中国药科大学刘李等合作取得重要工作进展。他们研究提出，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，从而部分损害葡萄糖刺激的胰岛素分泌。相关研究成果2024年10月29日在线发表于《中国药理学报》杂志上。

据介绍，服用非典型抗精神病药物(AAP)（尤其是氯氮平）的患者经常伴有高血糖症。

氯氮平作为研究AAP如何诱发高血糖症的代表性药物。在正常小鼠和喂食高脂肪饮食(HFD)的小鼠中，腹膜内注射葡萄糖后，氯氮平会损害葡萄糖耐受性和葡萄糖刺激的胰岛素分泌(GSIS)，并增加血浆5-HT水平。腹膜内注射5-HT也会损害小鼠的葡萄糖耐受性和GSIS。在INS-1细胞中，高5-HT水平会损害GSIS，而5-HTR₃拮抗剂托烷司琼或沉默5-HTR_3a会减弱这种损害。5-HTR_2a激动剂TCB2会减弱氯氮平引起的GSIS损害。沉默5-HTR_2a或5-HTR_2a拮抗剂酮色林会损害GSIS。

在小鼠中，5-HT给药会损害GSIS，托烷司琼可减轻这种损害，但氯氮平会加剧这种损害。氯氮平静脉给药后可增加小鼠血浆[²H]5-HT暴露。在HEK293-OCT1细胞中，氯氮平可抑制[²H]5-HT和MPP⁺的摄取。氯氮平或OCT1沉默会损害小鼠原代肝细胞中的5-HT代谢，表明氯氮平通过抑制OCT1介导的肝脏5-HT摄取来增加血浆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和葡萄糖耐受性。

总之，氯氮平通过抑制OCT1介导的肝脏5-HT摄取而增加血浆5-HT水平，从而损害GSIS和葡萄糖耐受性。增加的5-HT通过激活胰岛5-HTR_3a损害GSIS。氯氮平对胰岛5-HTR_2a的拮抗作用也导致了GSIS受损。氯氮平诱导的GSIS受损归因于通过抑制OCT1介导的肝脏5-HT摄取而增加的5-HT水平，这一发现可能部分解释了其他AAP引起的高血糖症。

附：英文原文

Title: 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

Author: Wu, Wen-han, Zhi, Hao, Feng, Wen-ke, Jiang, Ling, Yang, Lu, Qian, Li-qiang, Zhao, Rui-xi, Tan, Yong-mei, Yang, Han-yu, Liu, Xiao-dong, Liu, Li

Issue&Volume: 2024-10-29

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.

DOI: 10.1038/s41401-024-01401-w

Source: https://www.nature.com/articles/s41401-024-01401-w