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

Chaodong Wu, David A. Okar, Christopher B. Newgard, Alex J. Lange

Research output: Contribution to journalArticlepeer-review

36 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)E38-E45
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Volume282
Issue number1 45-1
DOIs
StatePublished - 2002

Keywords

  • Adenovirus
  • Glucokinase
  • Glucose-6-phosphatase
  • Hepatic glucose production

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