Mechanisms by which liver-specific PEPCK knockout mice preserve euglycemia during starvation.
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.
She
Pengxiang
P
Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0615, USA.
Burgess
Shawn C
SC
Shiota
Masakazu
M
Flakoll
Paul
P
Donahue
E Patrick
EP
Malloy
Craig R
CR
Sherry
A Dean
AD
Magnuson
Mark A
MA
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D005941:Glucokinase / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D005990:Glycerol / Q000378:metabolism; D006006:Glycogen Synthase / Q000378:metabolism; D006706:Homeostasis; D008099:Liver / Q000201:enzymology / Q000378:metabolism*; D008112:Liver Glycogen / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000378:metabolism; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D013217:Starvation / Q000503:physiopathology*
D001786:Blood Glucose; D008112:Liver Glycogen; D006006:Glycogen Synthase; D005941:Glucokinase; D010729:Phosphoenolpyruvate Carboxykinase (GTP); D005947:Glucose; D005990:Glycerol