title: Glucagon receptor knockout mice display increased insulin sensitivity and impaired beta-cell function.
abstract: In previous studies, glucagon receptor knockout mice (Gcgr(-/-)) display reduced blood glucose and increased glucose tolerance, with hyperglucagonemia and increased levels of glucagon-like peptide (GLP)-1. However, the role of glucagon receptor signaling for the regulation of islet function and insulin sensitivity is unknown. We therefore explored beta-cell function and insulin sensitivity in Gcgr(-/-) and wild-type mice. The steady-state glucose infusion rate during hyperinsulinemic-euglycemic clamp was elevated in Gcgr(-/-) mice, indicating enhanced insulin sensitivity. Furthermore, the acute insulin response (AIR) to intravenous glucose was higher in Gcgr(-/-) mice. The augmented AIR to glucose was blunted by the GLP-1 receptor antagonist, exendin-3. In contrast, AIR to intravenous administration of other secretagogues was either not affected (carbachol) or significantly reduced (arginine, cholecystokinin octapeptide) in Gcgr(-/-) mice. In islets isolated from Gcgr(-/-) mice, the insulin responses to glucose and several insulin secretagogues were all significantly blunted compared with wild-type mice. Furthermore, glucose oxidation was reduced in islets from Gcgr(-/-) mice. In conclusion, the present study shows that glucagon signaling is required for normal beta-cell function and that insulin action is improved when disrupting the signal. In vivo, augmented GLP-1 levels compensate for the impaired beta-cell function in Gcgr(-/-) mice.
authors.affiliation: Diabetes Research Unit, Novo Nordisk Park, 2760 Måløv, Denmark. hesn@novonordisk.com
authors.forename: Heidi
authors.initials: H
authors.lastname: Sørensen
authors.forename: Maria Sörhede
authors.initials: MS
authors.lastname: Winzell
authors.forename: Christian L
authors.initials: CL
authors.lastname: Brand
authors.forename: Keld
authors.initials: K
authors.lastname: Fosgerau
authors.forename: Richard W
authors.initials: RW
authors.lastname: Gelling
authors.forename: Erica
authors.initials: E
authors.lastname: Nishimura
authors.forename: Bo
authors.initials: B
authors.lastname: Ahren
mesh_terms: D000818:Animals; D001120:Arginine / Q000494:pharmacology; D001786:Blood Glucose / Q000378:metabolism; D002217:Carbachol / Q000494:pharmacology; D005934:Glucagon / Q000502:physiology; D005947:Glucose / Q000378:metabolism; D015309:Glucose Clamp Technique; D005951:Glucose Tolerance Test; D006946:Hyperinsulinism; D007328:Insulin / Q000378:metabolism / Q000494:pharmacology*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D007700:Kinetics; D051379:Mice; D018345:Mice, Knockout; D018027:Receptors, Glucagon / Q000172:deficiency* / Q000235:genetics*
chemical_list: D001786:Blood Glucose; D007328:Insulin; D018027:Receptors, Glucagon; D002217:Carbachol; D005934:Glucagon; D001120:Arginine; D005947:Glucose