Glucagon receptor knockout mice display increased insulin sensitivity and impaired beta-cell function

Research output: Contribution to journalArticle

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 P-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 P-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.

Details

Authors
  • Heidi Sorensen
  • Maria Sörhede Winzell
  • Christian L. Brand
  • Keld Fosgerau
  • Richard W. Gelling
  • Erica Nishimura
  • Bo Ahrén
Organisations
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Endocrinology and Diabetes
Original languageEnglish
Pages (from-to)3463-3469
JournalDiabetes
Volume55
Issue number12
Publication statusPublished - 2006
Publication categoryResearch
Peer-reviewedYes