To determine the effect of diabetes mellitus on the renin-aldosterone system, independent of age, nephropathy, or hypertension, 16 normotensive diabetics with long-term disease (mean duration, 15 years) and no (14) or minimal (2) proteinuria, were compared to nine age-matched, normotensive controls. Plasma renin activity (PRA) measured supine and after 4 hours of quiet ambulation, both on an ad libitum diet and on Day 4 of a 10 mEq low sodium diet, was always lower in the diabetics (31%-56% of control values). After the combined stimulus of sodium depletion and ambulation, PRA was 2.2 +/- 0.4 in the diabetics compared to 3.4 +/- 0.2 ng/ml/hr in controls (p less than 0.025). On the low sodium diet, PRA and the postural response of PRA correlated directly with the degree of autonomic dysfunction as quantitated by the velocity of esophageal peristalsis (r = 0.60, p less than 0.05; r = 0.75, p less than 0.005 respectively), suggesting that autonomic neuropathy was an important factor contributing to low PRA in these patients. No other parameters correlated with PRA. Plasma renin substrate (PRS) tended to be lower in diabetics (1053 +/- 95 vs 1358 +/- 132 ng AI/ml; p less than 0.07) but not sufficiently so to account for the substantial difference in PRA. Furthermore, PRS did not correlate with PRA. Fasting blood sugar, while higher in diabetics (209 vs 96 mg/dl), and creatinine clearance, which was lower (112 +/- 13 vs 78 +/- 4 ml/min; p less than 0.01), also did not correlate with PRA. Other factors, including serum creatinine, serum potassium, urinary aldosterone, blood pressure, and body weight, and the responses of these parameters to sodium depletion, were similar in diabetics and controls. These data implicate visceral neuropathy as a major factor in the hyporeninemia of these diabetics.