The response of human pancreatic polypeptide (hPP) to a protein-rich meal was investigated in 4 groups of subjects: 1) normal controls (n = 11); 2) patients with recent onset type I diabetes, showing no sign of cardiovascular autonomic neuropathy (CAN) (n = 9); 3 and 4) patients with long standing type I diabetes without and with overt CAN (n = 12 and 10 respectively). Patients belonging the group 3 and 4 had equivalent duration of diabetes (17 and 20 years respectively). The mean integrated early hPP responses (0-30 minutes) were respectively (ng. min. ml-1; mean with range): 1) 9.4 (3.3-24.2); 2) 7.4 (0.7-22); 3) 4.8 (0-14.2); 4) 5.4 (0-14.9). The integrated total responses (0-120 minutes) were respectively: 1) 44.0 (12.7-98.7); 2) 39.0 (11.6-118.1); 3) 29.8 (0-81.2); 4) 25.9 (0-71.6). In the group with long standing diabetes, the early and total integrated hPP responses of the patients with CAN did not differ significantly from those without CAN. Early hPP responses of patients with long standing diabetes (group 3 and 4) were slightly (P less than 0.05) lower than those of controls. 5 patients with long standing diabetes had no detectable post-prandial hPP rise, a feature never observed in normals or recent onset diabetics. Two of these had no sign of CAN. These data suggest that an absence of hPP response to a mixed meal may be one of the expression of digestive autonomic neuropathy in long standing diabetes and that impaired hPP response may sometimes be dissociated from overt CAN.