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

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 abnor...

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Autores principales: Pincus, Seth H., Kyro, Alexi, Maresh, Grace A., Peters, Tami, Kempa, Jacob, Marcotte, Tamera K., Gao, Zhanguo, Ye, Jianping, Copié, Valérie, Song, Kejing
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9786807/
https://www.ncbi.nlm.nih.gov/pubmed/36548717
http://dx.doi.org/10.3390/toxins14120820
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author Pincus, Seth H.
Kyro, Alexi
Maresh, Grace A.
Peters, Tami
Kempa, Jacob
Marcotte, Tamera K.
Gao, Zhanguo
Ye, Jianping
Copié, Valérie
Song, Kejing
author_facet Pincus, Seth H.
Kyro, Alexi
Maresh, Grace A.
Peters, Tami
Kempa, Jacob
Marcotte, Tamera K.
Gao, Zhanguo
Ye, Jianping
Copié, Valérie
Song, Kejing
author_sort Pincus, Seth H.
collection PubMed
description 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.
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spelling pubmed-97868072022-12-24 Parenteral Exposure of Mice to Ricin Toxin Induces Fatal Hypoglycemia by Cytokine-Mediated Suppression of Hepatic Glucose-6-Phosphatase Expression Pincus, Seth H. Kyro, Alexi Maresh, Grace A. Peters, Tami Kempa, Jacob Marcotte, Tamera K. Gao, Zhanguo Ye, Jianping Copié, Valérie Song, Kejing Toxins (Basel) Article 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. MDPI 2022-11-23 /pmc/articles/PMC9786807/ /pubmed/36548717 http://dx.doi.org/10.3390/toxins14120820 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Pincus, Seth H.
Kyro, Alexi
Maresh, Grace A.
Peters, Tami
Kempa, Jacob
Marcotte, Tamera K.
Gao, Zhanguo
Ye, Jianping
Copié, Valérie
Song, Kejing
Parenteral Exposure of Mice to Ricin Toxin Induces Fatal Hypoglycemia by Cytokine-Mediated Suppression of Hepatic Glucose-6-Phosphatase Expression
title Parenteral Exposure of Mice to Ricin Toxin Induces Fatal Hypoglycemia by Cytokine-Mediated Suppression of Hepatic Glucose-6-Phosphatase Expression
title_full Parenteral Exposure of Mice to Ricin Toxin Induces Fatal Hypoglycemia by Cytokine-Mediated Suppression of Hepatic Glucose-6-Phosphatase Expression
title_fullStr Parenteral Exposure of Mice to Ricin Toxin Induces Fatal Hypoglycemia by Cytokine-Mediated Suppression of Hepatic Glucose-6-Phosphatase Expression
title_full_unstemmed Parenteral Exposure of Mice to Ricin Toxin Induces Fatal Hypoglycemia by Cytokine-Mediated Suppression of Hepatic Glucose-6-Phosphatase Expression
title_short Parenteral Exposure of Mice to Ricin Toxin Induces Fatal Hypoglycemia by Cytokine-Mediated Suppression of Hepatic Glucose-6-Phosphatase Expression
title_sort parenteral exposure of mice to ricin toxin induces fatal hypoglycemia by cytokine-mediated suppression of hepatic glucose-6-phosphatase expression
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9786807/
https://www.ncbi.nlm.nih.gov/pubmed/36548717
http://dx.doi.org/10.3390/toxins14120820
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