Clozapine impaired glucose-stimulated insulin secretion partly by increasing plasma 5-HT levels due to the inhibition of OCT1-mediated hepatic 5-HT uptake in mice.

IF 6.9 1区 医学 Q1 CHEMISTRY, MULTIDISCIPLINARY
Wen-Han Wu, Hao Zhi, Wen-Ke Feng, Ling Jiang, Lu Yang, Li-Qiang Qian, Rui-Xi Zhao, Yong-Mei Tan, Han-Yu Yang, Xiao-Dong Liu, Li Liu
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引用次数: 0

Abstract

Patients taking atypical antipsychotics (AAPs), especially clozapine, are often associated with hyperglycaemia. Here, clozapine served as a representative agent for investigating how AAPs induce hyperglycaemia. In normal mice and mice fed a high fat diet (HFD), clozapine impaired glucose tolerance and glucose-stimulated insulin secretion (GSIS) following intraperitoneal glucose administration and increased plasma 5-HT levels. Intraperitoneal 5-HT administration also impaired glucose tolerance and GSIS in mice. In INS-1 cells, high 5-HT levels impaired GSIS, which was attenuated by the 5-HTR3 antagonist tropisetron or by silencing 5-HTR3a. The 5-HTR2a agonist TCB2 attenuated clozapine-induced GSIS impairment. Silencing 5-HTR2a or the 5-HTR2a antagonist ketanserin impaired GSIS. In mice, 5-HT administration impaired GSIS, which was attenuated by tropisetron but aggravated by clozapine. Clozapine increased plasma [2H]5-HT exposure following intravenous administration to mice. In HEK293-OCT1 cells, clozapine inhibited [2H]5-HT and MPP+ uptake. Clozapine or OCT1 silencing impaired 5-HT metabolism in mouse primary hepatocytes, demonstrating that clozapine increased plasma 5-HT levels via the inhibition of OCT1-mediated hepatic 5-HT uptake. Liver-specific silencing of OCT1 increased plasma [2H]5-HT exposure and 5-HT levels and impaired GSIS and glucose tolerance in mice. In conclusion, clozapine impaired GSIS and glucose tolerance by increasing plasma 5-HT levels via the inhibition of OCT1-mediated hepatic 5-HT uptake. Increased 5-HT impaired GSIS by activating islet 5-HTR3a. The antagonistic effect of clozapine on islet 5-HTR2a also contributed to GSIS impairment. The finding that clozapine-induced GSIS impairment was attributed to increased 5-HT levels via the inhibition of OCT1-mediated hepatic 5-HT uptake may partly explain hyperglycaemia caused by other AAPs.

氯氮平通过抑制小鼠肝脏对 OCT1 介导的 5-HT 摄取,部分增加血浆 5-HT 水平,从而损害葡萄糖刺激的胰岛素分泌。
服用非典型抗精神病药物(AAPs),尤其是氯氮平的患者经常会出现高血糖。在这里,氯氮平是研究非典型抗精神病药如何诱发高血糖的代表性药物。在正常小鼠和喂食高脂饮食(HFD)的小鼠中,氯氮平可损害葡萄糖耐量和腹腔注射葡萄糖后的葡萄糖刺激胰岛素分泌(GSIS),并增加血浆中的 5-HT 水平。腹腔注射 5-HT 也会损害小鼠的葡萄糖耐量和葡萄糖刺激胰岛素分泌(GSIS)。在 INS-1 细胞中,高水平的 5-HT 会损害 GSIS,而 5-HTR3 拮抗剂 tropisetron 或沉默 5-HTR3a 可减轻 GSIS 的损害。5-HTR2a 激动剂 TCB2 可减轻氯氮平诱导的 GSIS 损伤。沉默 5-HTR2a 或 5-HTR2a 拮抗剂酮塞林会损害 GSIS。给小鼠注射 5-HT 会损害 GSIS,托品司琼会减轻这种损害,而氯氮平则会加重这种损害。给小鼠静脉注射氯氮平可增加血浆中[2H]5-HT的暴露量。在 HEK293-OCT1 细胞中,氯氮平抑制了 [2H]5-HT 和 MPP+ 的摄取。氯氮平或沉默 OCT1 会损害小鼠原代肝细胞中的 5-HT 代谢,这表明氯氮平通过抑制 OCT1 介导的肝脏 5-HT 摄取来增加血浆中的 5-HT 水平。肝脏特异性沉默 OCT1 会增加血浆 [2H]5-HT 暴露和 5-HT 水平,并损害小鼠的 GSIS 和葡萄糖耐量。总之,氯氮平通过抑制 OCT1 介导的肝脏 5-HT 摄取,增加血浆 5-HT 水平,从而损害 GSIS 和葡萄糖耐量。增加的 5-HT 通过激活胰岛 5-HTR3a 损害 GSIS。氯氮平对胰岛 5-HTR2a 的拮抗作用也是 GSIS 受损的原因之一。氯氮平诱导的 GSIS 损伤可归因于通过抑制 OCT1 介导的肝脏 5-HT 摄取而增加的 5-HT 水平,这一发现可部分解释其他 AAPs 引起的高血糖。
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来源期刊
Acta Pharmacologica Sinica
Acta Pharmacologica Sinica 医学-化学综合
CiteScore
15.10
自引率
2.40%
发文量
4365
审稿时长
2 months
期刊介绍: APS (Acta Pharmacologica Sinica) welcomes submissions from diverse areas of pharmacology and the life sciences. While we encourage contributions across a broad spectrum, topics of particular interest include, but are not limited to: anticancer pharmacology, cardiovascular and pulmonary pharmacology, clinical pharmacology, drug discovery, gastrointestinal and hepatic pharmacology, genitourinary, renal, and endocrine pharmacology, immunopharmacology and inflammation, molecular and cellular pharmacology, neuropharmacology, pharmaceutics, and pharmacokinetics. Join us in sharing your research and insights in pharmacology and the life sciences.
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