title: Glucagon receptor antibody completely suppresses type 1 diabetes phenotype without insulin by disrupting a novel diabetogenic pathway.
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.
authors: Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390;
authors: May-Yun
authors: MY
authors: Wang
authors: REMD Biotherapeutics, Inc., Camarillo, CA 93012; Beijing Cosci-REMD Biotherapeutics Inc., Beijing 102206, China;
authors: Hai
authors: H
authors: Yan
authors: REMD Biotherapeutics, Inc., Camarillo, CA 93012; Beijing Cosci-REMD Biotherapeutics Inc., Beijing 102206, China;
authors: Zhiqing
authors: Z
authors: Shi
authors: Department of Biochemistry and.
authors: Matthew R
authors: MR
authors: Evans
authors: Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390;
authors: Xinxin
authors: X
authors: Yu
authors: Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390;
authors: Young
authors: Y
authors: Lee
authors: Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390;
authors: Shiuhwei
authors: S
authors: Chen
authors: University of Notre Dame, Notre Dame, IN 46556;
authors: Annie
authors: A
authors: Williams
authors: University of Geneva School of Medicine, 1211 Geneva, Switzerland; and.
authors: Jacques
authors: J
authors: Philippe
authors: Department of Biochemistry and roger.unger@utsouthwestern.edu michael.roth@utsouthwestern.edu.
authors: Michael G
authors: MG
authors: Roth
authors: Touchstone Diabetes Center, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390; Department of Medical Service, Veteran's Administration North Texas Health Care System, Dallas, TX 75216 roger.unger@utsouthwestern.edu michael.roth@utsouthwestern.edu.
authors: Roger H
authors: RH
authors: Unger
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use*; D001786:Blood Glucose / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000188:drug therapy* / Q000473:pathology*; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000188:drug therapy* / Q000473:pathology*; D005260:Female; D005934:Glucagon / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000627:therapeutic use*; D051379:Mice; D016688:Mice, Inbred NOD; D019899:Paracrine Communication / Q000187:drug effects; D051381:Rats; D011924:Rats, Zucker; D018027:Receptors, Glucagon / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D001786:Blood Glucose; D007328:Insulin; D018027:Receptors, Glucagon; D005934:Glucagon
keywords: antibody; glucagon receptor; insulin; type 1 diabetes