[The intestinal hormone glucagon-like peptide 1 (GLP-1): from experiment to the clinic]. / Das Darmhormon Glucagon-like peptide-1 (GLP-1): aus dem Experiment in die Klinik.

A functional connection between the small intestine and endocrine pancreas was proved in the sixties, after it became possible to determine the exact amount of insulin in plasma. The insulin response after oral doses of glucose is substantially stronger than after intravenous doses of sugar, even when identical glucose plasma levels are attained. This incretin effect is explained by the connection of the entero-insular axis. The intestinal hormones, that are released by the small intestine after meals, circulate measurably in plasma, and strengthen the glucose-induced insulin secretion, are responsible for this effect. In addition to the classical incretin hormone "Gastric inhibitory polypeptide-1" (GIP), "Glucagon-like peptide-1" (GLP-1) is very interesting to investigators today. In a relatively short amount of time, GLP-1 has matured from a physiologically interesting incretin hormone candidate to a potentially therapeutical alternative for the treatment of diabetes mellitus. GLP-1 stimulates glucose-dependent insulin secretion, decreases plasma glucagon levels, delays gastric emptying, and putatively exerts an additional effect on peripheral glucose utilization. On top of that, GLP-1 has effects on the central nervous system thereby impacting on feeding behavior.

The positive charge of the imidazole side chain of histidine7 is crucial for GLP-1 action.

Glucagon-like peptide-1(7-36)amide/(7-37) (GLP-1) is an incretin hormone 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 understanding of the structural/functional moieties of the peptide is mandatory. The present study investigates the importance of structural features of histidine7 at the N-terminus for GLP-1 action. Based upon binding and activity data obtained from ten different GLP-1 analogues we show that not the positive charge of the free alpha-amino group but the positive 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.