Metabolic manifestations of insulin deficiency do not occur without glucagon action

Young Lee, Eric D. Berglund, May Yun Wang, Xiaorong Fu, Xinxin Yu, Maureen J. Charron, Shawn C. Burgess, Roger H. Unger

Research output: Contribution to journalArticle

81 Citations (Scopus)

Abstract

To determine unambiguously if suppression of glucagon action will eliminate manifestations of diabetes, we expressed glucagon receptors in livers of glucagon receptor-null (GcgR-/-) mice before and after β-cell destruction by high-dose streptozotocin. Wild type (WT) mice developed fatal diabetic ketoacidosis after streptozotocin, whereas GcgR-/- mice with similar β-cell destruction remained clinically normal without hyperglycemia, impaired glucose tolerance, or hepatic glycogen depletion. Restoration of receptor expression using adenovirus containing the GcgR cDNA restored hepatic GcgR, phospho-cAMP response element binding protein (P-CREB), and phosphoenol pyruvate carboxykinase, markers of glucagon action, rose dramatically and severe hyperglycemia appeared. When GcgR mRNA spontaneously disappeared 7 d later, P-CREB declined and hyperglycemia disappeared. In conclusion, the metabolic manifestations of diabetes cannot occur without glucagon action and, once present, disappear promptlywhen glucagon action is abolished. Glucagon suppression should be a major therapeutic goal in diabetes.

Original languageEnglish (US)
Pages (from-to)14972-14976
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number37
DOIs
StatePublished - Sep 11 2012

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Glucagon
Glucagon Receptors
Insulin
Hyperglycemia
Cyclic AMP Response Element-Binding Protein
Streptozocin
Diabetic Ketoacidosis
Liver Glycogen
Glucose Intolerance
Liver
Pyruvic Acid
Adenoviridae
Complementary DNA
Messenger RNA
Therapeutics

Keywords

  • Glucagon receptor knockout
  • Glucose turnover
  • Type 1 diabetes

ASJC Scopus subject areas

  • General

Cite this

Metabolic manifestations of insulin deficiency do not occur without glucagon action. / Lee, Young; Berglund, Eric D.; Wang, May Yun; Fu, Xiaorong; Yu, Xinxin; Charron, Maureen J.; Burgess, Shawn C.; Unger, Roger H.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 109, No. 37, 11.09.2012, p. 14972-14976.

Research output: Contribution to journalArticle

Lee, Young ; Berglund, Eric D. ; Wang, May Yun ; Fu, Xiaorong ; Yu, Xinxin ; Charron, Maureen J. ; Burgess, Shawn C. ; Unger, Roger H. / Metabolic manifestations of insulin deficiency do not occur without glucagon action. In: Proceedings of the National Academy of Sciences of the United States of America. 2012 ; Vol. 109, No. 37. pp. 14972-14976.
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