TY - JOUR
T1 - Metabolic manifestations of insulin deficiency do not occur without glucagon action
AU - Lee, Young H
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
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U2 - 10.1073/pnas.1205983109
DO - 10.1073/pnas.1205983109
M3 - Article
C2 - 22891336
AN - SCOPUS:84866299596
SN - 0027-8424
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
IS - 37
ER -