title: Glucagon receptor antagonist-mediated improvements in glycemic control are dependent on functional pancreatic GLP-1 receptor.
abstract: Antagonism of the glucagon receptor (GCGR) is associated with increased circulating levels of glucagon-like peptide-1 (GLP-1). To investigate the contribution of GLP-1 to the antidiabetic actions of GCGR antagonism, we administered an anti-GCGR monoclonal antibody (mAb B) to wild-type mice and GLP-1 receptor knockout (GLP-1R KO) mice. Treatment of wild-type mice with mAb B lowered fasting blood glucose, improved glucose tolerance, and enhanced glucose-stimulated insulin secretion during an intraperitoneal glucose tolerance test (ipGTT). In contrast, treatment of GLP-1R KO mice with mAb B had little efficacy during an ipGTT. Furthermore, pretreatment with the GLP-1R antagonist exendin-(9-39) diminished the antihyperglycemic effects of mAb B in wild-type mice. To determine the mechanism whereby mAb B improves glucose tolerance, we generated a monoclonal antibody that specifically antagonizes the human GLP-1R. Using a human islet transplanted mouse model, we demonstrated that pancreatic islet GLP-1R signaling is required for the full efficacy of the GCGR antagonist. To identify the source of the elevated GLP-1 observed in GCGR mAb-treated mice, we measured active GLP-1 content in pancreas and intestine from db/db mice treated with anti-GCGR mAb for 8 wk. Elevated GLP-1 in GCGR mAb-treated mice was predominantly derived from increased pancreatic GLP-1 synthesis and processing. All together, these data show that pancreatic GLP-1 is a significant contributor to the glucose-lowering effects observed in response to GCGR antagonist treatment.
authors.affiliation: Dept. of Metabolic Disorders, Amgen Inc., One Amgen Center Dr., Mail Stop 29-1-A, Thousand Oaks, CA 91320, USA. wgu@amgen.com
authors.forename: Wei
authors.initials: W
authors.lastname: Gu
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Winters
authors.forename: Alykhan S
authors.initials: AS
authors.lastname: Motani
authors.forename: Renée
authors.initials: R
authors.lastname: Komorowski
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.forename: Qingxiang
authors.initials: Q
authors.lastname: Liu
authors.forename: Xiaosu
authors.initials: X
authors.lastname: Wu
authors.forename: Ingrid C
authors.initials: IC
authors.lastname: Rulifson
authors.forename: Glenn
authors.initials: G
authors.lastname: Sivits
authors.forename: Melissa
authors.initials: M
authors.lastname: Graham
authors.forename: Hai
authors.initials: H
authors.lastname: Yan
authors.forename: Paul
authors.initials: P
authors.lastname: Wang
authors.forename: Steve
authors.initials: S
authors.lastname: Moore
authors.forename: Tina
authors.initials: T
authors.lastname: Meng
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 / Q000494:pharmacology; D004195:Disease Models, Animal; D005260:Female; D005934:Glucagon / Q000097:blood / Q000502:physiology*; D052216:Glucagon-Like Peptide 1 / Q000502:physiology*; D000067757:Glucagon-Like Peptide-1 Receptor; D005951:Glucose Tolerance Test; D007515:Islets of Langerhans / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008819:Mice, Nude; D010446:Peptide Fragments / Q000494:pharmacology; D018027:Receptors, Glucagon / Q000037:antagonists & inhibitors* / Q000097:blood / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000911:Antibodies, Monoclonal; C000593833:GLP1R protein, human; C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D010446:Peptide Fragments; D018027:Receptors, Glucagon; C083773:exendin (9-39); D052216:Glucagon-Like Peptide 1; D005934:Glucagon