A potential role for fructose-2,6-bisphosphate in the stimulation of hepatic glucokinase gene expression

Endocrinology. 2004 Feb;145(2):650-8. doi: 10.1210/en.2003-1290. Epub 2003 Nov 14.


The effects of fructose-2,6-bisphosphate (F-2,6-P(2)) on hepatic glucokinase (GK) and glucose-6-phosphatase (G-6-Pase) gene expression were investigated in streptozotocin-treated mice, which exhibited undetectable levels of insulin. Hepatic F-2,6-P(2) 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 F-2,6-P(2) content compared with normal nondiabetic mice. This is accompanied by a 14-fold decrease in GK and a 3-fold increase in G-6-Pase 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 F-2,6-P(2). Surprisingly, these mice had a 13-fold increase in GK protein and a 2-fold decrease in G-6-Pase protein compared with diabetic controls. The restoration of GK is associated with increases in the phosphorylation of Akt upon increasing hepatic F-2,6-P(2) content. Moreover, the changes in levels of F-2,6-P(2) and Akt phosphorylation revealed a pattern similar to that of streptozotocin mice treated with insulin, indicating that increasing hepatic content of F-2,6-P(2) mimics the action of insulin. Because G-6-Pase gene expression was down-regulated only after the restoration of euglycemia, the effect of F-2,6-P(2) was indirect. Also, the lowering of blood glucose by high F-2,6-P(2) was associated with an increase in hepatic nuclear factor 1-alpha protein, a transcription factor involved in G-6-Pase gene expression. In conclusion, F-2,6-P(2) can stimulate hepatic GK gene expression in an insulin-independent manner and can secondarily affect G-6-Pase gene expression by lowering the level of plasma glucose.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Blood Glucose / analysis
  • CCAAT-Enhancer-Binding Proteins / genetics
  • DNA-Binding Proteins / genetics
  • Diabetes Mellitus, Experimental / enzymology*
  • Fructosediphosphates / pharmacology*
  • Gene Expression / drug effects*
  • Glucokinase / genetics*
  • Glucokinase / metabolism
  • Glucose-6-Phosphatase / genetics
  • Glucose-6-Phosphatase / metabolism
  • Hepatocyte Nuclear Factor 1
  • Hepatocyte Nuclear Factor 1-alpha
  • Hepatocyte Nuclear Factor 1-beta
  • Homeostasis
  • Insulin / pharmacology
  • Kinetics
  • Liver / enzymology*
  • Male
  • Mice
  • Nuclear Proteins*
  • Phosphofructokinase-2 / genetics
  • Phosphorylation
  • Protein-Serine-Threonine Kinases*
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt
  • Recombinant Proteins
  • Sterol Regulatory Element Binding Protein 1
  • Transcription Factors / genetics
  • Transfection


  • Blood Glucose
  • CCAAT-Enhancer-Binding Proteins
  • DNA-Binding Proteins
  • Fructosediphosphates
  • Hepatocyte Nuclear Factor 1-alpha
  • Hnf1a protein, mouse
  • Hnf1b protein, mouse
  • Insulin
  • Nuclear Proteins
  • Proto-Oncogene Proteins
  • Recombinant Proteins
  • Srebf1 protein, mouse
  • Sterol Regulatory Element Binding Protein 1
  • Transcription Factors
  • Hepatocyte Nuclear Factor 1
  • Hepatocyte Nuclear Factor 1-beta
  • fructose 2,6-diphosphate
  • Phosphofructokinase-2
  • Glucokinase
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Glucose-6-Phosphatase