Metabolic manifestations of insulin deficiency do not occur without glucagon action.
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 promptly when glucagon action is abolished. Glucagon suppression should be a major therapeutic goal in diabetes.
University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Young
Y
Lee
Eric D
ED
Berglund
May-yun
MY
Wang
Xiaorong
X
Fu
Xinxin
X
Yu
Maureen J
MJ
Charron
Shawn C
SC
Burgess
Roger H
RH
Unger
D000256:Adenoviridae; D000818:Animals; D001786:Blood Glucose; D002849:Chromatography, Gas; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D017931:DNA Primers / Q000235:genetics; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005822:Genetic Vectors / Q000235:genetics; D005934:Glucagon / Q000378:metabolism*; D015151:Immunoblotting; D007328:Insulin / Q000172:deficiency*; D008099:Liver / Q000378:metabolism*; D013058:Mass Spectrometry; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D060888:Real-Time Polymerase Chain Reaction; D018027:Receptors, Glucagon / Q000235:genetics / Q000378:metabolism
D001786:Blood Glucose; D017362:Cyclic AMP Response Element-Binding Protein; D017931:DNA Primers; D007328:Insulin; D018027:Receptors, Glucagon; D005934:Glucagon