Multivalent activation of GLP-1 and Sulfonylurea receptors modulates β-cell Second Messenger Signaling and Insulin Secretion.

Linking two pharmacophores that bind different cell surface receptors into a single molecule can enhance cell-targeting specificity to cells that express the complementary receptor pair. In this report, we developed and tested a synthetic multivalent ligand consisting of glucagon-like peptide-1 (GLP-1) linked to glibenclamide (Glb) for signaling efficacy in β-cells. Expression of receptors for these ligands, as a combination, are relatively specific to the β-cell in the pancreas. The multivalent GLP-1/Glb increased both intracellular cAMP and Ca2+ , although Ca2+ responses were significantly depressed compared to the monomeric Glb. Moreover, GLP-1/Glb increased glucose-stimulated insulin secretion in a dose-dependent manner. However, unlike the combined monomers, GLP-1/Glb did not augment insulin secretion at non-stimulatory glucose concentrations in INS 832/13 β-cells or human islets of Langerhans. These data suggest that linking two binding elements into a single bivalent ligand, such as GLP-1 and Glb, can provide a unique functional agent targeted to β-cells.