The influence of impaired digestion on nutrient induced release of gastric inhibitory polypeptide (GIP) and insulin have been investigated in patients with chronic pancreatitis. All patients had massive steatorrhea (> 25 g/24 h), and glucose intolerance. A standard liquid test meal comprising fat and glucose were ingested with or without pancreatic enzyme substitution (9.0 g pancreatin). In the presence of pancreatin the response of serum levels of GIP to the test meal was significantly enhanced (81.2 vs 194.5 microgram/l X 180 min). Concurrently, the insulin response was augmented (3.4 vs 6.4 U/l X 180 min), resulting in improved glucose tolerance. Addition of pancreatin also significantly augmented the GIP response to oral fat (100 g), but not to oral glucose (100 g). In patients with pancreatogenic steatorrhea the insulin response to an IV glucose infusion (0.7 g/kg/h for 90 min) was augmented by oral fat only after addition of 9.0 g pancreatin to the fat load (3.5 vs 7.3 U/l X 180 min). After restoration of the GIP response to fat by pancreatin, the inhibitory effect of IV glucose on fat-induced GIP increase was restored. These data indicate that the GIP response to a mixed meal or triglycerides is dependent on the absorption of nutrients. In patients with chronic pancreatitis improvement of pancreatogenic insufficiency reverses the impaired GIP response, restores the incretin effect of fat, and improves glucose tolerance.