GLP-1(7–36)amid (GLP-1) mediates the ‘ileal brake’ in human

Nutrients appearing in the distal intestine induce a delay of upper gastrointestinal transit and inhibit gastropancreatic secretion. This ‘ileal brake’ is the primary inhibitory feedback mechanism that controls transit and digestion of a meal. The factors mediating this response are unknown. GLP-1 is a gut hormone postprandially released from intestinal L-cells. Well known endocrine effects of GLP-1 are stimulation of insulin and inhibition of glucagon release. However, the importance of the predominant presence of L-cells within the lower gut is not known. As GLP-1 is released by ileal nutrients, it is suggested as a humoral mediator of the ileal brake. Therefore, we examined the effects of ileal nutrients on pancreatic enzyme and gastric acid secretion with and without the specific GLP-1 receptor antagonist exendin(9–39).

Methods: In 12 healthy volunteers, an amino acid solution (3ml/min, 0.6 kcal/min) was perfused into the duodenum stimulating pancreatic enzyme and gastric acid secretion. After 40min, a mixed liquid meal (90ml, 44 kcal, starch, maltose, sodium oleate, lipid) was perfused for 15min into the ileum approximating the amount of physiologically unabsorbed nutrients. Gastroduodenal secretion was sampled in 10-min intervals until 240min after ileal perfusion and quantified using double-marker dilution technique. On 2 days in random order, Ex-9 (300 pmol×kg-1×min-1) or saline were IV infused. The output of gastric acid, amylase and trypsin was measured.

Results: Duodenal amino acids significantly increased the output of gastric acid and pancreatic enzymes on both study days (p<0.05). Ileal nutrient perfusion induced the ileal brake by causing a pronounced reduction of endogenously stimulated gastropancreatic secretion. The latter was markedly inhibited by IV Ex-9 (see table).

Conclusions: Physiological amounts of nutrients within the ileum induce a prolonged inhibition of gastric acid and pancreatic enzyme secretion. As this ‘ileal brake’ is largely prevented by the GLP-1 receptor antagonist, we suggest GLP-1 as mediator of this intestino-gastropancreatic reflex. We conclude that beside its endocrine action, GLP-1 plays an important role as an enterogastrone. This may explain the very high densities of L-cells within the ileum and colon.