Inhibition of glycogenolysis enhances gluconeogenic precursor
uptake by the liver of conscious dogs..
Shiota, Masakazu, Patricia A. Jackson, Hilmar Bischoff, Michael
McCaleb, Melanie Scott, Michael Monohan, Doss W. Neal, and Alan D.
Cherrington.
Department of Molecular Physiology and Biophysics, Vanderbilt
University School of Medicine, Nashville, TN 37232-0615; Bayer
Research Center, West Haven, CT 06516-4175.
APStracts 4:0133E, 1997.
We investigated the effect of inhibiting glycogenolysis on
gluconeogenesis in 18 h-fasted conscious dogs using intragastric
administration of BAY R3401, a glycogen phosphorylase inhibitor.
Isotopic ([3-3H]-glucose and [U-14C]-alanine) and A-V 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 secretion were inhibited
with somatostatin (0.8 [mu]g[acute]akg-1[acute]amin-1) and the two
hormones were replaced intraportally (insulin; 0.25mU[acute]akg
-1[acute]amin-1, glucagon; 0.6 ng[acute]akg-1[acute]amin-1). Drug (DG)
(10 mg/kg) or placebo (PG) were given after the control period.
Insulin and glucagon were kept at basal levels in the first test
period after which glucagon was increased. As a result portal
glucagon increased from 81 +/- 6 to 307 +/- 33 and from 73 +/- 7 to
287 +/- 16 pg/ml in PG and DG, respectively. BAY R3401 decreased
tracer-determined endogenous glucose production (Ra; 14 +/- 1 to 7
+/- 1 [mu]mol[acute]akg-1[acute]amin-1; P<0.05) and net hepatic
glucose output (NHGO: 11 +/- 1 to 3 +/- 2 [mu]mol[acute]akg
-1[acute]amin-1; P<0.05) during test period one. It increased the
net hepatic uptake of gluconeogenic substrates (lactate, glycerol and
amino acids) from 9.0 +/- 2.0 to 11.6 +/- 0.6 [mu]mol[acute]akg
-1[acute]amin-1. Placebo had no effect on Ra or the uptake of
gluconeogenic precursors by the liver. Basal glycogenolysis was not
altered by placebo (7.3 +/- 0.5 to 7.6 +/- 0.8 [mu]mol glucosyl
unit[acute]akg-1[acute]a min-1) but was decreased by drug (9.1 +/-
0.7 to 1.5 +/- 0.2 [mu]mol glucosyl unit[acute]akg-1[acute]amin-1)
(P<0.05).
The rise in glucagon increased Ra by 22 +/- 3 (P<0.05) and by 8 +/-
2 [mu]mol[acute]akg-1[acute]amin-1 (P<0.05) (at 10 min) in PG and
DG, respectively. The rise in glucagon caused little change in the
net hepatic uptake of gluconeogenic substrates in PG (8.2 +/- 0.6 to
9.0 +/- 1.0 [mu]mol[acute]akg-1[acute]amin-1) but increased it
markedly (11.6 +/- 0.6 to 15.4 +/- 1.0 [mu]mol[acute]akg
-1[acute]amin-1; P<0.05) in DG. Glucagon increased glycogenolysis by
22.1 +/- 2.5 (P<0.05) and by 7.8 +/- 1.6 [mu]mol[acute]akg
-1[acute]amin-1 (P<0.05) in PG and DG, respectively. The amount of
glycogen synthesized from gluconeogenic carbon was four times higher
in DG (48.6 +/- 9.7 [mu]mol glucosyl unit/kg) than in PG (11.3 +/-
1.7 [mu]mol glucocyl unit/kg) (P<0.05). We conclude that BAY R3401
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.
Received 5 November 1996; accepted in final form 12 June 1997
APS Manuscript Number E557-6.
Article publication pending Am. J. Physiol. (Endocrinol. Metab.).
ISSN 1080-4757 Copyright 1997 The American Physiological Society.
Published in APStracts on 1 July 1997