THE POSITIVE CHARGE OF THE IMIDAZOLE SIDE-CHAIN OF HISTIDINE(7) IS CRUCIAL FOR GLP-1 ACTION

Glucagon-like peptide-1(7-36)amide/(7-37) (GLP-1) is an incretin hormo ne which plays an important role in postprandial glucose homeostasis. Since GLP-1 potentiates glucose-induced insulin secretion, stimulates insulin biosynthesis and inhibits glucagon release, it is a potential tool for the treatment of diabetes mellitus. For this, an exact unders tanding of the structural/functional moieties of the peptide is mandat ory. The present study investigates the importance of structural featu res of histidine(7) at the N-terminus for GLP-1 action. Based upon bin ding and activity data obtained from ten different GLP-1 analogues we show that not the positive charge of the free a-amino group but the po sitive charge of the imidazole side chain of histidine is crucial for GLP-1 action. The presence of a ring structure and a basic function as well as the correct positioning of both seems to be decisive.