We have quantitatively assessed the percentage of lower limb arterio-venous (a-v) shunting using a radioisotopic technique and correlated it with autonomic neuropathy evaluated by cardiovascular tests. We have studied three groups of diabetic patients: Group A, 12 non-neuropathic subjects without foot lesions; Group B, 12 neuropathic subjects without foot lesions; Group C, 12 neuropathic subjects with recurrent foot ulcers. Shunting was higher in Group C (10.4 +/- 2.7%) than in Group B (6.8 +/- 2.3%, P less than 0.01) and Group A (3.8 +/- 1.2%, P less than 0.001). Shunts in Group B were higher than in Group A (P less than 0.05). All the tests exploring autonomic function were more impaired in Groups B and C than in Group A, with no difference between Groups B and C. A direct correlation was found between a-v shunting and the following cardiovascular tests: postural hypotension (PH) (r = 0.41, P less than 0.02), sustained handgrip (SH) (r = 0.56, P less than 0.001), deep breathing (DB) (r = 0.40, P less than 0.005) and lying to standing (LS) (r = 0.44, P less than 0.01). A positive correlation was also found between a-v shunts and duration of the disease (r = 0.62, P less than 0.001). Arterio-venous shunting was found to be directly related to autonomic neuropathy even if the higher shunting found in the patients with foot ulcers was not related to a higher degree of autonomic involvement; in addition, this group of patients was characterized by having a more advanced sensory and motor neuropathy. In conclusion, autonomic neuropathy, through its influence on a-v shunts, may play a role in the pathogenesis of diabetic foot, but peripheral neuropathy probably plays a key role in conditioning the development of the overt clinical manifestations of diabetic foot.