Glucagon-like peptide (GLP)-2 is formed from proglucagon in the intestinal L cells and is secreted postprandially in parallel with the insulinotropic hormone GLP-1, the latter of which, in addition, acts to inhibit gastric secretion and motility by inhibiting central parasympathetic outflow. We now studied the effect of GLP-2 on gastric secretion stimulated by sham feeding to test the hypothesis that also GLP-2 acts as an enterogastrone. Eight healthy volunteers were studied twice on separate days. They were sham fed with and without GLP-2 infused iv at a rate of 0.8 pmol/kg x min. Gastric contents were aspirated continuously by a nasogastric tube for determination of acid secretion, volume, and osmolarity. Sham feeding increased gastric acid secretion nearly 5-fold. Infusion of GLP-2 reduced incremental acid secretion by 65+/-6%, compared with saline infusion (delta8.75+/-0.37 vs. delta3.04+/-0.47 mmol x 60 min; P<0.01). Plasma concentrations of GLP-2 rose from a basal mean of 3.3+/-0.9 to a mean of 115+/-8 pmol/L (range, 57-149 pmol/L) during infusion of GLP-2 and remained at basal level during saline infusion. Plasma concentrations of GLP-1, gastrin, cholecystokinin, and secretin remained low and unchanged on both study days. We conclude that GLP-2 is a powerful inhibitor of gastric acid secretion in man. Further investigations will show to what extent GLP-2 contributes to the inhibitory effects on gastric secretion exerted by hormones from the distal small intestine, under physiological circumstances.