Human Molecular Genetics Advance Access originally published online on August 12, 2003
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Human Molecular Genetics, 2003, Vol. 12, No. 19 2547-2558
DOI: 10.1093/hmg/ddg263
© 2003 Oxford University Press
Impaired glucose homeostasis, neutrophil trafficking and function in mice lacking the glucose-6-phosphate transporter
1Section on Cellular Differentiation, Heritable Disorders Branch and 2Laboratory of Mammalian Genes and Development, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA, 3Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA, 4Department of Pediatrics, University of Southern California School of Medicine, Los Angeles, CA 90027, USA, 5Pediatric Division, Ben-Gurion University of the Negev, Beer-Sheva, Israel and 6Veterinary and Tumor Pathology Section, Office of Laboratory Animal Science, National Cancer Institute, Frederick, MD 21702, USA
Received June 10, 2003; Revised July 22, 2003; Accepted July 30, 2003
Glycogen storage disease type Ib (GSD-Ib) is caused by a deficiency in the glucose-6-phosphate transporter (G6PT). In addition to disrupted glucose homeostasis, GSD-Ib patients have unexplained and unexpected defects in neutrophil respiratory burst, chemotaxis and calcium flux, in response to the bacterial peptide f-Met-Leu-Phe, as well as intermittent neutropenia. We generated a G6PT knockout (G6PT-/-) mouse that mimics all known defects of the human disorder and used the model to further our understanding of the pathogenesis of GSD-Ib. We demonstrate that the neutropenia is caused directly by the loss of G6PT activity; that chemotaxis and calcium flux, induced by the chemokines KC and macrophage inflammatory protein-2, are defective in G6PT-/- neutrophils; and that local production of these chemokines and the resultant neutrophil trafficking in vivo are depressed in G6PT-/- ascites during an inflammatory response. The bone and spleen of G6PT-/- mice are developmentally delayed and accompanied by marked hypocellularity of the bone marrow, elevation of myeloid progenitor cell frequencies in both organs and a corresponding dramatic increase in granulocyte colony stimulating factor levels in both GSD-Ib mice and humans. So, in addition to transient neutropenia, a sustained defect in neutrophil trafficking due to both the resistance of neutrophils to chemotactic factors, and reduced local production of neutrophil-specific chemokines at sites of inflammation, may underlie the myeloid deficiency in GSD-Ib. These findings demonstrate that G6PT is not just a G6P transport protein but also an important immunomodulatory protein whose activities need to be addressed in treating the myeloid complications in GSD-Ib patients.
* To whom correspondence should be addressed at: Building 10, Room 9S241, NIH, Bethesda, MD 20892-1830, USA. Tel: +1 3014961094; Fax: +1 3014026035; Email: chou{at}helix.nih.gov
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  S. Y. Kim, H. S. Jun, P. A. Mead, B. C. Mansfield, and J. Y. Chou Neutrophil stress and apoptosis underlie myeloid dysfunction in glycogen storage disease type Ib Blood, June 15, 2008; 111(12): 5704 - 5711. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. A. Walker, A. Ahmed, G. G. Lavery, J. W. Tomlinson, S. Y. Kim, M. S. Cooper, J. P. Ride, B. A. Hughes, C. H. L. Shackleton, P. McKiernan, et al. 11beta-Hydroxysteroid Dehydrogenase Type 1 Regulation by Intracellular Glucose 6-Phosphate Provides Evidence for a Novel Link between Glucose Metabolism and Hypothalamo-Pituitary-Adrenal Axis Function J. Biol. Chem., September 14, 2007; 282(37): 27030 - 27036. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. W. Sloop, A. D. Showalter, A. L. Cox, J. X. C. Cao, A. M. Siesky, H. Y. Zhang, A. R. Irizarry, S. F. Murray, S. L. Booten, E. A. Finger, et al. Specific Reduction of Hepatic Glucose 6-Phosphate Transporter-1 Ameliorates Diabetes while Avoiding Complications of Glycogen Storage Disease J. Biol. Chem., June 29, 2007; 282(26): 19113 - 19121. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Marcolongo, S. Piccirella, S. Senesi, L. Wunderlich, I. Gerin, J. Mandl, R. Fulceri, G. Banhegyi, and A. Benedetti The Glucose-6-Phosphate Transporter-Hexose-6-Phosphate Dehydrogenase-11{beta}-Hydroxysteroid Dehydrogenase Type 1 System of the Adipose Tissue Endocrinology, May 1, 2007; 148(5): 2487 - 2495. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-C. Currie, S. Fortier, A. Sina, J. Galipeau, J. Cao, and B. Annabi MT1-MMP Down-regulates the Glucose 6-Phosphate Transporter Expression in Marrow Stromal Cells: A MOLECULAR LINK BETWEEN PRO-MMP-2 ACTIVATION, CHEMOTAXIS, AND CELL SURVIVAL J. Biol. Chem., March 16, 2007; 282(11): 8142 - 8149. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Wang, J. K. Oeser, C. Yang, S. Sarkar, S. I. Hackl, A. H. Hasty, O. P. McGuinness, W. Paradee, J. C. Hutton, D. R. Powell, et al. Deletion of the Gene Encoding the Ubiquitously Expressed Glucose-6-phosphatase Catalytic Subunit-related Protein (UGRP)/Glucose-6-phosphatase Catalytic Subunit-beta Results in Lowered Plasma Cholesterol and Elevated Glucagon J. Biol. Chem., December 29, 2006; 281(52): 39982 - 39989. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Gyurko, C. C. Siqueira, N. Caldon, L. Gao, A. Kantarci, and T. E. Van Dyke Chronic Hyperglycemia Predisposes to Exaggerated Inflammatory Response and Leukocyte Dysfunction in Akita Mice J. Immunol., November 15, 2006; 177(10): 7250 - 7256. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Y. Kim, A. D. Nguyen, J.-L. Gao, P. M. Murphy, B. C. Mansfield, and J. Y. Chou Bone Marrow-derived Cells Require a Functional Glucose 6-Phosphate Transporter for Normal Myeloid Functions J. Biol. Chem., September 29, 2006; 281(39): 28794 - 28801. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Ghosh, Y. Y. Cheung, B. C. Mansfield, and J. Y. Chou Brain Contains a Functional Glucose-6-Phosphatase Complex Capable of Endogenous Glucose Production J. Biol. Chem., March 25, 2005; 280(12): 11114 - 11119. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-J. Shieh, C.-J. Pan, B. C. Mansfield, and J. Y. Chou A Potential New Role for Muscle in Blood Glucose Homeostasis J. Biol. Chem., June 18, 2004; 279(25): 26215 - 26219. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-J. Shieh, C.-J. Pan, B. C. Mansfield, and J. Y. Chou A Glucose-6-phosphate Hydrolase, Widely Expressed Outside the Liver, Can Explain Age-dependent Resolution of Hypoglycemia in Glycogen Storage Disease Type Ia J. Biol. Chem., November 21, 2003; 278(47): 47098 - 47103. [Abstract] [Full Text] [PDF]
|
|