PANCREATIC ?-CELL ACTIVATION OF INSULIN SECRETION BASED ON CHOLECYSTOKININ AND GLUCAGON-LIKE PEPTIDE-1 MULTIVALENT LIGANDS

Abstract

Multivalent ligands serve as a promising diabetes treatment option for delivery of therapeutic agents directly to pancreatic ?-cells for restoration of function. Linking multiple ligands for different receptors promotes binding to cells that express the receptor combination complimentary to the ligands, thus achieving specificity for the target cell. Three receptors that are specific for pancreatic ?- cells are glucagon-like peptide-1 (GLP-1), cholecystokinin (CCK), and ?2-adrenergic receptors. For this study, a dimeric ligand composed of GLP-1 and CCK6 and a trimeric ligand composed of GLP-1, CCK6, and yohimbine (Yhm), an ?2-AR antagonist, were designed and evaluated for their ability to effect insulin secretion. It was found that the GLP-1/CCK6 dimer potentiates GSIS at lower concentrations but its maximal response is lower than that of the combination of monomers. Overall, these effects of the dimeric ligand compared to its constituent monomers were not large indicating that it would not provide high specificity and affinity for pancreatic ?- cells. The GLP-1/CCK6/Yhm trimer significantly increased insulin secretion at concentrations >1 nM while the monomers had a negligible effect until >50 nM. The trimer also exhibited a 2-site activity curve with EC50 values of 6.24 nM (0.1 nM to 25 nM) and 83 nM (10nM to 250 nM). These results indicate the trimeric ligand is a favorable candidate for an effective ?-cell targeting agent.