title: Long-term inhibition of the glucagon receptor with a monoclonal antibody in mice causes sustained improvement in glycemic control, with reversible alpha-cell hyperplasia and hyperglucagonemia.
abstract: Uncontrolled hepatic glucose output (HGO) contributes significantly to the pathological hyperglycemic state of patients with type 2 diabetes. Glucagon, through action on its receptor, stimulates HGO, thereby leading to increased glycemia. Antagonizing the glucagon signaling pathway represents an attractive therapeutic approach for the treatment of type 2 diabetes. We previously reported the generation and characterization of several high-affinity monoclonal antibodies (mAbs) targeting the glucagon receptor (GCGR). In the present study, we demonstrate that a 5-week treatment of diet-induced obese mice with mAb effectively normalized nonfasting blood glucose. Similar treatment also reduced fasting blood glucose without inducing hypoglycemia or other undesirable metabolic perturbations. In addition, no hypoglycemia was found in db/db mice that were treated with a combination of insulin and mAb. Long-term treatment with the mAb caused dose-dependent hyperglucagonemia and minimal to mild alpha-cell hyperplasia in lean mice. There was no evidence of pancreatic alpha-cell neoplastic transformation in mice treated with mAb for as long as 18 weeks. Treatment-induced hyperglucagonemia and alpha-cell hyperplasia were reversible after treatment withdrawal for periods of 4 and 10 weeks, respectively. It is noteworthy that pancreatic beta-cell function was preserved, as demonstrated by improved glucose tolerance throughout the 18-week treatment period. Our studies further support the concept that long-term inhibition of GCGR signaling by a mAb could be an effective approach for controlling diabetic hyperglycemia.
authors.affiliation: Department of Metabolic Disorders, Amgen Inc., Thousand Oaks, California 91320, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Gu
authors.forename: Hai
authors.initials: H
authors.lastname: Yan
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Winters
authors.forename: Renée
authors.initials: R
authors.lastname: Komorowski
authors.forename: Steven
authors.initials: S
authors.lastname: Vonderfecht
authors.forename: Larissa
authors.initials: L
authors.lastname: Atangan
authors.forename: Glenn
authors.initials: G
authors.lastname: Sivits
authors.forename: David
authors.initials: D
authors.lastname: Hill
authors.forename: Jie
authors.initials: J
authors.lastname: Yang
authors.forename: Vivian
authors.initials: V
authors.lastname: Bi
authors.forename: Yuqing
authors.initials: Y
authors.lastname: Shen
authors.forename: Sylvia
authors.initials: S
authors.lastname: Hu
authors.forename: Tom
authors.initials: T
authors.lastname: Boone
authors.forename: Richard A
authors.initials: RA
authors.lastname: Lindberg
authors.forename: Murielle M
authors.initials: MM
authors.lastname: Véniant
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001786:Blood Glucose; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000188:drug therapy / Q000378:metabolism; D005934:Glucagon / Q000097:blood*; D050416:Glucagon-Secreting Cells / Q000473:pathology*; D005947:Glucose / Q000378:metabolism*; D006943:Hyperglycemia / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D006965:Hyperplasia; D007003:Hypoglycemia / Q000097:blood / Q000378:metabolism / Q000517:prevention & control; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D007328:Insulin / Q000008:administration & dosage / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000097:blood / Q000378:metabolism; D018027:Receptors, Glucagon / Q000037:antagonists & inhibitors*; D013618:Tachyphylaxis
chemical_list: D000911:Antibodies, Monoclonal; D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D018027:Receptors, Glucagon; D005934:Glucagon; D005947:Glucose