INHIBITION OF GLYCOGENOLYSIS ENHANCES GLUCONEOGENIC PRECURSOR UPTAKE BY THE LIVER OF CONSCIOUS DOGS

We investigated the effect of inhibiting glycogenolysis on gluconeogen esis in 18-h-fasted conscious dogs with the use of intragastric admini stration of BAY R 3401, a glycogen phosphorylase inhibitor. Isotopic ( [3-H-3]glucose and [U-C-14]alanine) and arteriovenous difference metho ds were used to assess glucose metabolism. Each study consisted of a 1 00-min equilibration, a 40-min control, and two 90-min test periods. E ndogenous insulin and glucagon secretions were inhibited with somatost atin (0.8 mu g.kg(-1).min(-1)), and the two hormones were replaced int raportally (insulin: 0.25 mU.kg(-1).min(-1); glucagon: 0.6 ng.kg(-1).m in(-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 per iod, after which glucagon infusion was increased to 2.4 ng.kg(-1).min( -1); BAY R 3401 decreased tracer-determined endogenous glucose product ion [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 ris e in glucagon increased R, by 22 +/- 3 and by 8 +/- 2 mu mol.kg(-1).mi n(-1) (at 10 min) in placebo and drug, respectively. The rise in gluca gon 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. Glu cagon increased glycogenolysis by 22.1 +/- 2.5 and by 7.8 +/- 1.6 mu m ol.kg(-1).min(-1) in placebo and drug, respectively. The amount of gly cogen (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, the re was an increase in the net hepatic uptake of gluconeogenic precurso rs and in glycogen synthesis.