Apelin is a novel islet peptide
Introduction
Apelin is a recently identified peptide hormone that turned out to be the endogenous ligand of the previously orphan receptor APJ [1]. APJ was identified by O'Dowd et al. [2] and remained orphan until Tatemoto et al. in 1998 identified apelin [1]. The peptide was given the name apelin for, APJ-receptor ligand [1], [3]. Several molecular forms, e.g. apelin-13, apelin-17, and apelin-36, are cleaved from the 77-amino-acid preproapelin precursor [1], [3], [4], [5].
In the central nervous system of both humans and rats, mRNA encoding APJ receptor and apelin are widely distributed, suggesting a role for apelin in central regulatory pathways [6], [7], [8], [9], [10]. In peripheral tissues, APJ and apelin expression has been shown in e.g. adipose tissue, lungs, heart and mammary glands [3], [6], [8], [9], [10], [11], [12]. Apelin has also been localized to endothelial cells of small arteries in several organs [13]. Apelin is involved in a broad range of physiological functions, e.g. fluid homeostasis [9], [14], regulation of food intake [14], [15], and angiogenesis [16]. Furthermore, apelin has been shown to have hypotensive properties, lowering both systolic and diastolic blood pressure [9], [13], [17] and increase heart rate [7], [18]. A potent positive inotropic action of apelin has been demonstrated in rat hearts in vitro [19] and in vivo [20]. Moreover, apelin and APJ may have a role in pathophysiology of human heart failure [17], [21] and plasma concentrations of apelin are decreased in patients suffering from parenchymal lung disease with preserved cardiac function [22].
Since apelin was originally isolated from bovine stomach extracts [2], a function in the gastrointestinal tract was expected. In rat stomach, apelin-positive cells were identified by immunohistochemistry as mucous neck, parietal and chief cells [23]. Further apelin was shown to be expressed in human and rodent colon [24], and apelin was shown to stimulate gastric cell proliferation in vitro, and to stimulate CCK secretion from a murine enteroendocrine cell line [25]. Apelin is produced in adipocytes in humans and mice [26], indicating that apelin could be an adipokine. Furthermore, insulin stimulates adipocyte apelin production both in vivo and in vitro, and apelin expression in adipocytes was inhibited by fasting and recovered after refeeding [26]. Interestingly, Sörhede Winzell et al. [27], demonstrated that apelin-36 decreased glucose-stimulated insulin secretion (GSIS) in mice, both in vivo and in vitro. Moreover, expression of APJ-receptor mRNA in isolated mouse islets was demonstrated [27]. A positive correlation between plasma insulin and apelin in both humans and mice has been shown [26], [28]. Further, basal and 2 h post glucose plasma levels of apelin are elevated in type 2 diabetic (T2D) subjects and in humans with impaired glucose tolerance [29]. Furthermore, plasma apelin is increased in obese and hyperinsulinemic mice [26]. On the other hand, Erdem et al. [30] and Zhang et al. [31] found circulating apelin levels to be lower in T2D patients. Interestingly, recent studies by Dray et al. [32] showed that apelin lowers plasma glucose via increased glucose utilization in fat and muscle. Taken together, a role for apelin as a regulator of insulin or glucose levels seems likely.
Many regulatory peptides are expressed within the islets of Langerhans, in islet cells or nerve fibers innervating the islets, and regulate islet hormone secretion via paracrine mechanisms. Among such peptides are e.g. IAPP [33], NPY [34], PYY [35], ghrelin [36], and CART [37]. Based on this knowledge, we studied the possibility of apelin expression in the pancreatic islets of humans and laboratory animals, using immunocytochemistry and in situ hybridization. In addition, to study a possible impact of T2D on islet apelin expression, we included rodent models of T2D. Furthermore, the effect of apelin on insulin secretion was examined using clonal beta cells. Our data show a high expression of apelin in human islets and in islets of all laboratory animals examined. Apelin had a dual, concentration-dependent effect on insulin secretion and human islet apelin expression is regulated by glucocorticoids.
Section snippets
Tissue and tissue processing
Human pancreatic specimens (adult: n = 10, fetal, 18–22 weeks of gestation: n = 5) were taken during autopsy or during pancreatic surgery. The studies were approved by the Human Ethics Committee in Lund. The specimens were immediately fixed in 4% paraformaldehyde in 0.1 M phosphate buffer, pH 7.2 at 4 °C, rinsed in graded ethanols, and embedded in paraffin. Sections (6 µm thickness) were mounted on slides, deparaffinized, and hydrated before further handling. Male GK-rats (n = 5, age 20w), Wistar rats (n =
Apelin in human islets
Immunocytochemistry for apelin revealed that apelin immunoreactive (IR) cells were abundant in pancreatic islet cells in both fetal (Fig. 1, Fig. 2) and adult humans (Fig. 2). Importantly, the same staining pattern was seen with three different antibodies against apelin. Pre-absorption of the apelin antisera with an excess of apelin-36 peptide blocked all staining in both islets (Fig. 1) and pituitary, which was used as a positive control (data not shown). To identify the apelin IR islet cells
Discussion
The islets of Langerhans are key regulators of metabolism and failure of islet function plays a central role during the development of T2D. The islets harbor and are regulated by a plethora of regulatory peptides. Increased knowledge about these peptides, where they are expressed and what actions they exert, in normal physiology and in T2D, will increase the understanding about islet hormone regulation and hopefully lead to new treatment strategies for T2D. Apelin is a recently identified
Acknowledgments
Grant supports from: Swedish Medical Research Council (Project Nos. 522-2008-4216, K2009-55X 21111-01-4, and K2007-55X-04499-33-3), SSMF, the Novo Nordisk Foundation, the Royal Physiographic Society in Lund, the Gyllenstiernska Krapperup, Tore Nilsson, Åke Wiberg, Lars Hierta, Fredrik and Ingrid Thuring, Magnus Bergwall, Albert Påhlsson, Åhlén, and the Swedish Society of Medicine Foundations. Doris Persson and Britt-Marie Nilsson for technical assistance.
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2018, Clinica Chimica ActaCitation Excerpt :It is worth noting that the apelin concentration decreases along the small intestine to the colon [14–16]. In human, mouse, rat, pig and cat pancreas islets, apelin is expressed in alpha, beta and PP cells [17]. Also, apelin is found in serum, colostrum and mature milk [18].