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This study investigates the underlying neuroimaging, physiological and genetic mechanisms. At baseline, 142 participants were categorized into four groups according to diagnoses of schizophrenia and MetS. During follow-up, schizophrenia patients with and without MetS (SCZ-MetS and SCZ-nMetS) underwent 4-week antipsychotic treatment. Functional and structural magnetic resonance images, metabolic indicators and clinical scales were collected to investigate effects of MetS on gray matter volume (GMV), functional connectivity (FC) of schizophrenia patients, and related clinical implications. Using cytochrome P450 2D6 (CYP2D6) polymorphisms and brain-wide gene expression profiles, we explored genetic mechanisms of the therapeutic link between MetS and schizophrenia. SCZ-MetS showed greater insular GMV atrophy and functional dysconnectivity. Indirect effects of fasting blood glucose (FBG) on negative symptoms via insular GMV atrophy were observed. However, during follow-up, we observed group \u00d7 time interactions on GMV and FC in insula. Increased GMV of the right insula in SCZ-MetS was correlated with the remission rate of positive symptoms. A moderation effect of FBG on this correlation was revealed. Finally, CYP2D6 polymorphisms and gene expression related to antipsychotic-response explained group \u00d7 time interaction of GMV. Collectively, glucose metabolism, insular volume and FC underlie two distinct effects of MetS on: residual negative symptoms and therapeutic outcomes of positive symptoms in schizophrenia. The genetic mechanisms linking MetS to therapeutic outcomes involve CYP2D6 polymorphisms and the expression of genes related to antipsychotic-response.<\/jats:p>","DOI":"10.1038\/s41398-026-04167-3","type":"journal-article","created":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T19:43:20Z","timestamp":1782935000000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The distinct effects of metabolic syndrome on negative symptoms and on antipsychotic therapy of schizophrenia involve insular volume, functional connectivity, and genetic polymorphisms"],"prefix":"10.1038","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6165-613X","authenticated-orcid":false,"given":"Jingyu","family":"Zhou","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingjun","family":"Duan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sisi","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2035-6456","authenticated-orcid":false,"given":"Huan","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fei","family":"Wen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuling","family":"Luo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingjie","family":"Tang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qizhong","family":"Yi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda Luisa Bringas","family":"Vega","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lang","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gang","family":"Yao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin","family":"Klugah-Brown","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8042-879X","authenticated-orcid":false,"given":"Dezhong","family":"Yao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0524-5886","authenticated-orcid":false,"given":"Cheng","family":"Luo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,1]]},"reference":[{"key":"4167_CR1","doi-asserted-by":"publisher","first-page":"473","DOI":"10.1016\/S0140-6736(21)01730-X","volume":"399","author":"S Jauhar","year":"2022","unstructured":"Jauhar S, Johnstone M, McKenna PJ. 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