Glucagon receptor knockout prevents insulin-deficient type 1 diabetes in mice

Diabetes. 2011 Feb;60(2):391-7. doi: 10.2337/db10-0426.


Objective: To determine the role of glucagon action in the metabolic phenotype of untreated insulin deficiency.

Research design and 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Blood Glucose
  • Blotting, Western
  • Diabetes Mellitus, Experimental / etiology*
  • Diabetes Mellitus, Experimental / metabolism
  • Diabetes Mellitus, Type 1 / etiology*
  • Diabetes Mellitus, Type 1 / metabolism
  • Enzyme-Linked Immunosorbent Assay
  • Fatty Acids / blood
  • Glucagon / metabolism*
  • Hyperglycemia / etiology
  • Hyperglycemia / metabolism
  • Immunohistochemistry
  • Insulin / blood
  • Insulin-Like Growth Factor I / metabolism
  • Liver / metabolism*
  • Mice
  • Mice, Knockout
  • Pancreas / metabolism*
  • Radioimmunoassay
  • Receptors, Glucagon / genetics
  • Receptors, Glucagon / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction


  • Blood Glucose
  • Fatty Acids
  • Insulin
  • Receptors, Glucagon
  • Insulin-Like Growth Factor I
  • Glucagon