Parenteral Exposure of Mice to Ricin Toxin Induces Fatal Hypoglycemia by Cytokine-Mediated Suppression of Hepatic Glucose-6-Phosphatase Expression

dc.contributor.authorPincus, Seth H.
dc.contributor.authorKyro, Alexi
dc.contributor.authorMaresh, Grace A.
dc.contributor.authorPeters, Tami
dc.contributor.authorKempa, Jacob
dc.contributor.authorMarcotte, Tamera K.
dc.contributor.authorGao, Zhanguo
dc.contributor.authorYe, Jianping
dc.contributor.authorCopié, Valérie
dc.contributor.authorSong, Kejing
dc.date.accessioned2023-02-27T18:04:20Z
dc.date.available2023-02-27T18:04:20Z
dc.date.issued2022-11
dc.description.abstractRicin 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.en_US
dc.identifier.citationPincus SH, Kyro A, Maresh GA, Peters T, Kempa J, Marcotte TK, Gao Z, Ye J, Copié V, Song K. Parenteral Exposure of Mice to Ricin Toxin Induces Fatal Hypoglycemia by Cytokine-Mediated Suppression of Hepatic Glucose-6-Phosphatase Expression. Toxins. 2022; 14(12):820. https://doi.org/10.3390/toxins14120820en_US
dc.identifier.issn2072-6651
dc.identifier.urihttps://scholarworks.montana.edu/handle/1/17743
dc.language.isoen_USen_US
dc.publisherMDPI AGen_US
dc.rightscc-byen_US
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/en_US
dc.subjectglucose metabolismen_US
dc.subjecthypoglycemiaen_US
dc.subjectinsulinen_US
dc.subjectricinen_US
dc.subjecttoxinen_US
dc.subjectTNF-αen_US
dc.subjectcytokine inductionen_US
dc.subjectβ-cellen_US
dc.subjectliver metabolismen_US
dc.subjectglucose-6-phosphataseen_US
dc.titleParenteral Exposure of Mice to Ricin Toxin Induces Fatal Hypoglycemia by Cytokine-Mediated Suppression of Hepatic Glucose-6-Phosphatase Expressionen_US
dc.typeArticleen_US
mus.citation.extentfirstpage1en_US
mus.citation.extentlastpage21en_US
mus.citation.issue12en_US
mus.citation.journaltitleToxinsen_US
mus.citation.volume14en_US
mus.data.thumbpage8en_US
mus.identifier.doi10.3390/toxins14120820en_US
mus.relation.collegeCollege of Letters & Scienceen_US
mus.relation.departmentChemistry & Biochemistry.en_US
mus.relation.universityMontana State University - Bozemanen_US

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