To assess the relationship between cardiac and extra-cardiac dysfunction in diabetic autonomic neuropathy, the gastric acid output and the pancreatic polypeptide (hPP) secretion in response to sham feeding were evaluated in diabetic patients with (group 1) and without (group 2) cardiac autonomic neuropathy (CAN), and in normal subjects (group 3). All patients assigned to the group with CAN exhibited an impaired beat-to-beat heart rate variation during deep breathing. The basal gastric acid output was comparable in the three groups (1.3 +/- 0.5, 2.8 +/- 1.5, and 3.9 +/- 1.5 mmol/h, respectively). In contrast, the gastric acid output stimulated by sham feeding was significantly lower in patients with CAN (5.3 +/- 1.3 mmol/h) than in diabetic subjects without CAN (14.0 +/- 3.5 mmol/h; P less than 0.01) and in controls (10.9 +/- 3.1; P less than 0.05). The maximal gastric acid secretion capacity, determined after pentagastrin injection, was similar in all patients. Mean basal hPP concentrations were comparable in the three groups (185 +/- 53 pg/ml, 131 +/- 29 pg/ml, and 116 +/- 19 pg/ml). In the controls and diabetic subjects without CAN, a significant mean 60% increase of the hPP levels above basal values was observed during sham feeding. In contrast, no significant hPP response occurred in the group with CAN. These data suggest that diabetic CAN is associated with dysfunctions of the vagal pathways controlling the gastric acid output and the hPP secretion. Moreover, the results demonstrate a strong association between cardiac autonomic neuropathy and gastric vagal neuropathy (P less than 0.001).