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; 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

doi:10.1038/s41401-024-01401-w

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. 2024 Oct 29. doi: 10.1038/s41401-024-01401-w. Online ahead of print.

Authors

Wen-Han Wu¹, Hao Zhi¹, Wen-Ke Feng¹, Ling Jiang¹, Lu Yang¹, Li-Qiang Qian¹, Rui-Xi Zhao¹, Yong-Mei Tan¹, Han-Yu Yang², Xiao-Dong Liu³, Li Liu⁴

Affiliations

¹ Center of Drug Metabolism and Pharmacokinetics, School of Pharmacy, China Pharmaceutical University, Nanjing, 210029, China.
² Center of Drug Metabolism and Pharmacokinetics, School of Pharmacy, China Pharmaceutical University, Nanjing, 210029, China. shenyhycpu@163.com.
³ Center of Drug Metabolism and Pharmacokinetics, School of Pharmacy, China Pharmaceutical University, Nanjing, 210029, China. xdliu@cpu.edu.cn.
⁴ Center of Drug Metabolism and Pharmacokinetics, School of Pharmacy, China Pharmaceutical University, Nanjing, 210029, China. liulee@cpu.edu.cn.

PMID: 39472495
DOI: 10.1038/s41401-024-01401-w

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-HTR_3a. The 5-HTR_2a agonist TCB2 attenuated clozapine-induced GSIS impairment. Silencing 5-HTR_2a or the 5-HTR_2a 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-HTR_3a. The antagonistic effect of clozapine on islet 5-HTR_2a 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.