title: Glucagon receptor knockout prevents insulin-deficient type 1 diabetes in mice.
abstract: OBJECTIVE
  To determine the role of glucagon action in the metabolic phenotype of untreated insulin deficiency.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  We conclude that blocking glucagon action prevents the deadly metabolic and clinical derangements of type 1 diabetic mice.
authors.affiliation: Touchstone Center for Diabetes Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Young
authors.initials: Y
authors.lastname: Lee
authors.forename: May-Yun
authors.initials: MY
authors.lastname: Wang
authors.forename: Xiu Quan
authors.initials: XQ
authors.lastname: Du
authors.forename: Maureen J
authors.initials: MJ
authors.lastname: Charron
authors.forename: Roger H
authors.initials: RH
authors.lastname: Unger
mesh_terms: D000818:Animals; D001786:Blood Glucose; D015153:Blotting, Western; D003921:Diabetes Mellitus, Experimental / Q000209:etiology* / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000209:etiology* / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005227:Fatty Acids / Q000097:blood; D005934:Glucagon / Q000378:metabolism*; D006943:Hyperglycemia / Q000209:etiology / Q000378:metabolism; D007150:Immunohistochemistry; D007328:Insulin / Q000097:blood; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D010179:Pancreas / Q000378:metabolism*; D011863:Radioimmunoassay; D018027:Receptors, Glucagon / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D001786:Blood Glucose; D005227:Fatty Acids; D007328:Insulin; D018027:Receptors, Glucagon; D007334:Insulin-Like Growth Factor I; D005934:Glucagon