review article Diabetes, Obesity and Metabolism 16 (Suppl. 1): 111 – 117, 2014. © 2014 John Wiley & Sons Ltd review article Ghrelin signalling in β -cells regulates insulin secretion and blood glucose T. Yada 1 , B. Damdindorj 1 , R. S. Rita 1 , T. Kurashina 1,2 , A. Ando 1,2 , M. Taguchi 1,3 , M. Koizumi 1,3 , H. Sone 1,4 , M. Nakata 1 , M. Kakei 5 & K. Dezaki 1 1 Division of Integrative Physiology, Department of Physiology, Jichi Medical University School of Medicine, Tochigi, Japan 2 Department of Endocrinology and Metabolism, Jichi Medical University School of Medicine, Tochigi, Japan 3 Department of Surgery, Jichi Medical University School of Medicine, Tochigi, Japan 4 Department of Human Life and Environmental Science, Niigata Women’s College, Niigata, Japan 5 Department of Comprehensive Medicine, Omiya Medical Center, Jichi Medical University, Saitama, Japan Insulin secretion from pancreatic islet β -cells is stimulated by glucose. Glucose-induced insulin release is potentiated or suppressed by hormones and neural substances. Ghrelin, an acylated 28-amino acid peptide, was isolated from the stomach in 1999 as the endogenous ligand for the growth hormone (GH) secretagogue-receptor (GHS-R). Circulating ghrelin is produced predominantly in the stomach and to a lesser extent in the intestine, pancreas and brain. Ghrelin, initially identified as a potent stimulator of GH release and feeding, has been shown to suppress glucose-induced insulin release. This insulinostatic action is mediated by Gα i2 subtype of GTP-binding proteins and delayed outward K + (Kv) channels. Interestingly, ghrelin is produced in pancreatic islets. The ghrelin originating from islets restricts insulin release and thereby upwardly regulates the systemic glucose level. Furthermore, blockade or elimination of ghrelin enhances insulin release, which can ameliorate glucose intolerance in high-fat diet fed mice and ob/ob mice. This review focuses on the insulinostatic action of ghrelin, its signal transduction mechanisms in islet β -cells, ghrelin’s status as an islet hormone, physiological roles of ghrelin in regulating systemic insulin levels and glycaemia, and therapeutic potential of the ghrelin-GHS-R system as the target to treat type 2 diabetes. Keywords: Ca 2+ , cAMP, diabetes, ghrelin, ghrelin-knockout, GHS-R, insulin release, islet, Kv channel, paracrine, β -cell Date submitted 23 March 2014; date of final acceptance 20 April 2014 Introduction Ghrelin, an acylated 28-amino acid peptide, was identified in 1999 from human and rat stomachs as the endogenous ligand [1] for the growth hormone (GH) secretagogue-receptor (GHS-R) [2]. Circulating ghrelin is produced predominantly in the stomach [3]. Ghrelin is a potent stimulator of GH release [1], feeding [4] and adiposity [5], as well as exhibiting positive cardiovascular effects [6]. From the early stages of ghrelin research, it was recognized that the plasma ghrelin level correlates inversely with body weight [7 – 9], and that low plasma ghrelin levels are associated with elevated fasting insulin levels [10,11]. Extensive research performed since has established a profound role of ghrelin in regulation of insulin release and glycaemia. Systemic administration of ghrelin increases blood glucose and decreases plasma insulin levels in fasted states and in glucose tolerance tests (GTT) in humans and rodents [12–17]. Ghrelin inhibits glucose-induced insulin Correspondence to: Dr Toshihiko Yada, Division of Integrative Physiology, Department of Physiology, Jichi Medical University School of Medicine, Yakushiji 3311-1, Shimotsuke, Tochigi 329-0498, Japan. E-mail: tyada@jichi.ac.jp release in perfused pancreas and isolated islets. In rats, single β -cells, glucose-induced action potentials and increases in cytosolic Ca 2+ concentration ([Ca 2+ ] i ) are suppressed by administration of ghrelin. Ghrelin activates delayed outward K + (Kv) channels, a mechanism possibly accounting for sup- pression of action potentials. Furthermore, ghrelin stimulates Gα i2 subtype of GTP-binding proteins and suppresses the cAMP signalling pathway in β -cells. These results indicate that ghrelin suppresses the cAMP signalling pathway and thereby activates Kv channels, which in turn suppresses glucose-induced action potentials, [Ca 2+ ] i increases and insulin release in islet β -cells [18]. GHS-R antagonists increase plasma insulin and decrease glycaemia, showing a systemic role of endogenous ghrelin. Ghrelin is expressed in pancreatic islet cells in addition to the stomach. GHS-R antagonism, ghrelin immunoneutralization and ghrelin-knockout (Ghr-KO) mice display enhanced glucose-induced insulin release from perfused pancreas and isolated islets [15,19]. Thus, pharmacological, immunological and genetic blockades of ghrelin in pancreatic islets all markedly augment glucose-induced insulin release, showing that islet- derived ghrelin physiologically restricts insulin release in rodents.