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- Title
Glucagon Receptor Knockout Prevents Insulin-Deficient Type 1 Diabetes in Mice.
- Authors
Young Lee; May-Yun Wang; Xiu Quan Du; Charron, Maureen J.; Unger, Roger H.
- 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 β-cell hyperplasia and hyper-glucagonemia (~1,200 pg/mL), but hepatic phosphorylated cAMP response element binding protein and phosphoenolpyruvate car-boxykinase 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.
- Publication
Diabetes, 2011, Vol 60, Issue 2, p391
- ISSN
0012-1797
- Publication type
Academic Journal
- DOI
10.2337/db10-0426