In diabetic patients, several factors contribute to volume expansion and have to be counteracted by humoral and neuronal feedback control systems. We investigated N-terminal proatrial natriuretic factor (ANF1-98) and digoxin-like immunoreactive factor (DLIF), which are two counteracting hormones, and their interrelationship, with additional consideration given to autonomic nervous function in diabetic patients. ANF1-98 and DLIF were measured in 64 diabetic patients. Autonomic nervous function was assessed using nine autonomic nervous function tests. The patients were subdivided into two groups, one with four or more (group 1) and one with less than four abnormal results in autonomic function tests (group 2). Compared with group 2, group 1 demonstrated detectable DLIF levels less often (17.2 vs. 45.7, P = 0.0195) and increased levels of ANF1-98 (mean +/- SEM: 850.0 +/- 108.8 vs. 554.8 +/- 45.9 pmol/L, P = 0.0099). However, the groups did not differ in blood pressure, daily sodium, and daily potassium excretion. The number of abnormal autonomic function tests correlated significantly with ANF1-98 (P = 0.0002). In patients with detectable DLIF, DLIF correlated with ANF1-98 (P = 0.0080). These results demonstrate close interactions between the autonomic nervous system and the two natriuretic hormones. In patients with autonomic nervous dysfunction, higher levels of ANF may possibly compensate for the lack of the natriuretic DLIF to counteract hypertension and chronic volume expansion.