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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| Format: | Article |
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MDPI AG
2022-11-01
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| Series: | Toxins |
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| Online Access: | https://www.mdpi.com/2072-6651/14/12/820 |
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| author | Seth H. Pincus Alexi Kyro Grace A. Maresh Tami Peters Jacob Kempa Tamera K. Marcotte Zhanguo Gao Jianping Ye Valérie Copié Kejing Song |
| author_facet | Seth H. Pincus Alexi Kyro Grace A. Maresh Tami Peters Jacob Kempa Tamera K. Marcotte Zhanguo Gao Jianping Ye Valérie Copié Kejing Song |
| author_sort | Seth H. Pincus |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-03-09T15:46:40Z |
| format | Article |
| id | doaj.art-5c7729c9e33b452381b18e0b8c1ca43f |
| institution | Directory Open Access Journal |
| issn | 2072-6651 |
| language | English |
| last_indexed | 2024-03-09T15:46:40Z |
| publishDate | 2022-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Toxins |
| spelling | doaj.art-5c7729c9e33b452381b18e0b8c1ca43f2023-11-24T18:26:19ZengMDPI AGToxins2072-66512022-11-01141282010.3390/toxins14120820Parenteral Exposure of Mice to Ricin Toxin Induces Fatal Hypoglycemia by Cytokine-Mediated Suppression of Hepatic Glucose-6-Phosphatase ExpressionSeth H. Pincus0Alexi Kyro1Grace A. Maresh2Tami Peters3Jacob Kempa4Tamera K. Marcotte5Zhanguo Gao6Jianping Ye7Valérie Copié8Kejing Song9Department of Chemistry & Biochemistry, Animal Resource Center (TM), Montana State University, Bozeman, MT 59717, USADepartment of Chemistry & Biochemistry, Animal Resource Center (TM), Montana State University, Bozeman, MT 59717, USAChildren’s Hospital of New Orleans, New Orleans, LA 70118, USADepartment of Chemistry & Biochemistry, Animal Resource Center (TM), Montana State University, Bozeman, MT 59717, USADepartment of Chemistry & Biochemistry, Animal Resource Center (TM), Montana State University, Bozeman, MT 59717, USADepartment of Chemistry & Biochemistry, Animal Resource Center (TM), Montana State University, Bozeman, MT 59717, USAPennington Biomedical Research Institute, Baton Rouge, LA 70808, USAPennington Biomedical Research Institute, Baton Rouge, LA 70808, USADepartment of Chemistry & Biochemistry, Animal Resource Center (TM), Montana State University, Bozeman, MT 59717, USAChildren’s Hospital of New Orleans, New Orleans, LA 70118, USARicin 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.https://www.mdpi.com/2072-6651/14/12/820glucose metabolismhypoglycemiainsulinricintoxinTNF-α |
| spellingShingle | Seth H. Pincus Alexi Kyro Grace A. Maresh Tami Peters Jacob Kempa Tamera K. Marcotte Zhanguo Gao Jianping Ye Valérie Copié Kejing Song Parenteral Exposure of Mice to Ricin Toxin Induces Fatal Hypoglycemia by Cytokine-Mediated Suppression of Hepatic Glucose-6-Phosphatase Expression Toxins glucose metabolism hypoglycemia insulin ricin toxin TNF-α |
| 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 | glucose metabolism hypoglycemia insulin ricin toxin TNF-α |
| url | https://www.mdpi.com/2072-6651/14/12/820 |
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