Lower blood glucose, hyperglucagonemia, and pancreatic α cell hyperplasia in glucagon receptor knockout mice

Abstract

Glucagon, the counter-regulatory hormone to insulin, is secreted from pancreatic ␣ cells in response to low blood glucose. To examine the role of glucagon in glucose homeostasis, mice were generated with a null mutation of the glucagon receptor (Gcgr ؊/؊ ). These mice display lower blood glucose levels throughout the day and improved glucose tolerance but similar insulin levels compared with control animals. Gcgr ؊/؊ mice displayed supraphysiological glucagon levels associated with postnatal enlargement of the pancreas and hyperplasia of islets due predominantly to ␣ cell, and to a lesser extent, ␦ cell proliferation. In addition, increased proglucagon expression and processing resulted in increased pancreatic glucogen-like peptide 1 (GLP-1) (1-37) and GLP-1 amide (1-36 amide) content and a 3-to 10-fold increase in circulating GLP-1 amide. Gcgr ؊/؊ mice also displayed reduced adiposity and leptin levels but normal body weight, food intake, and energy expenditure. These data indicate that glucagon is essential for maintenance of normal glycemia and postnatal regulation of islet and ␣ and ␦ cell numbers. Furthermore, the lean phenotype of Gcgr ؊/؊ mice suggests glucagon action may be involved in the regulation of whole body composition.

G-protein-coupled receptors and islet function—Implications for treatment of type 2 diabetes

“…These mice display low circulating glucose levels (Gelling et al, 2003). They have also improved glucose tolerance, observed after oral and intravenous glucose administration (Sorensen et al, 2006).…”

Reprogrammation des cellules pancréatiques en cellules β

“…(2) les îlots d'animaux exprimant de façon ectopique Pax4 dans les cellules α contiennent toujours quelques cellules  localisées au voisinage des canaux pancréatiques ; se pourrait-il donc que cette détection signifie qu'il existe un processus de régénération des cellules , précédant l'initiation de l'expression de Pax4 et leur conversion en cellules  ? Il est intéressant de noter que plusieurs études ont fait état d'une néo-genèse des cellules  en cas de perturbation de la voie de signalisation du glucagon, cette augmentation du nombre de cellules  entraînant une hypertrophie des îlots [12,13]. Afin de confirmer le rôle du glucagon dans des processus de régénération, nous avons supplémenté (ou non) les souris transgéniques Pax4 avec du glucagon durant plusieurs semaines.…”

Function and expression of somatostatin receptors of the endocrine pancreas

“…Hyperglucagonemia further exacerbates hyperglycemia Page 7 of 29 A c c e p t e d M a n u s c r i p t 7 through stimulation of hepatic glucose production (Ohneda et al, 1978;Dinneen et al, 1995;Shah et al, 2000;Unger and Orci 1975;Unger 1975). The immunoneutralization of the endogenous glucagon, administration of glucagon receptor antagonists, reduction of glucagon receptor expression or the deletion of glucagon receptors leads to a reduction of hyperglycemia in diabetic animal models (Brand et al, 1994;Liang et al, 2004;Gelling et al, 2003). Given the potential for SST to inhibit glucagon secretion it has been considered as adjunct therapy with insulin to treat diabetes (de Laszlo et al, 1999;Petersen and Sullivan 2001;Madsen et al, 2002).…”