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. 2012 Sep 11;109(37):14972-6.
doi: 10.1073/pnas.1205983109. Epub 2012 Aug 13.

Metabolic manifestations of insulin deficiency do not occur without glucagon action

Young Lee  1 , Eric D Berglund, May-yun Wang, Xiaorong Fu, Xinxin Yu, Maureen J Charron, Shawn C Burgess, Roger H Unger
Affiliations

Metabolic manifestations of insulin deficiency do not occur without glucagon action

Young Lee et al. Proc Natl Acad Sci U S A. .

Abstract

To determine unambiguously if suppression of glucagon action will eliminate manifestations of diabetes, we expressed glucagon receptors in livers of glucagon receptor-null (GcgR(-/-)) mice before and after β-cell destruction by high-dose streptozotocin. Wild type (WT) mice developed fatal diabetic ketoacidosis after streptozotocin, whereas GcgR(-/-) mice with similar β-cell destruction remained clinically normal without hyperglycemia, impaired glucose tolerance, or hepatic glycogen depletion. Restoration of receptor expression using adenovirus containing the GcgR cDNA restored hepatic GcgR, phospho-cAMP response element binding protein (P-CREB), and phosphoenol pyruvate carboxykinase, markers of glucagon action, rose dramatically and severe hyperglycemia appeared. When GcgR mRNA spontaneously disappeared 7 d later, P-CREB declined and hyperglycemia disappeared. In conclusion, the metabolic manifestations of diabetes cannot occur without glucagon action and, once present, disappear promptly when glucagon action is abolished. Glucagon suppression should be a major therapeutic goal in diabetes.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
Comparison of postprandial glycemia, glucose turnover, oral glucose tolerance, and C-peptide responses of normal wild-type mice and GcgR−/− mice before and after β-cell destruction (A) Postprandial (10:00 AM) blood glucose levels (mean ± SEM) in intact WT (open column) and in GcgR−/− mice (solid column) before and after treatment with high-dose STZ. (B) Glucose turnover in 5-h-fasted mice implanted with jugular catheters 5 d prior and infused with [3-3H] glucose for 90 min to achieve steady-state (n = 6–7 per group). Blood samples were taken from the cut tail at t = 90, 110, and 120 min to calculate glucose turnover. *P < 0.05 vs. vehicle-treated GcgR+/+ mice; †P < 0.05 vs. STZ-treated GcgR+/+ mice; and #P < 0.05 compared with vehicle-treated GcgR−/− mice. (C) OGTT in GcgR−/− mice before (○) and after (■) STZ treatment. (D) The peak level of C-peptide rise during an oral glucose challenge before and after high-dose STZ before and after STZ (*P < 0.01).
Fig. 2.
Fig. 2.
The effects of transient transgenic expression of GcgR in the liver of insulin-deficient GcgR-null mice upon markers of glucagon action and upon blood glucose levels. (A) Pattern of liver GcgR mRNA expression before and after injecting Adv-GcgR into insulin-deficient GcgR−/− mice. (B) Densitometric measurements of CREB, a transducer of glucagon action, in GcgR−/− mice before, during, and after expression of adenovirally delivered GcgR cDNA (P < 0.01). (See Fig. S1 for a representative immunoblot). (C) PEPCK mRNA in intact WT (open column) and in streptozotocinized GcgR−/− mice (solid column) before and at 5 and 10 d after the administration of adenovirus containing the GcgR cDNA (*P < 0.01; **P < 0.001). (D) Blood glucose levels (mean ± SEM) in GcgR−/− mice injected adv-β-gal (○) and Adv-GcgR (■) after destruction of β-cells by high-dose STZ (**P < 0.001).
Fig. 3.
Fig. 3.
Glycogen content of liver and skeletal muscle in normal mice and in GcgR−/− mice with and without insulin deficiency. Comparison of liver (A) and skeletal muscle (B) glycogen content in intact WT mice (white column) and in GcgR−/− mice before (black column) and after (grey column) treatment with high-dose STZ (*P < 0.02; **P < 0.001; ***P < 0.0001).
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References

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