Journal
TOXINS
Volume 14, Issue 12, Pages -Publisher
MDPI
DOI: 10.3390/toxins14120820
Keywords
glucose metabolism; hypoglycemia; insulin; ricin; toxin; TNF-alpha; cytokine induction; beta-cell; liver metabolism; glucose-6-phosphatase
Categories
Funding
- Research Institute for Children, Children's Hospital, New Orleans
- NIH
- [R01AI059376]
- [R01AI136758]
- [U54AI057156]
- [U54GM104940]
- [R56AI127398]
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Injection of ricin toxin causes hypoglycemia in mice, accompanied by lymphopenia and cytokine secretion. Abnormal pancreatic and hepatic function may contribute to the hypoglycemia.
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)-alpha. 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 beta-cells, but only mildly elevated levels of insulin secretion, and diminished hepatic insulin signaling. Drops in blood glucose were observed even after destruction of beta-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-alpha 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.
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