Glucagon receptor knockout mice are resistant to diet-induced obesity and streptozotocin-mediated beta cell loss and hyperglycaemia

• Published in: Diabetologia Vol. 50; no. 1; pp. 142 - 150
• Main Authors: CONARELLO, S. L, JIANG, G, CHARRON, M. J, ZHANG, B. B, MU, J, LI, Z, WOODS, J, ZYCBAND, E, RONAN, J, LIU, F, SINHA ROY, R, ZHU, L
• Format: Journal Article
• Language: English
• Published: Berlin Springer 01.01.2007; Springer Nature B.V
• Subjects: Animals; Apoptosis - physiology; Biological and medical sciences; Diabetes Mellitus, Experimental - metabolism; Diabetes Mellitus, Experimental - pathology; Diabetes Mellitus, Experimental - prevention & control; Diabetes. Impaired glucose tolerance; Dietary Fats - adverse effects; Disease Models, Animal; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Gene Deletion; Glucose - metabolism; Homeostasis - physiology; Hyperglycemia - metabolism; Hyperglycemia - physiopathology; Hyperglycemia - prevention & control; Insulin-Secreting Cells - metabolism; Insulin-Secreting Cells - pathology; Male; Medical sciences; Metabolic diseases; Mice; Mice, Inbred C57BL; Mice, Knockout; Obesity; Obesity - etiology; Obesity - metabolism; Obesity - prevention & control; Receptors, Glucagon - genetics; Receptors, Glucagon - metabolism; Streptozocin; Endocrinopathy; Pancreatic hormone; Glucagon; Peptide hormone; Gene; Gene knockout; β Cell; Streptozotocin; Nutritional status; Endocrine pancreas; Biological receptor; Obesity; Glucagon receptor; Diabetes mellitus; Metabolic control; Langerhans islet; Rodentia; Nutrition disorder; Feeding; Vertebrata; Mammalia; Diet; Mouse; Animal; Beta cell; Mutation
• ISSN: 0012-186X; 1432-0428
• DOI: 10.1007/s00125-006-0481-3

Under normal physiological conditions, glucagon signalling is important in glucose homeostasis. Hyperglucagonaemia or altered insulin:glucagon ratio plays a role in maintaining hyperglycaemia in subjects with type 2 diabetes. It has been reported that glucagon receptor knockout (Gcgr (-/-)) mice develop normally and have lower plasma glucose on a normal diet. The goal of the current research was to further investigate the role of glucagon signalling in metabolic control and glucose homeostasis. Gcgr (-/-) mice were challenged with a high-fat diet (HFD) and with streptozotocin, which induces beta cell damage. They were then analysed for whole-body and serum metabolic phenotypes as well as pancreatic islet morphology. In comparison with wild-type mice, Gcgr (-/-) mice exhibited decreased body weight and food intake, reduced plasma glucose levels, and improved oral and intraperitoneal glucose tolerance. Elevated glucagon-like peptide-1 levels and reduced gastric emptying were also observed in Gcgr (-/-) mice, which also had reduced HFD-induced hyperinsulinaemia and hyperleptinaemia, and were resistant to the development of hepatic steatosis. In addition, Gcgr (-/-) mice were resistant to STZ-induced hyperglycaemia and pancreatic beta cell destruction. This study demonstrates that blocking glucagon signalling by targeted Gcgr gene deletion leads to an improvement in metabolic control in this mouse model.