The second-generation antipsychotic drug aripiprazole modulates the serotonergic system in pancreatic islets and induces beta cell dysfunction in female mice
Publisher
SpringerDate
2021-12-21Citation
10.1007/s00125-021-05630-0
Diabetologia 65 (2022): 490-505
ISSN
0012-186X (print); 1432-0428 (online)DOI
10.1007/s00125-021-05630-0Funded by
Open Access funding provided thanks to the CRUE-CSIC agreement with Springer Nature. This work was funded by H2020 Marie Sklodowska-Curie ITN-TREATMENT (Grant Agreement 721236, European Commission). We also acknowledge grants RTI2018-094052-B-100/ AEI/10.13039/501100011033 (Ministerio de Ciencia e Innovación y Fondo Europeo de Desarrollo Regional [FEDER]) and S2017/BMD-3684 (Comunidad de Madrid, Spain), and grants from Fundación Ramón Areces (Spain) and CIBERDEM (ISCIII, Spain)Project
info:eu-repo/grantAgreement/EC/H2020/721236/EU; Comunidad de Madrid. S2017/BMD-3684; Gobierno de España. RTI2018-094052-B-100/AEI/ 10.13039/501100011033Editor's Version
https://doi.org/10.1007/s00125-021-05630-0Subjects
Beta cell dysfunction; Beta cell mass; Insulin secretion; Islets; Schizophrenia; Second-generation antipsychotics; Type 2 diabetes; MedicinaRights
© The Author(s) 2021Abstract
Aims/hypothesis: Second-generation antipsychotic (SGA) drugs have been associated with the development of type 2 diabetes and the metabolic syndrome in patients with schizophrenia. In this study, we aimed to investigate the effects of two different SGA drugs, olanzapine and aripiprazole, on metabolic state and islet function and plasticity. Methods: We analysed the functional adaptation of beta cells in 12-week-old B6;129 female mice fed an olanzapine- or aripiprazole-supplemented diet (5.5–6.0 mg kg−1 day−1) for 6 months. Glucose and insulin tolerance tests, in vivo glucose-stimulated insulin secretion and indirect calorimetry were performed at the end of the study. The effects of SGAs on beta cell plasticity and islet serotonin levels were assessed by transcriptomic analysis and immunofluorescence. Insulin secretion was assessed by static incubations and Ca2+ fluxes by imaging techniques. Results: Treatment of female mice with olanzapine or aripiprazole for 6 months induced weight gain (p<0.01 and p<0.05, respectively), glucose intolerance (p<0.01) and impaired insulin secretion (p<0.05) vs mice fed a control chow diet. Aripiprazole, but not olanzapine, induced serotonin production in beta cells vs controls, likely by increasing tryptophan hydroxylase 1 (TPH1) expression, and inhibited Ca2+ flux. Of note, aripiprazole increased beta cell size (p<0.05) and mass (p<0.01) vs mice fed a control chow diet, along with activation of mechanistic target of rapamycin complex 1 (mTORC1)/S6 signalling, without preventing beta cell dysfunction. Conclusions/interpretation: Both SGAs induced weight gain and beta cell dysfunction, leading to glucose intolerance; however, aripiprazole had a more potent effect in terms of metabolic alterations, which was likely a result of its ability to modulate the serotonergic system. The deleterious metabolic effects of SGAs on islet function should be considered while treating patients as these drugs may increase the risk for development of the metabolic syndrome and diabetes
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Google Scholar:Grajales, Diana
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Vázquez, Patricia
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Ruíz Rosario, Mónica
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Tudurí, Eva
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Mirasierra, Mercedes
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Ferreira, Vítor
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Hitos, Ana B.
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Koller, Dora
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Zubiaur Precioso, Pablo
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Cigudosa, Juan C.
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Abad Santos, Francisco
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Vallejo, Mario
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Quesada, Iván
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Tirosh, Boaz
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Leibowitz, Gil
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Valverde, Ángela M.
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