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 language | English (US) |
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Pages (from-to) | 14972-14976 |
Number of pages | 5 |
Journal | Proceedings of the National Academy of Sciences of the United States of America |
Volume | 109 |
Issue number | 37 |
DOIs | |
State | Published - Sep 11 2012 |
Keywords
- Glucagon receptor knockout
- Glucose turnover
- Type 1 diabetes
ASJC Scopus subject areas
- General