The exercise-induced rise in glucagon is an important regulator of hepatic glutamine extraction and urea output

The role of the exercise-induced rise in glucagon in the regulation of hepatic glutamine extraction and urea output were studied during moderate treadmill exercise in ten 18-h fasted dogs. Surgery was done at least 16 days prior to study at which time catheters were implanted in the carotid artery, portal vein and hepatic vein for sampling and the portal vein and vena cava for infusions. In addition, Doppler flow cuffs were implanted on the portal vein and hepatic artery. Experiments consisted of a 120 min equilibration period, a 30 min basal period and a 150 min exercise period. Pancreatic hormones were clamped at basal levels before exercise (using somatostatin and intraportal hormone replacement), then altered during exercise to simulate the exercise-induced fall in insulin, while glucagon was 1) increased (n=5) to mimic its exercise-induced rise (SG) or 2) maintained (n=5) at a basal level (BG). Isotopic (5-¹⁵N-glutamine) dilution and arteriovenous difference methods were used to assess hepatic function. Data presented are the exercise-induced changes from basal. Exercise led to a fall in arterial glutamine of 151 ± 49 μM in SG, but to a small rise of 65 ± 42 μM in BG. Unidirectional glutamine uptake and fractional extraction rose by 4.7 ± 1.7 μmol/kg·min and 0.38 ± 0.09 in SG, but were unchanged in BG (1.1 ± 1.6 n mol/kg·min and 0.07 ± 0.12). The greater rate of hepatic glutamine uptake was concurrent with an increase in net hepatic urea output of 15.3 ± 5.0 n mol/kg min in SG. Net hepatic urea output, however, was unchanged in BG (0.2 ± 2.6 n mol/kg·min). In conclusion, the increased hepatic glutamine extraction during exercise is caused by the rise in glucagon. Through this mechanism, glucagon is a primary regulator of hepatic nitrogen disposal and urea formation during exercise.