Ghrelin’s Novel Signaling in Islet β-Cells to Inhibit Insulin Secretion and Its Blockade As a Promising Strategy to Treat Type 2 Diabetes

Ghrelin, an acylated 28-amino acid peptide, was isolated from the stomach and circulating ghrelinis produced predominantly in the oxyntic mucosa of stomach. In addition to its unique role in regulating mealtime hunger and lipid metabolism, we here review the physiological role of ghrelinin the regulation of insulin release and glucose metabolism. Ghrelinis expressed in pancreatic isletsand released into pancreatic microcirculation. Ghrelininhibits insulin release in mice, rats, and humans. The signal transduction mechanisms of ghrelinin isletβ-cells are very unique, being distinct from those utilized for growth hormone release. Pharmacological and genetic blockades of islet-derived ghrelinmarkedly 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– growth hormone-secretagogue receptorsystem, 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.