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

May-Yun Wang, Hai Yan, Zhiqing Shi, Matthew R. Evans, Xinxin Yu, Young H Lee, Shiuhwei Chen, Annie Williams, Jacques Philippe, Michael G Roth, Roger H Unger

Research output: Contribution to journalArticle

53 Scopus citations


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 insulindeficient 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.

Original languageEnglish (US)
Pages (from-to)2503-2508
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number8
Publication statusPublished - Feb 24 2015



  • Antibody
  • Glucagon receptor
  • Insulin
  • Type 1 diabetes

ASJC Scopus subject areas

  • General

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