These experiments examined the role of the exercise-induced increment in glucagon in the control of ketogenesis during prolonged moderate-intensity (100 m/min, 12% grade) treadmill exercise. Dogs were studied during 150 min of exercise with saline infusion alone (C; n = 6) with the glucagon levels clamped at basal values (somatostatin infusion with basal glucagon replacement and the normal fall in insulin simulated; BG; n = 5) or with the normal exercise-induced rise in glucagon simulated (somatostatin infusion with the rise in glucagon and the fall in insulin simulated; SG; n = 5). Glucose was infused as needed in SG and BG to maintain the glycemic response seen in C. In all dogs, catheters were inserted into the carotid artery and the portal and hepatic veins for blood sampling and the vena cava and the splenic vein for infusions. Glucagon rose from 62 +/- 5 and 57 +/- 4 pg/ml at rest to 104 +/- 20 and 120 +/- 12 pg/ml during exercise in C and SG but did not deviate from basal in BG (56 +/- 3 pg/ml). Insulin fell similarly from rest to the end of exercise in C (13 +/- 2 to 5 +/- 1 microU/ml), SG (11 +/- 1 to 6 +/- 1 microU/ml), and BG (10 +/- 1 to 6 +/- 1 microU/ml). In C, SG, and BG, free-fatty acid (FFA) levels rose from 941 +/- 81, 1240 +/- 155, and 938 +/- 36 mu eq/L at rest to 1615 +/- 149, 1558 +/- 175, and 1391 +/- 160 mu eq/L with exercise.2+n C,