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. 2025 Mar;46(3):687-701.
doi: 10.1038/s41401-024-01401-w. Epub 2024 Oct 29.

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

Wen-Han Wu  1 , Hao Zhi  1 , Wen-Ke Feng  1 , Ling Jiang  1 , Lu Yang  1 , Li-Qiang Qian  1 , Rui-Xi Zhao  1 , Yong-Mei Tan  1 , Han-Yu Yang  2 , Xiao-Dong Liu  3 , Li Liu  4
Affiliations

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

Wen-Han Wu et al. Acta Pharmacol Sin. 2025 Mar.

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.

Keywords: 5-HT; atypical antipsychotics; clozapine; glucose intolerance; glucose-stimulated insulin secretion; organic cation transporter-1.

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Conflict of interest statement

Competing interests: The authors declare no competing interests.

References

    1. Henderson DC. Atypical antipsychotic-induced diabetes mellitus: how strong is the evidence? CNS Drugs. 2002;16:77–89. - PubMed
    1. Scheen AJ, De Hert MA. Abnormal glucose metabolism in patients treated with antipsychotics. Diabetes Metab. 2007;33:169–75. - PubMed
    1. Cernea S, Dima L, Correll CU, Manu P. Pharmacological management of glucose dysregulation in patients treated with second-generation antipsychotics. Drugs. 2020;80:1763–81. - PubMed
    1. Grajales D, Ferreira V, Valverde ÁM. Second-generation antipsychotics and dysregulation of glucose metabolism: beyond weight gain. Cells. 2019;8:1336. - PMC - PubMed
    1. Pillinger T, McCutcheon RA, Vano L, Mizuno Y, Arumuham A, Hindley G, et al. Comparative effects of 18 antipsychotics on metabolic function in patients with schizophrenia, predictors of metabolic dysregulation, and association with psychopathology: a systematic review and network meta-analysis. Lancet Psychiatry. 2020;7:64–77. - PMC - PubMed

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