Exercise-Induced Rise in Glucagon and Ketogenesis During Prolonged Muscular Work

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 μU/ml), SG (11 ± 1 to 6 ± 1 μU/ml), and BG (10 ± 1 to 6 ± 1 μU/ml). In C, SG, and BG, free-fatty acid (FFA) levels rose from 941 ± 81,1240 ± 155, and 938 ± 36 μeq/L at rest to 1615 ± 149, 1558 ± 175, and 1391 ± 160 μeq/L with exercise. In C, SG, and BG, net hepatic FFA uptake was 2.9 ± 0.4, 4.6 ± 0.6, and 3.6 ± 0.3 μmol · kg⁻¹ · min⁻¹ at rest and rose to 7.8 ± 1.8, 7.2 ± 0.8, and 7.1 ± 1.3 μmol · kg⁻¹ · min⁻¹ with exercise. Arterial blood β-hydroxybutyrate levels rose from 20 ± 3 to 69 ± 25 μM and from 21 ± 4 to 66 ± 16 μM by the end of exercise in C and SG but from only 16 ± 2 to 27 ± 5 μM in BG. Net hepatic β-hydroxybutyrate output rose by 2.3 ± 0.6 and 2.9 ± 1.0 μmol · kg⁻¹ · min⁻¹ with exercise in C and SG compared to an increase of only 0.6 ± 0.2 μmol · kg⁻¹ · min⁻¹ in BG. Arterial blood acetoacetate did not increase appreciably from resting levels of 86 ± 7, 78 ± 7, and 60 ± 5 μM during exercise in C, SG, or BG. In C and SG, net hepatic acetoacetate output increased from 0.4 ± 0.1 and 0.9 ± 0.2 μmol · kg⁻¹ · min⁻¹ at rest to 1.7 ± 0.5 and 1.5 ± 0.3 μmol · kg⁻¹ · min⁻¹ by the end of exercise. In BG, acetoacetate production increased from 0.5 ± 0.1 to only 0.8 ± 0.2 μmol · kg⁻¹ · min⁻¹with exercise. The intrahepatic ketogenic efficiency was 0.13 ± 0.02, 0.10 ± 0.01, and 0.09 ± 0.01 at rest in C, SG, and BG. This variable was 0.16 ± 0.06 and 0.19 ± 0.04 by the end of exercise in C and SG but only 0.07 ± 0.02 in BG. These data indicate that, in normal dogs, the exercise-induced increment in glucagon is essential for the full rise in hepatic ketone output during muscular work and that this effect of the increase in glucagon is mediated by intrahepatic mechanisms.