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

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. In healthy volunteers ARI induces a higher rise in circulating sEV than OLA Circulating sEV from ARI-treated volunteers attenuate hepatocyte insulin signalling sEV from ARI-treated h-mac increase IL1B expression and promote hepatocyte insulin resistance First-episode psychosis elevated plasma sEV and SGAs enhanced this effect