Mechanisms by Which Liver-Specific PEPCK Knockout Mice Preserve Euglycemia During Starvation

• Published in: Diabetes (New York, N.Y.) Vol. 52; no. 7; pp. 1649 - 1654
• Main Authors: PENGXIANG SHE, BURGESS, Shawn C, SHIOTA, Masakazu, FLAKOLL, Paul, DONAHUE, E. Patrick, MALLOY, Craig R, SHERRY, A. Dean, MAGNUSON, Mark A
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01-07-2003
• Subjects: Animals; Biological and medical sciences; Blood Glucose - metabolism; Catheters; Chromatography; Diabetes; Diabetes mellitus; Diabetes research; Enzymes; Experiments; Fundamental and applied biological sciences. Psychology; Gene expression; Glucokinase - metabolism; Glucose; Glucose - metabolism; Glycerol; Glycerol - metabolism; Glycogen Synthase - metabolism; Homeostasis; Isotopes; Laboratories; Liver; Liver - enzymology; Liver - metabolism; Liver Glycogen - metabolism; Metabolism; Metabolites; Mice; Mice, Knockout; Muscle, Skeletal - metabolism; NMR; Nuclear magnetic resonance; Phosphoenolpyruvate Carboxykinase (GTP) - deficiency; Phosphoenolpyruvate Carboxykinase (GTP) - genetics; Phosphoenolpyruvate Carboxykinase (GTP) - metabolism; Physiological aspects; Plasma; Starvation - physiopathology; United States
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/diabetes.52.7.1649

Mechanisms by Which Liver-Specific PEPCK Knockout Mice Preserve Euglycemia During Starvation
Pengxiang She 1 ,
Shawn C. Burgess 2 ,
Masakazu Shiota 1 ,
Paul Flakoll 3 ,
E. Patrick Donahue 4 ,
Craig R. Malloy 2 5 ,
A. Dean Sherry 2 6 and
Mark A. Magnuson 1
1 Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee
2 Mary Nell and Ralph B. Rogers Magnetic Resonance Center, Department of Radiology, Veteran Affairs Medical Center, University
of Texas Southwestern Medical Center, Dallas, Texas
3 Department of Surgery, Vanderbilt University School of Medicine, Nashville, Tennessee
4 Vanderbilt Diabetes Center, Vanderbilt University School of Medicine, Nashville, Tennessee
5 Department of Internal Medicine, Veteran Affairs Medical Center, University of Texas Southwestern Medical Center, Dallas,
Texas
6 Department of Chemistry, University of Texas at Dallas, Dallas, Texas
Address correspondence and reprint requests to Dr. Mark A. Magnuson, 702 Light Hall, Vanderbilt University School of Medicine,
Nashville, TN 37232-0615. E-mail: mark.magnuson{at}vanderbilt.edu
Abstract
Liver-specific PEPCK knockout mice, which are viable despite markedly abnormal lipid metabolism, exhibit mild hyperglycemia
in response to fasting. We used isotopic tracer methods, biochemical measurements, and nuclear magnetic resonance spectroscopy
to show that in mice lacking hepatic PEPCK, 1 ) whole-body glucose turnover is only slightly decreased; 2 ) whole-body gluconeogenesis from phosphoenolpyruvate, but not from glycerol, is moderately decreased; 3 ) tricarboxylic acid cycle activity is globally increased, even though pyruvate cycling and anaplerosis are decreased; 4 ) the liver is unable to synthesize glucose from lactate/pyruvate and produces only a minimal amount of glucose; and 5 ) glycogen synthesis in both the liver and muscle is impaired. Thus, although mice without hepatic PEPCK have markedly impaired
hepatic gluconeogenesis, they are able to maintain a near-normal blood glucose concentration while fasting by increasing extrahepatic
gluconeogenesis coupled with diminishing whole-body glucose utilization.
G6P, glucose-6-phosphate
G6Pase, glucose-6-phosphatase
GCMS, gas chromatography−mass spectrometry
HPLC, high-performance liquid chromatography
MAG, monoacetone glucose
NMR, nuclear magnetic resonance
PEP, phosphoenolpyruvate
SA, specific activity
TCA, tricarboxylic acid
Footnotes
Accepted March 13, 2003.
Received July 12, 2002.
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