Physical exercise is often performed during absorption of meals. We have characterized the metabolic response to 45 min of moderate exercise (approximately 55% of estimated maximal oxygen uptake) beginning 30 min after breakfast in seven healthy controls. Nine insulin-dependent diabetes were studied in an identical manner, with glycemia controlled by a closed-loop "artificial endocrine pancreas" controlled by a closed-loop "artificial endocrine pancreas" (AEP). Responses were compared to those during breakfast without exercise. In the controls, onset of exercise rapidly reversed the rise in both glycemia and insulin (IRI) that occurred with breakfast alone, both returning to fasting levels (glycemia, 80 +/- 3 mg/dl; IRI, 0.38 +/- 0.10 ng/ml). After exercise, small and transient increments occurred (glycemia, 33 +/- 6 mg/dl; IRI, 0.81 +/- 0.15 ng/ml). In the diabetics, prior overnight intravenous insulin normalized fasting glycemia (98 +/- 4 mg/dl), and its postbreakfast excursion was identical to that of controls, as were those of most measured substrates. Similarly, with exercise, glycemia returned rapidly to fasting levels, accompanied by an appropriate decrease in insulin infusion rates. "Free" IRI levels mirrored changes in infusion rates by the AEP, with a decrease in insulin requirement of 30% during exercise as compared to breakfast alone (P less than 0.05). Thus, in both diabetics treated with the AEP and in normals, the responses to postprandial exercise required rapid modulation of insulin delivery. To demonstrate the effect of postprandial exercise on preprogrammed open-loop insulin replacement, four diabetic subjects were studied during breakfast with and without exercise while receiving a fixed open-loop insulin infusion pattern (6.1 +/- 0.7 U over 140 +/- 8 min). The glycemic response to breakfast alone was entirely normalized. However, symptomatic hypoglycemia occurred in all subjects when exercise was initiated 30 min after breakfast. The diabetic responses to closed-loop insulin infusion provide important data in defining the appropriate preprogrammed open-loop insulin infusion pattern for postprandial exercise.