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J Biol Chem, Vol. 274, Issue 35, 24559-24566, August 27, 1999

Glucose-6-phosphatase Overexpression Lowers Glucose 6-Phosphate and Inhibits Glycogen Synthesis and Glycolysis in Hepatocytes without Affecting Glucokinase Translocation
EVIDENCE AGAINST FEEDBACK INHIBITION OF GLUCOKINASE

Susan Aiston, Khiet Y. Trinh^§, Alex J. Lange^¶, Christopher B. Newgard, and Loranne Agius

From the  Department of Diabetes, The Medical School, University of Newcastle upon Tyne, Newcastle upon Tyne NE2 4HH, United Kingdom, ^§ Department of Medicine, University of Toronto, Toronto, Ontario M5G 2C4, Canada, ^¶ Department of Biochemistry, University of Minnesota Medical School, Minneapolis, Minnesota 55455, and  Gifford Laboratories for Diabetes Research, Departments of Biochemistry and Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75235

In hepatocytes glucokinase (GK) and glucose-6-phosphatase (Glc-6-Pase)¹ have converse effects on glucose 6-phosphate (and fructose 6-phosphate) levels. To establish whether hexose 6-phosphate regulates GK binding to its regulatory protein, we determined the effects of Glc-6-Pase overexpression on glucose metabolism and GK compartmentation. Glc-6-Pase overexpression (4-fold) decreased glucose 6-phosphate levels by 50% and inhibited glycogen synthesis and glycolysis with a greater negative control coefficient on glycogen synthesis than on glycolysis, but it did not affect the response coefficients of glycogen synthesis or glycolysis to glucose, and it did not increase the control coefficient of GK or cause dissociation of GK from its regulatory protein, indicating that in hepatocytes fructose 6-phosphate does not regulate GK translocation by feedback inhibition. GK overexpression increases glycolysis and glycogen synthesis with a greater control coefficient on glycogen synthesis than on glycolysis. On the basis of the similar relative control coefficients of GK and Glc-6-Pase on glycogen synthesis compared with glycolysis, and the lack of effect of Glc-6-Pase overexpression on GK translocation or the control coefficient of GK, it is concluded that the main regulatory function of Glc-6-Pase is to buffer the glucose 6-phosphate concentration. This is consistent with recent findings that hyperglycemia stimulates Glc-6-Pase gene transcription.

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Copyright © 1999 by The American Society for Biochemistry and Molecular Biology, Inc.

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