The early (10 minute) immunoreactive insulin release in response to various stimuli in patients with severe pancreatic exocrine insufficiency was compared to controls. The mean 10 minute incremental area of the response to combined glucose, glucagon and tolbutamide was severely reduced in patients (728 ± 287.7 vs 2714 ± 479.9 µU minutes; p < 0.0025). Mean insulin responses to oral glucose were similar in patients and controls, but the insulin response to intravenous glucose was absent in 4 of 6 patients (patients 79.0 ±51.2 vs controls 874 ± 171.9 µU/minutes; p < 0.0025). All patients retained some insulin responsiveness to intravenous arginine. Intravenous secretin produced an insulin response in all patients (57.6 ± 17.6 and controls 220± 70.8 µU minutes; p < 0.05). Cholecystokinin pancreozymin (CCK-PZ) produced an insulin response in 5 of 6 patients (38± 17.9 vs 158 ± 30.7 µU minutes; p < 0.005). It is concluded that in chronic pancreatitis - (1) the beta cell glucose sensitive mechanism may be defective, while the glucose-stimulated pathway of the entero-insular axis is maintained; (2) Arginine-induced insulin secretion is mediated differently from the intravenous glucose-induced response; (3) insulin responses to Secretin and CCK-PZ are retained, which may partially explain the insulin response to oral glucose.