Inability of hyperglycemia to counter the ability of glucagon to increase net glucose output and activate glycogen phosphorylase in the perfused rat liver

Abstract

We examined the ability of hyperglycemia to alter the ability of glucagon to activate phosphorylase and stimulate glucose output in perfused rat livers. The livers were perfused with a Krebs-Henseleit buffer containing washed bovine erythrocytes and albumin at 37°C for 90 or 120 minutes. In the first 60 minutes, the livers were perfused with insulin (10 μU/mL), glucagon (11 pg/mL), and glucose (105, 230, or 440 mg/dL). In the second 30 or 60 minutes, the glucagon concentration in the perfusate was elevated to 44, 88, 176, or 352 pg/mL or the infusion of glucagon was terminated. In the presence of glucose at 105 mg/dL, the termination of glucagon infusion decreased phosphorylase activity and glucose output. In contrast, the elevation of glucagon from 11 to 352 pg/mL activated phosphorylase and increased net glucose output in a dose-dependent manner. A linear correlation was observed between net glucose output and glycogen phosphorylase activity. An elevation of the glucose concentration from 105 to 230 or 440 mg/dL decreased net glucose output from 0.81 ± 0.03 to 0.66 ± 0.09 or −0.004 ± 0.21 mg/min/100 g body weight, respectively, but did not cause significant change in phosphorylase-a activity (105 mg/dL, 50 ± 11; 230 mg/dL, 40 ± 2; 440 mg/dL, 69 ± 3 mU/mg protein). The elevation of the glucagon concentration from 11 to 88 μU/mL in the presence of glucose at 105, 230, or 440 mg/dL increased net glucose output by 0.65 ± 0.06, 0.61 ± 0.08 or 0.64 ± 0.26 mg/min/100 g body weight and raised phosphorylase-a activity by 65 ± 5, 82 ± 11, or 55 ± 4 mU/mg protein, respectively. These results suggest that hyperglycemia decreases net hepatic glucose output without changing the activity of phosphorylase-a. Further hyperglycemia does not alter the ability of glucagon to activate phosphorylase or to stimulate net hepatic glucose output.