In normal subjects, the early human pancreatic polypeptide increase induced by food is mainly dependent on vagal activity. Parasympathetic function and plasma human pancreatic polypeptide response to a protein rich meal were evaluated in 105 insulin nondependent diabetic patients: 20 only with autonomic neuropathy (group A), diagnosed by clonidin test and tests of cardiovascular reflexes, 35 patients with neurophysiological evidence of polyneuropathy (group B), 30 patients with autonomic neuropathy and polyneuropathy (group C) and 20 patients without any sign of neuropathy (group D). Plasma human pancreatic polypeptide levels were determined by radioimmunoassay using an anti-human pancreatic polypeptide antiserum. Blood was taken at 0, 45 and 60 minutes after the beginning of the meal. In groups A and C, the meal induced human pancreatic polypeptide increase was significantly lower than in group D (45. min:, 65.8 + 16.2(A), 54.0 + 19.2 pg/ml (C) in regard to 130.0 + 27.6 pg/ml (D); 60, min: 55.2 + 15.6 (A), 37.0 + 11.2 pg/ml (C) in regard to 121.7 + 15.4 pg/ml (D). In group B patients had a marked increase of peptide, similar to that in diabetics without neuropathy. These results suggest that diabetic autonomic neuropathy is associated with the dysfunction of human pancreatic polypeptide secretion and that evaluation of his response to test meal may be a sensitive and simple method for the assessment of parasympathetic impairment in diabetics.