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Diabetes 52:1649-1654, 2003
© 2003 by the American Diabetes Association, Inc.

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

Pengxiang She1, Shawn C. Burgess2, Masakazu Shiota1, Paul Flakoll3, E. Patrick Donahue4, Craig R. Malloy2,5, A. Dean Sherry2,6, and Mark A. Magnuson1

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

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.

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


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