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Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0615; and Bayer Research Center, West Haven, Connecticut 06516-4175
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
([3-3H]glucose and
[U-14C]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 µg · kg
1 · min1),
and the two hormones were replaced intraportally (insulin: 0.25 mU · kg1 · min1;
glucagon: 0.6 ng · kg1 · min1).
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 · kg1 · min1;
BAY R 3401 decreased tracer-determined endogenous glucose production [rate of glucose production
(Ra): 14 ± 1 to 7 ± 1 µmol · kg1 · min1]
and net hepatic glucose output (11 ± 1 to 3 ± 2 µmol · kg1 · min1)
during test
1. It increased the net hepatic uptake
of gluconeogenic substrates from 9.0 ± 2.0 to 11.6 ± 0.6 µmol · kg1 · min1.
Basal glycogenolysis was decreased by drug (9.1 ± 0.7 to 1.5 ± 0.2 µmol glucosyl
U · kg1 · min1).
Placebo had no effect on Ra or the
uptake of gluconeogenic precursors by the liver. The rise in glucagon
increased Ra by 22 ± 3 and by
8 ± 2 µmol · kg1 · min1
(at 10 min) in placebo and drug, respectively. The rise in glucagon caused little change in the net hepatic uptake
(µmol · kg1 · min1)
of gluconeogenic substrates in placebo (8.2 ± 0.6 to 9.0 ± 1.0) but increased it 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 µmol · kg1 · min1
in placebo and drug, respectively. The amount of glycogen (µmol 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.
BAY R 3401; glucagon
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