| Autor: |
Pincus SH; Department of Chemistry & Biochemistry, Animal Resource Center (TM), Montana State University, Bozeman, MT 59717, USA.; Children's Hospital of New Orleans, New Orleans, LA 70118, USA.; Departments of Pediatrics and of Microbiology, Immunology and Parasitology, LSU School of Medicine, New Orleans, LA 70112, USA., Kyro A; Department of Chemistry & Biochemistry, Animal Resource Center (TM), Montana State University, Bozeman, MT 59717, USA., Maresh GA; Children's Hospital of New Orleans, New Orleans, LA 70118, USA., Peters T; Department of Chemistry & Biochemistry, Animal Resource Center (TM), Montana State University, Bozeman, MT 59717, USA., Kempa J; Department of Chemistry & Biochemistry, Animal Resource Center (TM), Montana State University, Bozeman, MT 59717, USA., Marcotte TK; Department of Chemistry & Biochemistry, Animal Resource Center (TM), Montana State University, Bozeman, MT 59717, USA., Gao Z; Pennington Biomedical Research Institute, Baton Rouge, LA 70808, USA., Ye J; Pennington Biomedical Research Institute, Baton Rouge, LA 70808, USA., Copié V; Department of Chemistry & Biochemistry, Animal Resource Center (TM), Montana State University, Bozeman, MT 59717, USA., Song K; Children's Hospital of New Orleans, New Orleans, LA 70118, USA. |
| Abstrakt: |
Ricin toxin is an agent of biodefense concern and we have been developing countermeasures for ricin threats. In doing so, we sought biomarkers of ricin toxicosis and found that in mice parenteral injection of ricin toxin causes profound hypoglycemia, in the absence of other clinical laboratory abnormalities. We now seek to identify the mechanisms underlying this hypoglycemia. Within the first hours following injection, while still normoglycemic, lymphopenia and pro-inflammatory cytokine secretion were observed, particularly tumor necrosis factor (TNF)-α. The cytokine response evolved over the next day into a complex storm of both pro- and anti-inflammatory cytokines. Evaluation of pancreatic function and histology demonstrated marked islet hypertrophy involving predominantly β-cells, but only mildly elevated levels of insulin secretion, and diminished hepatic insulin signaling. Drops in blood glucose were observed even after destruction of β-cells with streptozotocin. In the liver, we observed a rapid and persistent decrease in the expression of glucose-6-phosphatase (G6Pase) RNA and protein levels, accompanied by a drop in glucose-6-phosphate and increase in glycogen. TNF-α has previously been reported to suppress G6Pase expression. In humans, a genetic deficiency of G6Pase results in glycogen storage disease, type-I (GSD-1), a hallmark of which is potentially fatal hypoglycemia. |
