cells.
Changes in the free Ca2+ concentration ([Ca2+]) in different compartments (cytosol, endoplamic reticulum, mitochondria, Golgi, nucleus, secretory vesicles, endo/lysosomes) are crucial for the control of various cellular functions. Here, we review the mechanisms by which glucose, the main physiological stimulus of β-cells, controls [Ca2+] in each compartment, and the crosstalk between the different intracellular locales. We also briefly review alterations of β-cell Ca2+ homestasis in pathophysiological situations including T2D. Of course, changes in [Ca2+] in subcellular compartments control a wide variety of processes such as exocytosis of insulin-containing large-dense core vesicles (LDCV) and synaptic-like microvesicles (SLMV), cell metabolism, apoptosis, gene expression, ER stress, etc. Given space constraints, we will only briefly discuss the crosstalk between cell metabolism and Ca2+, a crucial aspect of β-cell stimulus-secretion coupling.
Section snippets
β-Cell electrical activity and [Ca2+]c
β-Cells are electrically excitable and possess a large number of channels which modulate Ca2+ influx. The insulinotropic effect of glucose essentially depends on glucose metabolism which is mainly oxidative in β-cells [7], [8] and leads to a large increase in the ATP/ADP ratio [9], [10]. An effect of glucose through taste receptors (T1R) has also been suggested but is probably very minor in physiological conditions [11]. β-Cell electrical activity is mainly controlled by ATP-sensitive K+
Ca2+ changes in the β-cell endoplasmic reticulum ([Ca2+]ER)
In most cells, cytosolic Ca2+ is taken up by the endoplasmic reticulum (ER) mainly by sarco-endoplasmic reticulum Ca2+-ATPases (SERCAs) (Fig. 1). Three genes have been described in humans (ATP2A1-3) which can produce up to 11 different pumps because of alternative splicing (SERCA1a-b, SERCA2a-c and SERCA3a-f). SERCAs can transport two Ca2+ ions per ATP hydrolyzed. For each two Ca2+ ions transported from the cytosol to the lumen of the ER, 2–3 H+ are counter transported, making SERCA an
Acidic Ca2+ stores
Acidic Ca2+ stores include endosomes, lysosomes, secretory vesicles and the Golgi complex [205]. In mouse β-cells, these acidic stores constitute the vast majority of organelle Ca2+ and accumulate even more Ca2+ than the ER [155], [206].
The Golgi can be considered as an acidic store since its pH is ∼6.6 [207]. In various cell types, it takes up Ca2+ to a large extent by SERCAs and to a lower extent by secretory pathway Ca2+-ATPases (SPCAs, previously named PMR, 2 genes: ATP2C1-2) [208], [209],
Ca2+ changes in β-cell mitochondria ([Ca2+]m)
[Ca2+]c controls mitochondrial motility along microtubules and fusion/fission process [229], but this aspect will not be addressed further in this review. Additionally, we will not go into detail on the role of the malate-aspartate shuttle and the glycerol-phosphate shuttle, two critical redox shuttle systems, that are known to be activated by cytosolic [Ca2+] (and not mitochondrial [Ca2+]). Both shuttles are responsible for the transfer of reducing equivalents into mitochondria after cytosolic
Impaired Ca2+ homeostasis in diabetes
In this part of the review, only [Ca2+] changes in T2D will be discussed. Modifications due to cytokines challenge or in other pathologies than T2D (such as Wolfram syndrome) will not be addressed. Moreover, genes associated with increased risk of T2D identified from linkage and genome-wide association studies will not be discussed, as it remains uncertain whether β-cell defect could be functionally linked to the identified genes [300]. Recent reviews about the topic can also be found [297],
Conclusions
The development in recent years of imaging technologies based on recombinant and other targeted probes has allowed Ca2+ dynamics to be examined in unprecedented details in multiple compartments within the single β-cell. The combination of this strategy with genetic ablation approaches, usually in mice, has complemented this with an in-depth knowledge of the most likely molecular players in each case. Combined with human genetics, and increasingly by studies on primary human cells, the hope now
Acknowledgments
This review is partly based on work from the authors and supported by the Fonds de la Recherche Scientifique (Brussels), by an ARC (13/18-051) from the General Direction of Scientific Research of the French Community of Belgium and by the Interuniversity Poles of Attraction Programme (PAI 6/40) from the Belgian Science Policy. P. Gilon is Research Director and H.Y. Chae is Postdoctoral Researchers of the Fonds National de la Recherche Scientifique, Brussels. M.A. Ravier is Chargé de Recherche
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