title: Endogenous ghrelin in pancreatic islets restricts insulin release by attenuating Ca2+ signaling in beta-cells: implication in the glycemic control in rodents.
abstract: Ghrelin, isolated from the human and rat stomach, is the endogenous ligand for the growth hormone (GH) secretagogue receptor, which is expressed in a variety of tissues, including the pancreatic islets. It has been shown that low plasma ghrelin levels correlates with elevated fasting insulin levels and type 2 diabetes. Here we show a physiological role of endogenous ghrelin in the regulation of insulin release and blood glucose in rodents. Acylated ghrelin, the active form of the peptide, was detected in the pancreatic islets. Counteraction of endogenous ghrelin by intraperitoneal injection of specific GH secretagogue receptor antagonists markedly lowered fasting glucose concentrations, attenuated plasma glucose elevation, and enhanced insulin responses during the glucose tolerance test (GTT). Conversely, intraperitoneal exogenous ghrelin GH-independently elevated fasting glucose concentrations, enhanced plasma glucose elevation, and attenuated insulin responses during GTT. Neither GH secretagogue receptor antagonist nor ghrelin affected the profiles of the insulin tolerance test. In isolated islets, GH secretagogue receptor blockade and antiserum against acylated ghrelin markedly enhanced glucose-induced increases in insulin release and intracellular Ca2+ concentration ([Ca2+]i), whereas ghrelin at a relatively high concentration (10 nmol/l) suppressed insulin release. In single beta-cells, ghrelin attenuated glucose-induced first-phase and oscillatory [Ca2+]i increases via the GH secretagogue receptor and in a pertussis toxin-sensitive manner. Ghrelin also increased tetraethylammonium-sensitive delayed outward K+ currents in single beta-cells. These findings reveal that endogenous ghrelin in islets acts on beta-cells to restrict glucose-induced insulin release at least partly via attenuation of Ca2+ signaling, and that this insulinostatic action may be implicated in the upward control of blood glucose. This function of ghrelin, together with inducing GH release and feeding, suggests that ghrelin underlies the integrative regulation of energy homeostasis.
authors.affiliation: Department of Physiology, Division of Integrative Physiology, Jichi Medical School, Kawachi, Tochigi, Japan.
authors.forename: Katsuya
authors.initials: K
authors.lastname: Dezaki
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Hosoda
authors.forename: Masafumi
authors.initials: M
authors.lastname: Kakei
authors.forename: Suzuko
authors.initials: S
authors.lastname: Hashiguchi
authors.forename: Masatomo
authors.initials: M
authors.lastname: Watanabe
authors.forename: Kenji
authors.initials: K
authors.lastname: Kangawa
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Yada
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism*; D020013:Calcium Signaling / Q000502:physiology*; D054439:Ghrelin; D005934:Glucagon / Q000494:pharmacology; D005951:Glucose Tolerance Test; D013006:Growth Hormone / Q000172:deficiency / Q000378:metabolism; D007150:Immunohistochemistry; D007328:Insulin / Q000378:metabolism* / Q000494:pharmacology; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000166:cytology / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D036361:Peptide Hormones / Q000494:pharmacology / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D001786:Blood Glucose; D054439:Ghrelin; D007328:Insulin; D036361:Peptide Hormones; D013006:Growth Hormone; D005934:Glucagon