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Glucagon Receptor Knockout Mice Display Increased Insulin Sensitivity and Impaired ß-Cell Function

¹ Diabetes Research Unit, Novo Nordisk, Måløv, Denmark
² Department of Clinical Sciences, Section of Medicine, Lund University, Lund, Sweden
³ Department of Medicine, University of Washington, Seattle, Washington

Address correspondence and reprint requests to Heidi Sørensen, Diabetes Research Unit, Novo Nordisk Park, 2760 Måløv, Denmark. E-mail: hesn{at}novonordisk.com

Abbreviations: AIR, acute insulin response; CCK-8, cholecystokinin octapeptide; GIP, glucose-dependent insulinotropic polypeptide; GIR, glucose infusion rate; GLP, glucagon-like peptide; GSIS, glucose-stimulated insulin secretion; HGP, hepatic glucose production; IVGTT, intravenous glucose tolerance test

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 ß-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 ß-cell function and that insulin action is improved when disrupting the signal. In vivo, augmented GLP-1 levels compensate for the impaired ß-cell function in Gcgr^–/– mice.

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