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Submitted on September 26, 2003
Accepted on November 3, 2003
1 Department of Biochemistry, Molecular Biology and Biophysics, Medical School, University of Minnesota, 6-155 Jackson Hall, 321 Church Street SE, Minneapolis, Minnesota 55455, USA; Veterans Administration Medical Center, 1 Veterans Drive, Minneapolis, MN 55417, USA.
* To whom correspondence should be addressed. E-mail: lange024{at}umn.edu.
The effects of fructose-2,6-bisphosphate on hepatic glucokinase and glucose-6-phosphatase gene expression were investigated in streptozotocin-treated mice, which exhibited undetectable levels of insulin. Hepatic fructose-2,6-bisphosphate levels were manipulated by adenovirus-mediated overexpression of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase. Streptozotocin treatment alone or with infusion of control adenovirus leads to a dramatic decrease in hepatic fructose-2,6-bisphosphate content compared with normal nondiabetic mice. This is accompanied by a 14-fold decrease in glucokinase and a 3-fold increase in glucose-6-phosphatase protein levels, consistent with a diabetic phenotype. Streptozotocin-treated mice that were infused with adenovirus-overexpressing an engineered 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase with high kinase activity and little bisphosphatase activity showed high levels of hepatic fructose-2,6-bisphosphate. Surprisingly, these mice had a 13-fold increase in glucokinase protein and a 2-fold decrease in glucose-6-phosphatase protein compared with diabetic controls. The restoration of glucokinase is associated with increases in the phosphorylation of Akt upon increasing hepatic fructose-2,6-bisphosphate content. Moreover, the changes in levels of fructose-2,6-bisphosphate and Akt phosphorylation revealed a pattern similar to that of streptozotocin mice treated with insulin, indicating that increasing hepatic content of fructose-2,6-bisphosphate mimics the action of insulin. Since glucose-6-phosphatase gene expression was down-regulated only after the restoration of euglycemia, the effect of fructose-2,6-bisphosphate was indirect. Also, the lowering of blood glucose by high fructose-2,6-bisphosphate was associated with an increase in hepatic nuclear factor 1-
protein, a transcription factor involved in glucose-6-phosphatase gene expression. In conclusion, fructose-2,6-bisphosphate can stimulate hepatic glucokinase gene expression in an insulin-independent manner and can secondarily affect glucose-6-phosphatase gene expression by lowering the level of plasma glucose.
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