The effect of pancreatin on insulinopenic diabetes was studied in 10 patients with chronic pancreatitis and exocrine function impairment. All patients were treated for 4 days in a randomized crossover trial with either pancreatin (6 x 2 capsules, 6 x 300 mg/d) or placebo. Blood glucose levels were determined 7 times every day and night. On day 5, the patients were studied by a glucose sensor with adjustment of blood glucose to 120 mg/dl until 8.00 in the morning. A test meal was applied with 2 capsules pancreatin or placebo. Blood glucose and plasma levels of C-peptide, glucagon and pancreatic polypeptide (PP) were determined in regular intervals for 4 hours. Blood glucose levels were not significantly altered by pancreatin. As shown by M-value according to Schlichtkrull (21.6 +/- 2.9 versus 32.4 +/- 7.4), there was a tendency towards smaller oscillations of blood glucose with pancreatin treatment. C-peptide levels (basal 0.081 +/- 0.008 ng/ml; postprandial 0.119 +/- 0.013 ng/ml) were not significantly altered by the administration of pancreatin. Basal and postprandial glucagon and PP plasma levels were not influenced by pancreatin. From these results, we conclude that pancreatic enzyme supplementation does not significantly alter the requirement of insulin in patients with diabetes mellitus secondary to chronic pancreatitis. Possible disturbances of the enteroinsular axis are discussed in this paper.