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Diabetes. 2011 Feb;60(2):391-7. doi: 10.2337/db10-0426.

Glucagon receptor knockout prevents insulin-deficient type 1 diabetes in mice.

Author information

1
Touchstone Center for Diabetes Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA.

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.

PMID:
21270251
PMCID:
PMC3028337
DOI:
10.2337/db10-0426
[Indexed for MEDLINE]
Free PMC Article

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