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

Journal Article

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-A(y)/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.

Full Text

Duke Authors

Cited Authors

  • Wu, C; Okar, DA; Newgard, CB; Lange, AJ

Published Date

  • January 2002

Published In

Volume / Issue

  • 282 / 1

Start / End Page

  • E38 - E45

PubMed ID

  • 11739081

International Standard Serial Number (ISSN)

  • 0193-1849

Digital Object Identifier (DOI)

  • 10.1152/ajpendo.2002.282.1.E38

Language

  • eng

Conference Location

  • United States