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

Young H Lee, May-Yun Wang, Xiu Quan Du, Maureen J. Charron, Roger H Unger

Research output: Contribution to journalArticle

207 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)391-397
Number of pages7
JournalDiabetes
Volume60
Issue number2
DOIs
StatePublished - Feb 2011

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Glucagon Receptors
Type 1 Diabetes Mellitus
Glucagon
Insulin
Fasting
Cyclic AMP Response Element-Binding Protein
Obese Mice
Phosphoenolpyruvate
Butyrates
Glucose Tolerance Test
Streptozocin
Nonesterified Fatty Acids
Hyperplasia
Research Design
Phenotype
Glucose
Messenger RNA
Liver

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Glucagon receptor knockout prevents insulin-deficient type 1 diabetes in mice. / Lee, Young H; Wang, May-Yun; Du, Xiu Quan; Charron, Maureen J.; Unger, Roger H.

In: Diabetes, Vol. 60, No. 2, 02.2011, p. 391-397.

Research output: Contribution to journalArticle

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