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Am J Physiol Endocrinol Metab 282: E38-E45, 2002;
0193-1849/02 $5.00
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Vol. 282, Issue 1, E38-E45, January 2002

Increasing fructose 2,6-bisphosphate overcomes hepatic insulin resistance of type 2 diabetes

Chaodong Wu1, David A. Okar1, Christopher B. Newgard2, and Alex J. Lange1

1 Department of Biochemistry, Molecular Biology and Biophysics, Medical School, University of Minnesota, Minneapolis, Minnesota 55455; and 2 Departments of Biochemistry and Internal Medicine, Touchstone Center for Diabetes Research, University of Texas Southwestern Medical Center, Dallas, Texas 75390

Hepatic glucose production is increased as a metabolic consequence of insulin resistance in type 2 diabetes. Because fructose 2,6-bisphosphate is an important regulator of hepatic glucose production, we used adenovirus-mediated enzyme overexpression to increase hepatic fructose 2,6-bisphosphate to determine if the hyperglycemia in KK mice, polygenic models of type 2 diabetes, could be ameliorated by reduction of hepatic glucose production. Seven days after treatment with virus encoding a mutant 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase designed to increase fructose 2,6-bisphosphate levels, plasma glucose, lipids, and insulin were significantly reduced in KK/H1J and KK.Cg-Ay/J mice. Moreover, high fructose 2,6-bisphosphate levels downregulated glucose-6-phosphatase and upregulated glucokinase gene expression, thereby reversing the insulin-resistant pattern of hepatic gene expression of these two key glucose-metabolic enzymes. The increased hepatic fructose 2,6-bisphosphate also reduced adiposity in both KK mice. These results clearly indicate that increasing hepatic fructose 2,6-bisphosphate overcomes the impairment of insulin in suppressing hepatic glucose production, and it provides a potential therapy for type 2 diabetes.

hepatic glucose production; glucose-6-phosphatase; glucokinase; adenovirus


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