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

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

Young Lee  1 , May-Yun Wang, Xiu Quan Du, Maureen J Charron, Roger H Unger
Affiliations

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

Young Lee et al. Diabetes. 2011 Feb.

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.

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Figures

FIG. 1.
FIG. 1.
A: Comparison of plasma glucagon levels in Gcgr+/+ (■) and Gcgr−/− (□) mice before and 6 weeks after STZ induction of β-cell destruction. B: Glucagon in Gcgr+/+ mice before and after STZ. C: Representative immunoblots for CREB and P-CREB in livers of Gcgr+/+ (■) and Gcgr−/− (□) mice after β-cell destruction by treatment with STZ and in untreated controls (upper panel). The P-CREB/CREB ratio in densitometric units in six Gcgr+/+ (■) and six Gcgr−/− (□) mice after β-cell destruction by treatment with STZ (lower panel).
FIG. 2.
FIG. 2.
A: Comparison of food intake in nondiabetic and STZ-treated Gcgr+/+ (■) and Gcgr−/− (□) mice (n = 6). B: Comparison of body weight in Gcgr+/+ (■) and Gcgr−/− (□) before and after STZ induction of β-cell destruction. C: Comparisons of weekly nonfasting glucose levels in Gcgr+/+ (●) and Gcgr−/− (□) after STZ-induced β-cell destruction, and overnight fasting glucose levels for Gcgr+/+ (♦) and Gcgr−/− (◇) at the end of the study (n = 6). D: Glucose values for oral glucose tolerance test (OGTT) (2 g/kg) performed after a 16-h fast in normal Gcgr+/+ (●), Gcgr−/− (☐), and STZ-treated Gcgr−/− (▲) mice (n = 4). E: Insulin levels for OGTT in normal Gcgr+/+ (●), Gcgr−/− (☐), and STZ-treated Gcgr−/− (▲) mice (n = 4).
FIG. 3.
FIG. 3.
Comparison of fasting (▨) and nonfasting FFAs (formula image) (A) and nonfasting β-OH butyrate levels (B) in STZ-treated Gcgr+/+ (■) and Gcgr−/− (□) mice and untreated controls (N = 6).
FIG. 4.
FIG. 4.
Comparison of the ratio of PEPCK mRNA to 36B4 mRNA (A) and plasma lactate levels (B) in STZ-treated Gcgr+/+ (■) and Gcgr−/− (□) mice (N = 6).
See this image and copyright information in PMC

Comment in

References

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