Therapeutic potential of a bi‐functional GLP‐1/Glibenclamide targeted to the pancreatic β‐cell

Abstract

Glucagon like Peptide 1 (GLP‐1) analogs and sulfonyurea drugs are used clinically to enhance pancreatic β‐cell function and treat diabetes. However, rapid degradation and off‐target effects limit their usefulness. Here we describe an approach for targeting β‐cells by synthesizing a bi‐functional agent composed GLP‐1 attached via a flexible linker to a Sulfonyurea receptor antagonist Glibenclamide (Glb). Microscopy shows that this bivalent ligand (Cy5 tagged) binds to, and is rapidly internalized into βTC3 cells which express both receptors. However, GLP‐1/Glb‐Cy5 did not bind significantly to PANC‐1 cells and exhibited right shifted binding to cells that express only one receptor. Glb increases cell Ca2+ and GLP‐1 elevates cAMP. In βTC3 cells, GLP‐1/Glb elicits a half maximal Ca2+ response at ~10nM, but the magnitude of the maximal Ca2+ response was significantly less than that observed for monomeric Glb (~25% of the Glb increase). Unlike the Ca2+response, cAMP production over a range of concentrations elicited by GLP‐1 and GLP‐1/Glb were essentially equal. Even though Ca2+ signaling is reduced, glucose activated insulin secretion remains potentiated by the GLP‐1/Glb ligand (353 +/− 63% increase). The bivalent ligand binds specifically to both receptors and activates signaling in β‐cells. These data suggest that the GLP‐1/Glb ligand has potential as a β‐cell specific therapeutic. Supported by JDRF