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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

Acta Pharmacologica Sinica volume 46, pages 687–701 (2025)Cite this article

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.

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Fig. 1: Effects of clozapine on glucose homeostasis and GSIS in C57BL/6 J mice.
Fig. 2: The association between increased plasma 5-HT levels and impairments of GSIS and glucose tolerance in C57BL/6 J mice.
Fig. 3: Effects of clozapine on glucose tolerance, GSIS, and plasma 5-HT levels in HFD-fed mice.
Fig. 4: Increased 5-HT levels inhibited GSIS partly by activating 5-HTR3a and clozapine aggravated 5-HT-induced GSIS impairment partly by blocking 5-HTR2a on pancreatic β-cells.
Fig. 5: Effects of clozapine on intestinal 5-HT synthesis and hepatic 5-HT elimination in C57BL/6 J mice.
Fig. 6: Clozapine inhibited hepatic 5-HT elimination by inhibiting 5-HT uptake.
Fig. 7: The contribution of OCT1 on hepatic 5-HT uptake and effects of clozapine on the function of OCT1.
Fig. 8: Effects of hepatic OCT1 knockdown on the disposition of 5-HT, glucose tolerance, and GSIS in C57BL/6 J mice.
Fig. 9: Olanzapine and quetiapine impaired GSIS and glucose tolerance partly by increasing 5-HT levels due to the inhibition of hepatic 5-HT uptake.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (Nos. 82373943, 82173884, China), the “Double First-Class” university project (No. CPU2022QZ21, China).

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  1. Center of Drug Metabolism and Pharmacokinetics, School of Pharmacy, China Pharmaceutical University, Nanjing, 210029, China

    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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WHW: conceptualization, methodology, investigation, formal analysis, validation, and writing-original draft. LL, XDL: conceptualization, methodology, writing-reviewing, editing, supervision, and funding acquisition. HYY: methodology, writing-reviewing, and editing. HZ and WKF: investigation, validation, and data curation. LJ, LY, LQQ, RXZ, YMT: investigation.

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Wu, Wh., Zhi, H., Feng, Wk. et al. 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. Acta Pharmacol Sin 46, 687–701 (2025). https://doi.org/10.1038/s41401-024-01401-w

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