Glucagon receptor antagonist-mediated improvements in glycemic control are dependent on functional pancreatic GLP-1 receptor

• Published in: American journal of physiology: endocrinology and metabolism 2010-10, Vol.299 (4), p.E624-E632
• Main Authors: Gu, Wei, Winters, Katherine A, Motani, Alykhan S, Komorowski, Renée, Zhang, Ying, Liu, Qingxiang, Wu, Xiaosu, Rulifson, Ingrid C, Sivits, Jr, Glenn, Graham, Melissa, Yan, Hai, Wang, Paul, Moore, Steve, Meng, Tina, Lindberg, Richard A, Véniant, Murielle M
• Format: Article
• Language: English
• Subjects: Animals; Antibodies, Monoclonal - pharmacology; Diabetes; Disease Models, Animal; Female; Glucagon - blood; Glucagon - physiology; Glucagon-Like Peptide 1 - physiology; Glucagon-Like Peptide-1 Receptor; Glucose; Glucose Tolerance Test; Islets of Langerhans - drug effects; Islets of Langerhans - physiology; Lipids; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Nude; Peptide Fragments - pharmacology; Peptides; Receptors, Glucagon - antagonists & inhibitors; Receptors, Glucagon - blood; Receptors, Glucagon - physiology; Rodents; Signal transduction; Signal Transduction - drug effects; T cell receptors
• ISSN: 0193-1849; 1522-1555
• DOI: 10.1152/ajpendo.00102.2010

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.