Glucagon receptor knockout mice display increased insulin sensitivity and impaired beta-cell function.
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.
Sørensen
Heidi
H
Diabetes Research Unit, Novo Nordisk Park, 2760 Måløv, Denmark. hesn@novonordisk.com
Winzell
Maria Sörhede
MS
Brand
Christian L
CL
Fosgerau
Keld
K
Gelling
Richard W
RW
Nishimura
Erica
E
Ahren
Bo
B
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*
D001786:Blood Glucose; D007328:Insulin; D018027:Receptors, Glucagon; D002217:Carbachol; D005934:Glucagon; D001120:Arginine; D005947:Glucose