In normal subjects during moderate exercise there is a strong negative correlation between plasma glucose and hepatic glucose output (HGO) suggesting a negative feedback regulation of HGO by plasma glucose. Little information is available about HGO responses to exercise in non-insulin-dependent diabetes mellitus (NIDDM). To determine whether the same feedback relationship is operative, we have compared the glucose turnover responses to moderate exercise (50% Vo2max for 60 minutes) of nonobese non-insulin-dependent diabetic subjects (NIDDM, n = 7) with a group of age-matched controls (n = 5). Glucose turnover responses to exercise in NIDDM were heterogeneous. Plasma glucose showed sustained falls, no change, or sustained rises in different individuals. Similarly, HGO responses ranged from undetectable to responses comparable to those of normal subjects. The mean integrated HGO response in NIDDM was significantly reduced compared with controls (11 +/- 6 [SEM] v 33 +/- 7 mmol/h/70 kg, P less than .05); mean glucose utilization response was also reduced but not significantly different from controls (NIDDM 18 +/- 5 v control 35 +/- 6). In NIDDM there was no significant feedback-control relationship between plasma glucose and HGO (r = -0.20, P = NS) in contrast to controls (r = -0.87, P less than .01). We conclude that feedback control of HGO by plasma glucose during moderate exercise is impaired in NIDDM. This impairment may be due to defective nonpancreatic glucoregulatory mechanisms.