Ghrelin is a physiological regulator of insulin release in pancreatic islets and glucose homeostasis

Abstract

Ghrelin, an acylated 28-amino acid peptide, was isolated from the stomach as the endogenous ligand for the growth hormone (GH) secretagogue receptor (GHS-R). Circulating ghrelin is produced predominantly in the oxyntic mucosa of stomach. Ghrelin potently stimulates GH release and feeding, and exhibits positive cardiovascular effects, suggesting a possible clinical application. Low plasma ghrelin levels are associated with elevated fasting insulin levels and insulin resistance, suggesting both physiological and pathophysiological roles for ghrelin in glucose metabolism. Here, we review the physiological role of ghrelin in the regulation of insulin release and glucose metabolism, and a potential therapeutic avenue to treat type 2 diabetes by manipulating ghrelin and/or its signaling. Ghrelin inhibits insulin release in mice, rats and humans. The signal transduction mechanisms of ghrelin in islet β-cells are distinct from those utilized in GH-releasing and/or GHS-R-expressing cells. Ghrelin is expressed in pancreatic islets and released into pancreatic microcirculations. Pharmacological and genetic blockades of islet-derived ghrelin markedly augment glucose-induced insulin release in vitro. In high-fat diet-induced mildly obese mice, ghrelin-deficiency enhances insulin release and prevents impaired glucose tolerance. Thus, manipulation of insulinostatic function of ghrelin — GHS-R system, particularly that in islets, could optimize the amount of insulin release to meet the systemic demand, providing a potential therapeutic application to prevent type 2 diabetes.

Introduction

Ghrelin, a novel acylated 28-amino acid peptide, was isolated from the human and rat stomach as the endogenous ligand (Kojima et al., 1999) for the growth hormone (GH) secretagogue-receptor (GHS-R) (Howard et al., 1996). This novel peptide has an n-octanoylated serine residue at the third N-terminal position; this acylation is essential for ghrelin bioactivity (Kojima et al., 1999). Circulating ghrelin is produced predominantly in the stomach (Ariyasu et al., 2001), while substantially lower amounts are detected in the intestine, pancreas, kidney, immune system, placenta, testis, pituitary, lung, and hypothalamus (Kojima et al., 1999, Hosoda et al., 2000, Date et al., 2000a, Mori et al., 2000, Gualillo et al., 2001, Tanaka et al., 2001, Date et al., 2002, Gnanapavan et al., 2002, Hattori et al., 2001, Muccioli et al., 2002, Tena-Sempere et al., 2002, Volante et al., 2002a, Volante et al., 2002b). GHS-Rs are expressed in the hypothalamus-pituitary unit, and are also distributed in other central and peripheral tissues (Howard et al., 1996, Guan et al., 1997, Smith et al., 1997, Muccioli et al., 1998, Papotti et al., 2000, Cassoni et al., 2001, Ghigo et al., 2001, Gnanapavan et al., 2002, Katugampola et al., 2002, Muccioli et al., 2002). Ghrelin is a potent stimulator of GH release (Kojima et al., 1999, Arvat et al., 2000, Arvat et al., 2001, Date et al., 2000b, Peino et al., 2000, Takaya et al., 2000). Ghrelin also stimulates feeding; ghrelin injected either centrally (Kamegai et al., 2001, Nakazato et al., 2001, Shintani et al., 2001, Wren et al., 2001b) or peripherally (Nakazato et al., 2001, Wren et al., 2001a) potently stimulates food intake. In humans, ghrelin peaks before meals, suggesting its role as a hunger signal (Cummings et al., 2002, Cummings and Overduin, 2007). Cardiovascular actions of ghrelin are also reported (Nagaya et al., 2001a, Nagaya et al., 2001b, Nagaya et al., 2001c, Nagaya and Kangawa, 2003a, Nagaya and Kangawa, 2003b, Lin et al., 2004, Matsumura et al., 2002). Given this wide spectrum of biological activities, the discovery of ghrelin opened many new perspectives within neuroendocrine, metabolic and cardiovascular research, thus suggesting its possible clinical application (Kojima & Kangawa, 2006). Ghrelin and GHS-R are also located in pancreatic islets (Date et al., 2002, Gnanapavan et al., 2002, Volante et al., 2002a, Wierup et al., 2002, Dezaki et al., 2004, Prado et al., 2004, Wierup et al., 2004, Wierup and Sundler, 2005). Ghrelin inhibits insulin release in mice, rats and humans (Broglio et al., 2001, Egido et al., 2002, Reimer et al., 2003, Dezaki et al., 2004). Low plasma ghrelin levels are associated with elevated fasting insulin levels and insulin resistance in humans (Ikezaki et al., 2002, Poykko et al., 2003). These findings suggest both physiological and pathophysiological roles for ghrelin in the regulation of insulin release. In addition, the plasma ghrelin level correlates inversely with obesity (Tschop et al., 2001, Ariyasu et al., 2002, Shiiya et al., 2002). Hence, ghrelin could be involved in energy and glucose metabolism, in which insulin plays a crucial role.

Here we review the physiological role of ghrelin in the regulation of insulin release and glucose metabolism, and present a potential therapeutic avenue to manipulate ghrelin signaling and thereby counteract the progression of type 2 diabetes.