title: Novel insight into glucagon receptor action: lessons from knockout and transgenic mouse models.
abstract: Using knockout and transgenic technology, genetically modified animal models allowed us to understand the role of glucagon signalling in metabolism. Mice with a global deletion of the glucagon receptor gene (Gcgr) were designed using gene targeting. The phenotype of Gcgr(-/-) mouse provided important clues about the role of Gcgr in foetal growth, pancreatic development and glucose and lipid homeostasis. The lack of Gcgr activation was associated with: (i) hypoglycaemic pregnancies, poor foetal growth and increased foetal-neonatal demise; (ii) altered cytoarchitecture of pancreatic islets; (iii) altered glucose, lipid and hormonal milieu; (iv) reduced gastric emptying; (v) altered body composition and protection from diet-induced obesity; (vi) altered energy state; (vii) impaired hepatocyte survival; (viii) altered metabolic response to prolonged fasting and exercise and (ix) prevented development of diabetes in insulin-deficient mice. In contrast, mice overexpressing the Gcgr on pancreatic β-cells displayed an increase insulin secretion, pancreatic insulin content and β-cell mass, and partially protected against hyperglycaemia and impaired glucose tolerance when fed a high-fat diet. These findings suggest that glucagon signalling plays a significant role in the regulation of glucose and lipid homeostasis. Treatment options designed to block Gcgr activation may have negative implications in the treatment of diabetes.
authors.affiliation: Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10467, USA. patricia.vuguin@einstein.yu.edu
authors.forename: P M
authors.initials: PM
authors.lastname: Vuguin
authors.forename: M J
authors.initials: MJ
authors.lastname: Charron
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D005260:Female; D005934:Glucagon / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D023421:Models, Animal; D011247:Pregnancy; D018027:Receptors, Glucagon / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D018027:Receptors, Glucagon; D005934:Glucagon