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) |
|---|---|
| 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 |
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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 journal › Article
}
TY - JOUR
T1 - Metabolic manifestations of insulin deficiency do not occur without glucagon action
AU - Lee, Young
AU - Berglund, Eric D.
AU - Wang, May Yun
AU - Fu, Xiaorong
AU - Yu, Xinxin
AU - Charron, Maureen J.
AU - Burgess, Shawn C.
AU - Unger, Roger H.
PY - 2012/9/11
Y1 - 2012/9/11
N2 - 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.
AB - 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.
KW - Glucagon receptor knockout
KW - Glucose turnover
KW - Type 1 diabetes
UR - http://www.scopus.com/inward/record.url?scp=84866299596&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84866299596&partnerID=8YFLogxK
U2 - 10.1073/pnas.1205983109
DO - 10.1073/pnas.1205983109
M3 - Article
C2 - 22891336
AN - SCOPUS:84866299596
VL - 109
SP - 14972
EP - 14976
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 37
ER -