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.

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