A great deal is known about hepatic glucose production and its response to a variety of factors such as redox state, substrate supply and hormonal control, but the effects of these parameters on the flux through biochemical pathways which integrate to control glucose production are less clear. A combination of 13C and [2H]water tracers and NMR isotopomer analysis were used to investigate metabolic fluxes in response to altered cytosolic redox state and insulin. In livers isolated from fed mice and perfused with a mixture of substrates including lactate/pyruvate (10:1, w/w), hepatic glucose production had substantial contributions from glycogen, PEP (phosphoenolpyruvate) and glycerol. Inversion of the lactate/pyruvate ratio (1:10, w/w) resulted in a surprising decrease in the contribution from glycogen and an increase in that from PEP to glucose production. A change in the lactate/pyruvate ratio from 10:1 to 1:10 also stimulated flux through the tricarboxylic acid cycle (2-fold), while leaving oxygen consumption and overall glucose output unchanged. When lactate and pyruvate were eliminated from the perfusion medium, both gluconeogenesis and tricarboxylic-acid-cycle flux were dramatically lower. Insulin lowered glucose production by inhibiting glycogenolysis at both low and high doses, but only at high levels of insulin did gluconeogenesis or tricarboxylic-acid-cycle flux tend towards lower values (P<0.1). Our data demonstrate that, in the isolated mouse liver, substrate availability and cellular redox state have a dramatic impact on liver metabolism in both the tricarboxylic acid cycle and gluconeogenesis. The tight correlation of these two pathways under multiple conditions suggest that interventions which increase or decrease hepatic tricarboxylic-acid-cycle flux will have a concomitant effect on gluconeogenesis and vice versa.
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Research Article|
February 10 2006
Effects of insulin and cytosolic redox state on glucose production pathways in the isolated perfused mouse liver measured by integrated 2H and 13C NMR
Natasha Hausler;
Natasha Hausler
*Advanced Imaging Research Center, University of Texas Southwestern Medical Center, 5801 Forest Park Road, Dallas, TX 75235-9085, U.S.A.
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Jeffrey Browning;
Jeffrey Browning
*Advanced Imaging Research Center, University of Texas Southwestern Medical Center, 5801 Forest Park Road, Dallas, TX 75235-9085, U.S.A.
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Matthew Merritt;
Matthew Merritt
*Advanced Imaging Research Center, University of Texas Southwestern Medical Center, 5801 Forest Park Road, Dallas, TX 75235-9085, U.S.A.
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Charles Storey;
Charles Storey
*Advanced Imaging Research Center, University of Texas Southwestern Medical Center, 5801 Forest Park Road, Dallas, TX 75235-9085, U.S.A.
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Angela Milde;
Angela Milde
*Advanced Imaging Research Center, University of Texas Southwestern Medical Center, 5801 Forest Park Road, Dallas, TX 75235-9085, U.S.A.
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F. Mark H. Jeffrey;
F. Mark H. Jeffrey
*Advanced Imaging Research Center, University of Texas Southwestern Medical Center, 5801 Forest Park Road, Dallas, TX 75235-9085, U.S.A.
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A. Dean Sherry;
A. Dean Sherry
*Advanced Imaging Research Center, University of Texas Southwestern Medical Center, 5801 Forest Park Road, Dallas, TX 75235-9085, U.S.A.
†Department of Chemistry, University of Texas at Dallas, Dallas, TX 75083-0688, U.S.A.
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Craig R. Malloy;
Craig R. Malloy
*Advanced Imaging Research Center, University of Texas Southwestern Medical Center, 5801 Forest Park Road, Dallas, TX 75235-9085, U.S.A.
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Shawn C. Burgess
Shawn C. Burgess
1
*Advanced Imaging Research Center, University of Texas Southwestern Medical Center, 5801 Forest Park Road, Dallas, TX 75235-9085, U.S.A.
1To whom correspondence should be addressed (email shawn.burgess@utsouthwestern.edu).
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Publisher: Portland Press Ltd
Received:
July 19 2005
Revision Received:
November 03 2005
Accepted:
November 17 2005
Accepted Manuscript online:
November 17 2005
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London
2006
Biochem J (2006) 394 (2): 465–473.
Article history
Received:
July 19 2005
Revision Received:
November 03 2005
Accepted:
November 17 2005
Accepted Manuscript online:
November 17 2005
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Citation
Natasha Hausler, Jeffrey Browning, Matthew Merritt, Charles Storey, Angela Milde, F. Mark H. Jeffrey, A. Dean Sherry, Craig R. Malloy, Shawn C. Burgess; Effects of insulin and cytosolic redox state on glucose production pathways in the isolated perfused mouse liver measured by integrated 2H and 13C NMR. Biochem J 1 March 2006; 394 (2): 465–473. doi: https://doi.org/10.1042/BJ20051174
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