Impaired glucose homeostasis, neutrophil trafficking and function in mice lacking the glucose-6-phosphate transporter.

Abstract

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.

• Authors: Li-Yuan Chen, Jeng-Jer Shieh, Baochuan Lin, Chi-Jiunn Pan, Ji-Liang Gao, Philip M Murphy, Thomas F Roe, Shimon Moses, Jerrold M Ward, Eric J Lee, Heiner Westphal, Brian C Mansfield, Janice Yang Chou
• Journal: Human molecular genetics (Hum Mol Genet) Vol. 12 Issue 19 Pg. 2547-58 (Oct 01 2003) ISSN: 0964-6906 [Print] England
• PMID: 12925567 (Publication Type: Journal Article)

Chemical References

• Antiporters
• Chemokines
• Monosaccharide Transport Proteins
• SLC37A4 protein, human
• Slc37a4 protein, mouse
• glucose 6-phosphate(transporter)
• Glucose
• Calcium

Topics

• Animals
• Antiporters (deficiency)
• Calcium (metabolism)
• Chemokines (metabolism)
• Chemotaxis, Leukocyte
• Disease Models, Animal
• Genes, Recessive
• Genetic Variation
• Glucose (metabolism)
• Glycogen Storage Disease Type I (etiology, pathology)
• Homeostasis
• Kidney (pathology)
• Kinetics
• Liver (pathology)
• Mice
• Mice, Knockout
• Monosaccharide Transport Proteins (deficiency)
• Neutropenia (etiology, physiopathology)
• Neutrophils (metabolism)
• Respiratory Burst
• Restriction Mapping
• Time Factors