of work: Glucagon-like peptide (GLP-1) is an incretin hormone that is secreted from gastrointestinal endocrine cells in response to food intake. GLP-1 is a promising new approach for treatment of type 2 diabetes since GLP-1 has been shown to have antidiabetogenic action. GLP-1 enhances insulin secretion from pancreatic beta cells via activation of GLP-1 receptor, a G-protein linked receptor, and increases of intracellular cAMP levels. However, there is little information about the structural components in either GLP-1 or its receptor. In addition, GLP-1 has some shortcomings as a therapeutic agent. For instance, GLP-1 (a 30 amino acid peptide) is rapidly metabolized in blood and no oral derivatives are yet available. A therapeutic agent that can mimic GLP-1 action would be very useful for treatment of type 2 diabetes. We are interested to study the structure-function relationship of GLP-1 and its receptor as a mean of understanding and potentially enhancing the action of GLP-1 as a therapeutic agent. In our study we have used GLP-1 and exendin-4 (a peptide agonist for pancreatic GLP-1 receptor isolated from Gila monster venom) to determine the binding and receptor activation sites of the peptides. Using peptides which combine GLP-1 and exendin-4 sequences and using truncated peptides, we have identified analogs of GLP-1 with a wide range of binding and cell physiologic properties. Our data suggest that specific regions of the GLP-1 molecule are implicated for binding and receptor activation. This suggests the exciting possibility of designing more potent analogs of GLP-1 and/or long lasting analogs of GLP-1. In addition we have identified a strong correlation between the binding affinity and the alpha helical structures of the peptides. Part of this work describing important binding sites for GLP-1 and exendin-4 is in press in J. Biol. Chem. and another study showing the correlation of binding affinity with alpha helical content of peptides is being written for submission to J. Biol. Chem. Our goal is to further devote efforts to identify single residues and structures in GLP-1 peptide and GLP-1 receptor necessary for efficient ligand-receptor interactions with the goal of finding improved therapies for type 2 diabetes.
