This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Wu, C. Articles by Lange, A. J. Search for Related Content PubMed PubMed Citation Articles by Wu, C. Articles by Lange, A. J.

A Potential Role for Fructose-2,6-Bisphosphate in the Stimulation of Hepatic Glucokinase Gene Expression

Department of Biochemistry, Molecular Biology and Biophysics (C.W., A.K.S., L.-J.P., A.H.H., J.E.H., H.C.T., A.J.L.), Medical School, University of Minnesota, Minneapolis, Minnesota 55455; and Veterans Administration Medical Center (D.A.O.), Minneapolis, Minnesota 55417

Address all correspondence and requests for reprints to: Alex J. Lange, Department of Biochemistry, Molecular Biology and Biophysics, Medical School, University of Minnesota, 6–155 Jackson Hall, 321 Church Street SE, Minneapolis, Minnesota 55455. E-mail: lange024{at}umn.edu.

The effects of fructose-2,6-bisphosphate (F-2,6-P₂) 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-P₂ 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-P₂ 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-P₂. 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-P₂ content. Moreover, the changes in levels of F-2,6-P₂ and Akt phosphorylation revealed a pattern similar to that of streptozotocin mice treated with insulin, indicating that increasing hepatic content of F-2,6-P₂ 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-P₂ was indirect. Also, the lowering of blood glucose by high F-2,6-P₂ was associated with an increase in hepatic nuclear factor 1- protein, a transcription factor involved in G-6-Pase gene expression. In conclusion, F-2,6-P₂ 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.

This article has been cited by other articles:

				Q. Wang, R. V. Donthi, J. Wang, A. J. Lange, L. J. Watson, S. P. Jones, and P. N. Epstein Cardiac phosphatase-deficient 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase increases glycolysis, hypertrophy, and myocyte resistance to hypoxia Am J Physiol Heart Circ Physiol, June 1, 2008; 294(6): H2889 - H2897. [Abstract] [Full Text] [PDF]

				H. S. Freitas, G. F. Anhe, K. F. S. Melo, M. M. Okamoto, M. Oliveira-Souza, S. Bordin, and U. F. Machado Na+-Glucose Transporter-2 Messenger Ribonucleic Acid Expression in Kidney of Diabetic Rats Correlates with Glycemic Levels: Involvement of Hepatocyte Nuclear Factor-1{alpha} Expression and Activity Endocrinology, February 1, 2008; 149(2): 717 - 724. [Abstract] [Full Text] [PDF]

				W. E. Smith, S. Langer, C. Wu, S. Baltrusch, and D. A. Okar Molecular Coordination of Hepatic Glucose Metabolism by the 6-Phosphofructo-2-Kinase/Fructose-2,6- Bisphosphatase:Glucokinase Complex Mol. Endocrinol., June 1, 2007; 21(6): 1478 - 1487. [Abstract] [Full Text] [PDF]

				Corrigendum Am J Physiol Endocrinol Metab, January 1, 2007; 292(1): E370 - E370. [Full Text] [PDF]

				S. Baltrusch, S. Langer, L. Massa, M. Tiedge, and S. Lenzen Improved Metabolic Stimulus for Glucose-Induced Insulin Secretion through GK and PFK-2/FBPase-2 Coexpression in Insulin-Producing RINm5F Cells Endocrinology, December 1, 2006; 147(12): 5768 - 5776. [Abstract] [Full Text] [PDF]

				C. Wu, S. A. Khan, L.-J. Peng, H. Li, S. G. Carmella, and A. J. Lange Perturbation of glucose flux in the liver by decreasing F26P2 levels causes hepatic insulin resistance and hyperglycemia Am J Physiol Endocrinol Metab, September 1, 2006; 291(3): E536 - E543. [Abstract] [Full Text] [PDF]

				V. A. Payne, C. Arden, C. Wu, A. J. Lange, and L. Agius Dual Role of Phosphofructokinase-2/Fructose Bisphosphatase-2 in Regulating the Compartmentation and Expression of Glucokinase in Hepatocytes Diabetes, July 1, 2005; 54(7): 1949 - 1957. [Abstract] [Full Text] [PDF]

				X.-L. Cui, A. M. Schlesier, E. L. Fisher, C. Cerqueira, and R. P. Ferraris Fructose-induced increases in neonatal rat intestinal fructose transport involve the PI3-kinase/Akt signaling pathway Am J Physiol Gastrointest Liver Physiol, June 1, 2005; 288(6): G1310 - G1320. [Abstract] [Full Text] [PDF]

				R. A. Baar, C. S. Dingfelder, L. A. Smith, D. A. Bernlohr, C. Wu, A. J. Lange, and E. J. Parks Investigation of in vivo fatty acid metabolism in AFABP/aP2-/- mice Am J Physiol Endocrinol Metab, January 1, 2005; 288(1): E187 - E193. [Abstract] [Full Text] [PDF]

				R. V. Donthi, G. Ye, C. Wu, D. A. McClain, A. J. Lange, and P. N. Epstein Cardiac Expression of Kinase-deficient 6-Phosphofructo-2-kinase/Fructose-2,6-bisphosphatase Inhibits Glycolysis, Promotes Hypertrophy, Impairs Myocyte Function, and Reduces Insulin Sensitivity J. Biol. Chem., November 12, 2004; 279(46): 48085 - 48090. [Abstract] [Full Text] [PDF]

				J. J. Collier and D. K. Scott Sweet Changes: Glucose Homeostasis Can Be Altered by Manipulating Genes Controlling Hepatic Glucose Metabolism Mol. Endocrinol., May 1, 2004; 18(5): 1051 - 1063. [Abstract] [Full Text] [PDF]