Glucagon Receptor Knockout Prevents Insulin-Deficient Type 1 Diabetes in Mice

• Published in: Diabetes (New York, N.Y.) Vol. 60; no. 2; pp. 391 - 397
• Main Authors: LEE, Young, WANG, May-Yun, XIU QUAN DU, CHARRON, Maureen J, UNGER, Roger H
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.02.2011
• Subjects: Animals; Biological and medical sciences; Blood Glucose; Blotting, Western; Care and treatment; Development and progression; Diabetes; Diabetes Mellitus, Experimental - etiology; Diabetes Mellitus, Experimental - metabolism; Diabetes Mellitus, Type 1 - etiology; Diabetes Mellitus, Type 1 - metabolism; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Enzyme-Linked Immunosorbent Assay; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Fatty acids; Fatty Acids - blood; Genetic aspects; Genotype & phenotype; Glucagon; Glucagon - metabolism; Glucose; Growth factors; Hormone receptors; Hyperglycemia - etiology; Hyperglycemia - metabolism; Immunohistochemistry; Insulin; Insulin - blood; Insulin-Like Growth Factor I - metabolism; Liver - metabolism; Medical sciences; Metabolism; Mice; Mice, Knockout; Pancreas - metabolism; Physiological aspects; Plasma; Radioimmunoassay; Receptors, Glucagon - genetics; Receptors, Glucagon - metabolism; Research design; Reverse Transcriptase Polymerase Chain Reaction; Risk factors; Type 1 diabetes; Texas; Endocrinopathy; Immunopathology; Pancreatic hormone; Glucagon; Peptide hormone; Rodentia; Autoimmune disease; Insulin; Vertebrata; Mammalia; Mouse; Type 1 diabetes; Animal; Mutation; Biological receptor
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db10-0426

To determine the role of glucagon action in the metabolic phenotype of untreated insulin deficiency. We compared pertinent clinical and metabolic parameters in glucagon receptor-null (Gcgr(-/-)) mice and wild-type (Gcgr(+/+)) controls after equivalent destruction of β-cells. We used a double dose of streptozotocin to maximize β-cell destruction. Gcgr(+/+) mice became hyperglycemic (>500 mg/dL), hyperketonemic, polyuric, and cachectic and had to be killed after 6 weeks. Despite comparable β-cell destruction in Gcgr(-/-) mice, none of the foregoing clinical or laboratory manifestations of diabetes appeared. There was marked α-cell hyperplasia and hyperglucagonemia (~1,200 pg/mL), but hepatic phosphorylated cAMP response element binding protein and phosphoenolpyruvate carboxykinase mRNA were profoundly reduced compared with Gcgr(+/+) mice with diabetes--evidence that glucagon action had been effectively blocked. Fasting glucose levels and oral and intraperitoneal glucose tolerance tests were normal. Both fasting and nonfasting free fatty acid levels and nonfasting β-hydroxy butyrate levels were lower. We conclude that blocking glucagon action prevents the deadly metabolic and clinical derangements of type 1 diabetic mice.