Glucagon-like peptide-1-(9-36) amide is a major metabolite of glucagon-like peptide-1-(7-36) amide after in vivo administration to dogs, and it acts as an antagonist on the pancreatic receptor

Abstract

This study assesses the importance of metabolites formed following exogenous administration of glucagon-like peptide-1-(7-36) amide (GLP-1). After subcutaneous (s.c.) administration of GLP-1 to dogs the plasma immunoreactivity of GLP-1 measured by two different radioimmunoassays (RIAs) were higher than that measured by a sandwich enzyme-linked immunosorbent assay (ELISA). This discrepancy was due to the formation of the metabolites GLP-1-(9-36) amide, GLP-1-(7-35) and GLP-1-(7-34). Receptor binding studies using baby hamster kidney cells expressing the human pancreatic GLP-1 receptor showed that the affinity of GLP-1-(9-36) amide, GLP-1-(7-35) and GLP-1-(7-34) was 0.95%, 12% and 2.8%, respectively, of the affinity of GLP-1-(7-36) amide. Furthermore, GLP-1-(9-36) amide was shown to be an antagonist to adenylyl cyclase activity, whereas GLP-1-(7-35) and GLP-1-(7-34) were shown to be agonists. GLP-1-(9-36) amide was shown to be present in vivo in amounts up to 10-fold that of GLP-1-(7-36) amide. Due to its low binding affinity, this antagonistic metabolite does not seem to be able to cause physiological antagonism upon s.c. administration of the peptide.