title: Blockade of pancreatic islet-derived ghrelin enhances insulin secretion to prevent high-fat diet-induced glucose intolerance.
abstract: The gastric hormone ghrelin and its receptor, growth hormone secretagogue receptor (GHSR), are expressed in pancreas. Here, we report that ghrelin is released from pancreatic islets to regulate glucose-induced insulin release. Plasma concentrations of ghrelin, as well as insulin, were higher in pancreatic veins than in arteries. GHSR antagonist and immunoneutralization of endogenous ghrelin enhanced glucose-induced insulin release from perfused pancreas, whereas exogenous ghrelin suppressed it. GHSR antagonist increased plasma insulin levels in gastrectomized and normal rats to a similar extent. Ghrelin knockout mice displayed enhanced glucose-induced insulin release from isolated islets, whereas islet density, size, insulin content, and insulin mRNA levels were unaltered. Glucose tolerance tests (GTTs) in ghrelin knockout mice showed increased insulin and decreased glucose responses. Treatment with high-fat diet produced glucose intolerance in GTTs in wild-type mice. In ghrelin knockout mice, the high-fat diet-induced glucose intolerance was largely prevented, whereas insulin responses to GTTs were markedly enhanced. These findings demonstrate that ghrelin originating from pancreatic islets is a physiological regulator of glucose-induced insulin release. Antagonism of the ghrelin function can enhance insulin release to meet increased demand for insulin in high-fat diet-induced obesity and thereby normalize glycemic control, which may provide a potential therapeutic application to counteract the progression of type 2 diabetes.
authors.affiliation: Division of Integrative Physiology, Department of Physiology, Jichi Medical University School of Medicine, Yakushiji 3311-1, Shimotsuke, Tochigi 329-0498, Japan.
authors.forename: Katsuya
authors.initials: K
authors.lastname: Dezaki
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Sone
authors.forename: Masaru
authors.initials: M
authors.lastname: Koizumi
authors.forename: Masanori
authors.initials: M
authors.lastname: Nakata
authors.forename: Masafumi
authors.initials: M
authors.lastname: Kakei
authors.forename: Hideo
authors.initials: H
authors.lastname: Nagai
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Hosoda
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 / Q000378:metabolism; D004041:Dietary Fats; D054439:Ghrelin; D018149:Glucose Intolerance / Q000517:prevention & control*; D007328:Insulin / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D036361:Peptide Hormones / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D001786:Blood Glucose; D004041:Dietary Fats; D054439:Ghrelin; D007328:Insulin; D036361:Peptide Hormones; D012333:RNA, Messenger