Inhibition of glycogenolysis enhances gluconeogenic precursor uptake by the liver of conscious dogs

We investigated the effect of inhibiting glycogenolysis on gluconeogenesis in 18-h-fasted conscious dogs with the use of intragastric administration of BAY R 3401, a glycogen phosphorylase inhibitor. Isotopic ([3-H-3]glucose and [U-C-14]alanine) and arteriovenous difference methods were used to assess glucose metabolism. Each study consisted of a 100-min equilibration, a 40-min control, and two 90-min test periods. Endogenous insulin and glucagon secretions were inhibited with somatostatin (0.8 mu g.kg(-1).min(-1)), and the two hormones were replaced intraportally (insulin: 0.25 mU.kg(-1).min(-1); glucagon: 0.6 ng.kg(-1).min(-1)). Drug (10 mg/kg) or placebo was given after the control period. Insulin and glucagon were kept at basal levels in the first test period, after which glucagon infusion was increased to 2.4 ng.kg(-1).min(-1); BAY R 3401 decreased tracer-determined endogenous glucose production [rate of glucose production (R-a): 14 +/- 1 to 7 +/- 1 mu mol.kg(-1).min(-1)] and net hepatic glucose output (11 +/- 1 to 3 +/- 2 mu mol.kg(-1).min(-1)) during test 1. It increased the net hepatic uptake of gluconeogenic substrates from 9.0 +/- 2.0 to 11.6 +/- 0.6 mu mol.kg(-1).min(-1). Basal glycogenolysis was decreased by drug (9.1 +/- 0.7 to 1.5 +/- 0.2 mu mol glucosyl U.kg(-1).min(-1)). Placebo had no effect on R-a or the uptake of gluconeogenic precursors by the liver. The rise in glucagon increased R, by 22 +/- 3 and by 8 +/- 2 mu mol.kg(-1).min(-1) (at 10 min) in placebo and drug, respectively. The rise in glucagon caused little change in the net hepatic uptake mu mol.kg(-1).min(-1) of gluconeogenic substrates in placebo (8.2 +/- 0.6 to 9.0 +/- 1.0) but increased in markedly (11.6 +/- 0.6 to 15.4 +/- 1.0) in drug. Glucagon increased glycogenolysis by 22.1 +/- 2.5 and by 7.8 +/- 1.6 mu mol.kg(-1).min(-1) in placebo and drug, respectively. The amount of glycogen (mu mol glucosyl U/kg) synthesized from gluconeogenic carbon was four times higher in drug (48.6 +/- 9.7) than in placebo (11.3 +/- 1.7). We conclude that BAY R 3401 caused a marked reduction in basal and glucagon-stimulated glycogenolysis. As a result of these changes, there was an increase in the net hepatic uptake of gluconeogenic precursors and in glycogen synthesis.