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 ([3-3H]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 microgram.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 (Ra): 14 +/- 1 to 7 +/- 1 mumol.kg-1.min-1] and net hepatic glucose output (11 +/- 1 to 3 +/- 2 mumol.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 mumol.kg-1.min-1. Basal glycogenolysis was decreased by drug (9.1 +/- 0.7 to 1.5 +/- 0.2 mumol glucosyl U.kg-1.min-1). 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 mumol.kg-1.min-1 (at 10 min) in placebo and drug, respectively. The rise in glucagon caused little change in the net hepatic uptake (mumol.kg-1.min-1) 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 mumol.kg-1.min-1 in placebo and drug, respectively. The amount of glycogen (mumol 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.
Shiota
M
M
Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0615, USA.
Jackson
P A
PA
Bischoff
H
H
McCaleb
M
M
Scott
M
M
Monohan
M
M
Neal
D W
DW
Cherrington
A D
AD
D000704:Analysis of Variance; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D004285:Dogs; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005215:Fasting; D005260:Female; D005934:Glucagon / Q000097:blood / Q000494:pharmacology; D005943:Gluconeogenesis / Q000187:drug effects / Q000502:physiology*; D007328:Insulin / Q000097:blood; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008112:Liver Glycogen / Q000378:metabolism*; D008297:Male; D006005:Phosphorylases / Q000037:antagonists & inhibitors; D012016:Reference Values; D013004:Somatostatin / Q000494:pharmacology
D001786:Blood Glucose; D004791:Enzyme Inhibitors; D007328:Insulin; D008112:Liver Glycogen; D013004:Somatostatin; D005934:Glucagon; D006005:Phosphorylases