Parenteral Exposure of Mice to Ricin Toxin Induces Fatal Hypoglycemia by Cytokine-Mediated Suppression of Hepatic Glucose-6-Phosphatase Expression.
Parenteral Exposure of Mice to Ricin Toxin Induces Fatal Hypoglycemia by Cytokine-Mediated Suppression of Hepatic Glucose-6-Phosphatase Expression.
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DOI：
10.3390/toxins14120820
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发表时间：
2022-11-23
期刊：
影响因子：
4.2
通讯作者：
Song K
中科院分区：
文献类型：
--
作者：
Pincus SH;Kyro A;Maresh GA;Peters T;Kempa J;Marcotte TK;Gao Z;Ye J;Copié V;Song K
蓖麻毒素是一种生物防御剂，我们一直在研究应对蓖麻毒素威胁的对策。在这样做的过程中，我们寻找蓖麻毒素中毒的生物标志物，并发现在没有其他临床实验室异常的情况下，小鼠胃肠外注射蓖麻毒素会导致严重的低血糖。我们现在试图确定这种低血糖的机制。在注射后的前几个小时内，虽然血糖仍然正常，但观察到淋巴细胞减少和促炎细胞因子分泌，特别是肿瘤坏死因子（TNF）-α。细胞因子反应在第二天演变成促炎和抗炎细胞因子的复杂风暴。胰腺功能和组织学评价显示显著的胰岛肥大，主要涉及β细胞，但胰岛素分泌水平仅轻度升高，肝脏胰岛素信号传导减少。即使在用链脲佐菌素破坏β细胞后，也观察到血糖下降。在肝脏中，我们观察到葡萄糖-6-磷酸酶（G6 β）RNA和蛋白质水平表达的快速和持续下降，伴随着葡萄糖-6-磷酸的下降和糖原的增加。TNF-α以前曾被报道抑制G6 β表达。在人类中，G6 β的遗传缺陷导致I型糖原累积病（GSD-1），其特征是潜在的致命性低血糖。
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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在蓖麻毒素或禁食诱导的小鼠低血糖症中观察到不同的代谢状态
影响因子：
4.2
作者：
Kempa J;O'Shea-Stone G;Moss CE;Peters T;Marcotte TK;Tripet B;Eilers B;Bothner B;Copié V;Pincus SH
通讯作者：
Pincus SH
影响因子：
4.6
作者：
Grela P;Li XP;Horbowicz P;Dźwierzyńska M;Tchórzewski M;Tumer NE
通讯作者：
Tumer NE
影响因子：
9.8
作者：
CHAJEKSHAUL, T;BARASH, V;SHILONI, E
通讯作者：
SHILONI, E
影响因子：
6.2
作者：
GOTOH, M;MAKI, T;MONACO, AP
通讯作者：
MONACO, AP
影响因子：
4.2
作者：
Pincus SH;Das A;Song K;Maresh GA;Corti M;Berry J
通讯作者：
Berry J