Exposure to second-generation antipsychotics increases circulating small extracellular vesicles that promote insulin resistance in hepatocytes

@article{ferreira2026exposure,
  title = {{Exposure to second-generation antipsychotics increases circulating small extracellular vesicles that promote insulin resistance in hepatocytes}},
  author = {Vitor Ferreira and Rosa Alén and Dora Koller and Adrián Povo-Retana and Diana Grajales and Yolanda Sanchez-Carro and Lisardo Boscá and Manuel Izquierdo and Pilar López-García and Paz Garcia-Portilla and Francisco Abad-Santos and Irma Garcia-Martinez and Ángela M. Valverde},
  journal = {Journal of Physiology and Biochemistry},
  year = {2026},
  month = nov,
  doi = {10.1007/s13105-026-01250-7},
  url = {https://doi.org/10.1007/s13105-026-01250-7},
  note = {CC BY 4.0},
}

TY  - JOUR
TI  - Exposure to second-generation antipsychotics increases circulating small extracellular vesicles that promote insulin resistance in hepatocytes
AU  - Vitor Ferreira
AU  - Rosa Alén
AU  - Dora Koller
AU  - Adrián Povo-Retana
AU  - Diana Grajales
AU  - Yolanda Sanchez-Carro
AU  - Lisardo Boscá
AU  - Manuel Izquierdo
AU  - Pilar López-García
AU  - Paz Garcia-Portilla
AU  - Francisco Abad-Santos
AU  - Irma Garcia-Martinez
AU  - Ángela M. Valverde
PY  - 2026
DA  - 2026/11/03
JO  - Journal of Physiology and Biochemistry
DO  - 10.1007/s13105-026-01250-7
UR  - https://doi.org/10.1007/s13105-026-01250-7
AB  - Second generation antipsychotics (SGAs) are widely prescribed for the management of psychiatric disorders, yet their use is associated with obesity, insulin resistance, and impaired glucose homeostasis. Small extracellular vesicles (sEV) are mediators of inter-tissue communication in metabolic diseases. Herein, we investigated the impact of the SGAs aripiprazole (ARI) and olanzapine (OLA) on circulating sEV in healthy volunteers and patients with first-episode psychosis, as well as the effects of these sEV on hepatocyte insulin signalling and systemic inflammation. Twenty-four healthy volunteers received OLA or ARI for five days. Seven individuals with first-episode psychosis were treated with SGAs; three were followed longitudinally for 6 months. sEV were isolated from plasma or culture media of SGA-treated human macrophages (h-mac) from donors. Huh7 human hepatocytes were exposed to sEV and insulin signalling was assessed. Inflammatory responses were evaluated by determining IκBα or IL1B expression in h-mac. In healthy volunteers, ARI significantly increased circulating sEV levels, which positively correlated with LDH, GGT, and free T4 plasma levels. sEV from ARI-treated subjects impaired hepatocyte insulin signalling in most cases, whereas sEV from OLA-treated patients produced milder effects. sEV from SGA-treated h-mac induced hepatocyte insulin resistance, accompanied, particularly with ARI, by reduced IκBα and increased IL1B expression in h-mac. Patients showed elevated baseline circulating sEV and increased baseline IL1B expression in PBMCs compared to healthy volunteers, and SGAs further enhanced these alterations. Our results suggest that elevations in circulating sEV associated to disease and SGA treatment may contribute to insulin-desensitization and inflammation, two hallmarks of metabolic dysfunction.  Graphical abstract:  Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1007/s13105-026-01250-7.
SN  - 1138-7548
SN  - 1877-8755
ER  -