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. 2015 Feb 24;112(8):2503-8.
doi: 10.1073/pnas.1424934112. Epub 2015 Feb 9.

Glucagon receptor antibody completely suppresses type 1 diabetes phenotype without insulin by disrupting a novel diabetogenic pathway

May-Yun Wang  1 , Hai Yan  2 , Zhiqing Shi  2 , Matthew R Evans  3 , Xinxin Yu  1 , Young Lee  1 , Shiuhwei Chen  4 , Annie Williams  5 , Jacques Philippe  6 , Michael G Roth  7 , Roger H Unger  8
Affiliations

Glucagon receptor antibody completely suppresses type 1 diabetes phenotype without insulin by disrupting a novel diabetogenic pathway

May-Yun Wang et al. Proc Natl Acad Sci U S A. .

Erratum in

Abstract

Insulin monotherapy can neither maintain normoglycemia in type 1 diabetes (T1D) nor prevent the long-term damage indicated by elevated glycation products in blood, such as glycated hemoglobin (HbA1c). Here we find that hyperglycemia, when unaccompanied by an acute increase in insulin, enhances itself by paradoxically stimulating hyperglucagonemia. Raising glucose from 5 to 25 mM without insulin enhanced glucagon secretion ∼two- to fivefold in InR1-G9 α cells and ∼18-fold in perfused pancreata from insulin-deficient rats with T1D. Mice with T1D receiving insulin treatment paradoxically exhibited threefold higher plasma glucagon during hyperglycemic surges than during normoglycemic intervals. Blockade of glucagon action with mAb Ac, a glucagon receptor (GCGR) antagonizing antibody, maintained glucose below 100 mg/dL and HbA1c levels below 4% in insulin-deficient mice with T1D. In rodents with T1D, hyperglycemia stimulates glucagon secretion, up-regulating phosphoenolpyruvate carboxykinase and enhancing hyperglycemia. GCGR antagonism in mice with T1D normalizes glucose and HbA1c, even without insulin.

Keywords: antibody; glucagon receptor; insulin; type 1 diabetes.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
In the absence of paracrine insulin, glucagon secretion increases in response to increases in glucose. (A) An increase from 5 to 25 mM in the glucose perfused into the isolated pancreata of nondiabetic mice causes profound suppression of glucagon secretion. n = 3. (B) In the absence of insulin, increasing glucose concentration progressively increases glucagon secretion by cultured InR1G9 α cells. n = 4. (C) Perfusing increasing glucose concentrations into pancreata of rats with streptozotocin-induced destruction of β cells causes progressive rise in glucagon secretion. n = 6. (D) Glucagon was measured in plasma collected twice daily (10:00 AM and 5:00 PM) from insulin-treated (0.1 U bid) mice with T1D. The average glucagon concentration, when blood glucose levels averaged 500 mg/dL (black bar) and when glucose levels averaged 130 mg/dL (white bar), are shown. The results are from 112 specimens collected from eight different mice. (E) The mean glucose measurements taken each day that were used to classify samples as high glucose or low glucose for D are presented. Error bars are SDs.
Fig. 2.
Fig. 2.
Glucagon action is chronically high in the livers of diabetic animals. (A) Hepatic markers of glucagon signaling (P-CREB) and of glucagon action (PEPCK) were measured by immunoblotting liver samples from nondiabetic and diabetic mice. (B) The ratio of activated P-CREB to total CREB protein was measured by densitometry of immunoblots of livers from nondiabetic mice (n = 2), untreated T1D mice (n = 3), and T1D mice (n = 4) treated with 5 mg antiglucagon receptor antibody mAb B. (C) Similar measurements were made of PEPCK protein in these specimens. (D) Blood glucose levels are plotted for T1D mice treated with buffer (n = 5) or 5 mg/kg anti-GCGR antibody mAb B (n = 6) for the time shown. Error bars in B–D are SDs.
Fig. 3.
Fig. 3.
Agents that suppress glucagon secretion or antagonize GCGR normalize glucagon action in liver and plasma glucose in diabetic mice. (A) Plasma glucose and glucagon levels in diabetic NOD mice (n= 3–10) treated with the agents shown. (B) Blood glucose levels are plotted for chemically induced T1D mice treated with buffer (n = 10) or 7.5 mg/kg mAb Ac anti-GCGR antibody (n = 10) for the time shown. P < 0.01 comparing antibody to vehicle for all measurements from weeks 1–12. (C) HbA1c was measured, with a Toshiba TBA-40FR automated biochemical analyzer, in blood from the animals shown in B after 12 wk; average values are graphed. P < 0.01 comparing antibody to vehicle. Error bars are SDs.
See this image and copyright information in PMC

Comment in

  • Diabetes: New treatment approach for T1DM.
    Greenhill C. Greenhill C. Nat Rev Endocrinol. 2015 May;11(5):255. doi: 10.1038/nrendo.2015.29. Epub 2015 Mar 3. Nat Rev Endocrinol. 2015. PMID: 25732518 No abstract available.

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