Glucagon Receptor Knockout Prevents Insulin-Deficient Type 1 Diabetes in Mice
Open Access
- 21 January 2011
- journal article
- Published by American Diabetes Association in Diabetes
- Vol. 60 (2), 391-397
- https://doi.org/10.2337/db10-0426
Abstract
OBJECTIVE To determine the role of glucagon action in the metabolic phenotype of untreated insulin deficiency. RESEARCH DESIGN AND METHODS We compared pertinent clinical and metabolic parameters in glucagon receptor-null (Gcgr−/−) mice and wild-type (Gcgr+/+) controls after equivalent destruction of β-cells. We used a double dose of streptozotocin to maximize β-cell destruction. RESULTS Gcgr+/+ mice became hyperglycemic (>500 mg/dL), hyperketonemic, polyuric, and cachectic and had to be killed after 6 weeks. Despite comparable β-cell destruction in Gcgr−/− mice, none of the foregoing clinical or laboratory manifestations of diabetes appeared. There was marked α-cell hyperplasia and hyperglucagonemia (∼1,200 pg/mL), but hepatic phosphorylated cAMP response element binding protein and phosphoenolpyruvate carboxykinase mRNA were profoundly reduced compared with Gcgr+/+ mice with diabetes—evidence that glucagon action had been effectively blocked. Fasting glucose levels and oral and intraperitoneal glucose tolerance tests were normal. Both fasting and nonfasting free fatty acid levels and nonfasting β-hydroxy butyrate levels were lower. CONCLUSIONS We conclude that blocking glucagon action prevents the deadly metabolic and clinical derangements of type 1 diabetic mice.Keywords
This publication has 47 references indexed in Scilit:
- Leptin therapy in insulin-deficient type I diabetesProceedings of the National Academy of Sciences, 2010
- Antidiabetic Effects of IGFBP2, a Leptin-Regulated GeneCell Metabolism, 2010
- The Glucagon-Like Peptide-1 Receptor Regulates Endogenous Glucose Production and Muscle Glucose Uptake Independent of Its Incretin ActionEndocrinology, 2008
- Making insulin-deficient type 1 diabetic rodents thrive without insulinProceedings of the National Academy of Sciences, 2008
- A Novel Glucagon Receptor Antagonist, NNC 25-0926, Blunts Hepatic Glucose Production in the Conscious DogJournal of Pharmacology and Experimental Therapeutics, 2007
- Increased amino acid clearance and urea synthesis in a patient with glucagonoma.Gut, 1990
- Mechanism of the Inhibition by Insulin of the Glucagon-Dependent Activation of the Phosphoenolpyruvate Carhoxykinase Gene in Rat Hepatocyte Cultures. Action on Gene Transcription, mRNA Level and -Stability as well as Hysteresis EffectBiological Chemistry Hoppe-Seyler, 1990
- Insulin within islets is a physiologic glucagon release inhibitor.JCI Insight, 1984
- Hyperglucagonemia and Its SuppressionNew England Journal of Medicine, 1978
- THE ESSENTIAL ROLE OF GLUCAGON IN THE PATHOGENESIS OF DIABETES MELLITUSThe Lancet, 1975