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

• DOI: 10.1073/pnas.1424934112
• Publication Date: 2015-02-10T04:13:27Z
• Authors: May-Yun Wang; Hai Yan; Zhiqing Shi; Matthew R. Evans; Xinxin Yu; Young Lee; Shiuhwei Chen; Annie Williams; Jacques Philippe; Michael G. Roth; Roger H. Unger
• Keywords: Blood Glucose; Diabetes Mellitus, Experimental/blood/drug therapy/pathology; Diabetes Mellitus, Experimental; Mice; Mice, Inbred NOD; info:eu-repo/classification/ddc/616; Antibodies, Monoclonal/pharmacology/therapeutic use; Paracrine Communication; Receptors, Glucagon; Animals; Humans; Insulin; ddc:616; Blood Glucose/metabolism; Diabetes Mellitus, Type 1/blood/drug therapy/pathology; Receptors, Glucagon/immunology; Paracrine Communication/drug effects; Antibodies, Monoclonal; Glucagon; Rats; Rats, Zucker; Diabetes Mellitus, Type 1; Insulin/therapeutic use; Glucagon/secretion; Female

Significance Subcutaneous injections of insulin sustain life in mammals unable to produce insulin (type 1 diabetes) but do not prevent hyperglycemic and hypoglycemic swings or decrease hemoglobin A1c levels to normal amounts. In mice treated with insulin alone, repeated episodes of transient elevated blood glucose cause long-term damage. We show that in mice with type 1 diabetes treated with insulin, the transient high blood glucose levels require production of glucagon, a hormone that will cause the liver to produce more glucose. Blocking the action of glucagon with an antibody to the glucagon receptor completely normalizes blood glucose and hemoglobin A1c in the complete absence of insulin therapy. Suppressing glucagon action in combination with low-dose insulin would be a superior treatment for type 1 diabetes.