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

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.