The second-generation antipsychotic drug aripiprazole modulates the serotonergic system in pancreatic islets and induces beta cell dysfunction in female mice

Diana Grajales, Patricia Vázquez, Mónica Ruíz-Rosario, Eva Tudurí, Mercedes Mirasierra, Vítor Ferreira, Ana B. Hitos, Dora Koller, Pablo Zubiaur, Juan C. Cigudosa, Francisco Abad-Santos, Mario Vallejo, Iván Quesada, Boaz Tirosh, Gil Leibowitz, Ángela M. Valverde*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

8 Scopus citations


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. Graphical abstract: [Figure not available: see fulltext.].

Original languageAmerican English
Pages (from-to)490-505
Number of pages16
Issue number3
StatePublished - Mar 2022

Bibliographical note

Funding Information:
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).

Funding Information:
The authors would like to thank M. Belinch?n (IIBm, CSIC, Madrid, Spain) for the technical assistance with confocal microscopy. We also acknowledge all members of ?MV?s laboratory for helpful discussions. Some of the data were presented as an abstract at the 55th EASD Annual Meeting in 2019. The authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work.

Publisher Copyright:
© 2021, The Author(s).


  • Beta cell dysfunction
  • Beta cell mass
  • Insulin secretion
  • Islets
  • Schizophrenia
  • Second-generation antipsychotics
  • Type 2 diabetes


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