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  

作　　者：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 

机构地区：[1]Center of Drug Metabolism and Pharmacokinetics,School of Pharmacy,China Pharmaceutical University,Nanjing,210029,China

出　　处：《Acta Pharmacologica Sinica》2025年第3期687-701,共15页中国药理学报(英文版)

基　　金：supported by the National Natural Science Foundation of China(Nos.82373943,82173884,China);the“Double First-Class”university project(No.CPU2022QZ21,China).

摘　　要：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.

关 键 词：CLOZAPINE glucose intolerance glucose-stimulated insulin secretion organic cation transporter-1 5-HT atypical antipsychotics 

分 类 号：R965[医药卫生—药理学]