Quantitation of hepatic glucose fluxes and pathways of hepatic
glycogen synthesis in conscious mice.
Massillon, Duna, Wei Chen, Meredith Hawkins, Rong Liu, Nir Barzilai,
and Luciano Rossetti.
Division of Endocrinology, Department of Medicine, Albert Einstein
College of Medicine, Bronx, NY 10461
APStracts 2:0158E, 1995.
We examined the relationship between the plasma glucose concentration
(PG) and the pathways of hepatic glucose production (HGP) and
glycogen formation in conscious mice. Mice were studied with the
euglycemic hyperinsulinemic and the hyperglycemic clamp technique
following 6 h fast: 1) Euglycemic (6.7+/-0.2 mM) hyperinsulinemia (18
mU/kg.min; 800 [mu]U/ml); 2) Hyperglycemic (15.3+/-0.4 mM)
hyperinsulinemia (800 [mu]U/ml). All mice received an infusion of [3
-3H]-glucose and [U-14C]-lactate. The ratio between hepatic 3H-UDPG SA
and portal vein 3H-glucose SA measured the portion of total glucose
output and glycogen synthesis directly derived from plasma glucose.
The ratio between hepatic 14C-UDPG SA and 2x14C-PEP SA measured the
portion of total glucose output and glycogen synthesis derived from
PEP-gluconeogenesis. After 6h fast, HGP averaged 170 [mu]mol/kg.min
in both groups. During euglycemic and hyperglycemic hyperinsulinemia,
HGP was decreased by 53% (to 76.7+/-11.1 [mu]mol/kg.min; p<0.01)
and 74% (to 43.3+/-7.2 [mu]mol/kg.min; p<0.01) in euglycemia and
hyperglycemia, respectively. Hyperglycemia increased glucose cycling
(by 2.1 fold; p<0.01) and the contribution of gluconeogenesis to
HGP (88 vs 43 %; p<0.01), while decreasing that of
glycogenolysis (12 vs 57%; p<0.01). Under similar plasma insulin
concentrations, the % of neo-synthetized hepatic glycogen formed via
the direct pathway (glucose --> glucose-6-phosphate -->
glycogen) was markedly increased during hyperglycemia (53+/-2% vs
23+/-3%; p<0.01). These data indicate that the assessment of
hepatic glucose fluxes can be accomplished in conscious unrestrained
mice, and, in the presence of hyperinsulinemia, hyperglycemia causes:
(a) a further inhibition of HGP mainly via inhibition of
glycogenolysis and increase in hepatic glucose cycling; and (b) a 5
fold stimulation in the direct pathway of hepatic glycogen formation.
Received 20 April 1995; accepted in final form 21 July 1995.
APS Manuscript Number E184-5.
Article publication pending Am. J. Physiol. (Endocrinol. Metab.).
ISSN 1080-4757 Copyright 1995 The American Physiological Society.
Published in APStracts on 30 July 1995.