{
  "abstract": "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.\n\nGraphical abstract:\n\nSupplementary Information: The online version contains supplementary material available at https://doi.org/10.1007/s13105-026-01250-7.",
  "abstract_shown": true,
  "affiliations": [
    "Instituto de Investigaciones Biomédicas Sols-Morreale (IIBM), Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid., Madrid, Spain",
    "Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, 28029 Spain",
    "Clinical Pharmacology Department, Hospital Universitario de La Princesa, Universidad Autónoma de Madrid (UAM), Instituto de Investigación Sanitaria La Princesa (IIS-Princesa), Madrid, Spain",
    "Faculty of Psychology and Health Sciences, Madrid Open University, Madrid, Spain",
    "Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares (CIBERCV), Instituto de Salud Carlos III, Madrid, Spain",
    "Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain",
    "Department of Psychiatry, Faculty of Medicine, Universidad Autónoma de Madrid, Madrid, Spain",
    "Department of Psychiatry, University of Oviedo, Psyhiatric Service of Servicio de Salud del Principado de Asturias (SESPA), Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Instituto Universitario de Investigación en Neurociencia del Principado de Asturias, Oviedo, Spain",
    "Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 13,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Vitor Ferreira"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Rosa Alén"
    },
    {
      "affs": [
        2
      ],
      "name": "Dora Koller"
    },
    {
      "affs": [
        0
      ],
      "name": "Adrián Povo-Retana"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Diana Grajales"
    },
    {
      "affs": [
        3
      ],
      "name": "Yolanda Sanchez-Carro"
    },
    {
      "affs": [
        0,
        4
      ],
      "name": "Lisardo Boscá"
    },
    {
      "affs": [
        0
      ],
      "name": "Manuel Izquierdo"
    },
    {
      "affs": [
        5,
        6
      ],
      "name": "Pilar López-García"
    },
    {
      "affs": [
        5,
        7
      ],
      "name": "Paz Garcia-Portilla"
    },
    {
      "affs": [
        2,
        8
      ],
      "name": "Francisco Abad-Santos"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Irma Garcia-Martinez",
      "orcid": "0000-0002-8828-6888"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Ángela M. Valverde",
      "orcid": "0000-0003-1192-9045"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/5zycc3nn6x6pb.bib",
  "cited_by": 0,
  "doi": "10.1007/s13105-026-01250-7",
  "fulltext_url": "https://pmc.ncbi.nlm.nih.gov/articles/PMC13731531/",
  "id": "5zycc3nn6x6pb",
  "issns": [
    "1138-7548",
    "1877-8755"
  ],
  "landing_url": "https://doi.org/10.1007/s13105-026-01250-7",
  "language": "en",
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Research"
    ],
    [
      "openalex",
      "1312|Extracellular vesicles in disease"
    ]
  ],
  "openalex": "W7225162851",
  "pdf_url": "https://link.springer.com/content/pdf/10.1007/s13105-026-01250-7.pdf",
  "pmcid": "PMC13731531",
  "pmid": "42975841",
  "published": "2026-11-03",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/5zycc3nn6x6pb.ris",
  "sources": [
    {
      "first_seen": "2026-11-08T12:21:42Z",
      "native_id": "PMC13731531",
      "source": "pmc",
      "url": "https://doi.org/10.1007/s13105-026-01250-7"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|Extracellular vesicles in disease",
      "subfield": "molecular-biology"
    }
  ],
  "title": "Exposure to second-generation antipsychotics increases circulating small extracellular vesicles that promote insulin resistance in hepatocytes",
  "title_text": "Exposure to second-generation antipsychotics increases circulating small extracellular vesicles that promote insulin resistance in hepatocytes",
  "type": "peer-reviewed",
  "updated_at": "2026-11-08T12:21:42Z",
  "url": "https://research.draconitic.com/paper/5zycc3nn6x6pb",
  "venue": "Journal of Physiology and Biochemistry",
  "versions": []
}