{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T11:44:57Z","timestamp":1787312697625,"version":"build-2736575974"},"reference-count":50,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,5,6]],"date-time":"2026-05-06T00:00:00Z","timestamp":1778025600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000780","name":"European Union","doi-asserted-by":"crossref","award":["101095672"],"award-info":[{"award-number":["101095672"]}],"id":[{"id":"10.13039\/501100000780","id-type":"DOI","asserted-by":"crossref"}]},{"award":["101095672"],"award-info":[{"award-number":["101095672"]}],"id":[{"id":"https:\/\/ror.org\/019w4f821","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003196","name":"Italian Ministry of Health","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Italian Liver Foundation NPO"},{"id":[{"id":"https:\/\/ror.org\/00zpwa373","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Department of Life Sciences of the University of Trieste, UNITS"},{"id":[{"id":"https:\/\/ror.org\/02n742c10","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Department of Science and Technology\u2014Philippine Council for Health Research and Development"},{"id":[{"id":"https:\/\/ror.org\/04rpdbq72","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Chronic low-grade inflammation is a key feature of obesity-associated dysglycemia, yet substantial heterogeneity exists in inflammatory responses among individuals with normoglycemia, prediabetes, and type 2 diabetes mellitus (T2DM). Whether circulating inflammatory protein profiles define distinct patient phenotypes beyond conventional glycemic classification remains incompletely understood. In this cross-sectional analysis of 142 individuals with severe obesity, plasma inflammatory proteins were quantified using Olink proximity extension assay technology. Subjects were stratified by glycemic status (noDM, normoglycemia; PreDM, prediabetes and T2DM) while maintaining comparable distributions of metabolic dysfunction-associated steatotic liver disease. Differential expression analyses were performed across glycemic groups, and unsupervised topological data analysis (TDA) was applied to identify inflammatory protein-based patient subgroups. Several inflammatory proteins were significantly upregulated in T2DM and PreDM compared with noDM, with interleukin-8 (IL-8), Fms-relatedlike tyrosine kinase 3 ligand (Flt3L), and CUB domain containing protein (CDCP1) showing the largest significant differences. NPX distributions of these proteins exhibited gradual increases across glycemic stages with substantial inter-individual variability. TDA identified seven clusters defined by distinct inflammatory protein signatures. One cluster was enriched for individuals with T2DM and characterized by coordinated upregulation of IL-8, Flt3L, CDCP1, and additional immune- and cytokine-related proteins, whereas other clusters displayed alternative inflammatory profiles that were not explained by glycemic status alone. Inflammatory proteomic profiling in severe obesity reveals both glycemia-associated protein changes and distinct inflammatory phenotypes that transcend conventional clinical classification. Integration of differential expression analysis with TDA highlights heterogeneity in inflammatory states, supporting a hypothesis-generating framework for future studies aimed at validating these proteomic patterns and clarifying their longitudinal relevance in obesity-related dysglycemia.<\/jats:p>","DOI":"10.3390\/ijms27094152","type":"journal-article","created":{"date-parts":[[2026,5,7]],"date-time":"2026-05-07T09:03:37Z","timestamp":1778144617000},"page":"4152","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Inflammatory Proteomic Heterogeneity Beyond Glycemia Status in Severe Obesity"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-3431-1649","authenticated-orcid":false,"given":"Melissa M.","family":"Milito","sequence":"first","affiliation":[{"name":"Metabolic Liver Disease Unit, Fondazione Italiana Fegato, 34012 Trieste, Italy"},{"name":"Department of Life Sciences, University of Trieste, 34127 Trieste, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7427-9954","authenticated-orcid":false,"given":"Mattia","family":"Chiesa","sequence":"additional","affiliation":[{"name":"Bioinformatics and Artificial Intelligence Facility, Centro Cardiologico Monzino IRCCS, 20138 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7088-9074","authenticated-orcid":false,"given":"Alice","family":"Mallia","sequence":"additional","affiliation":[{"name":"Unit of Functional Proteomics, Metabolomics, and Network Analysis, Centro Cardiologico Monzino IRCCS, 20138 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-3657-4043","authenticated-orcid":false,"given":"Giulia G.","family":"Papaianni","sequence":"additional","affiliation":[{"name":"Unit of Functional Proteomics, Metabolomics, and Network Analysis, Centro Cardiologico Monzino IRCCS, 20138 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-7323-0937","authenticated-orcid":false,"given":"Julia T.","family":"Regalado","sequence":"additional","affiliation":[{"name":"Metabolic Liver Disease Unit, Fondazione Italiana Fegato, 34012 Trieste, Italy"},{"name":"Department of Life Sciences, University of Trieste, 34127 Trieste, Italy"},{"name":"Department of Science and Technology, Philippine Council for Health Research and Development, Bicutan, Taguig 1631, Philippines"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6596-7595","authenticated-orcid":false,"given":"Claudio","family":"Tiribelli","sequence":"additional","affiliation":[{"name":"Metabolic Liver Disease Unit, Fondazione Italiana Fegato, 34012 Trieste, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deborah","family":"Bonazza","sequence":"additional","affiliation":[{"name":"Surgical Pathology Unit, Cattinara Hospital, Azienda Sanitaria Universitaria Giuliano Isontina, 34149 Trieste, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4251-3547","authenticated-orcid":false,"given":"Natalia","family":"Rosso","sequence":"additional","affiliation":[{"name":"Metabolic Liver Disease Unit, Fondazione Italiana Fegato, 34012 Trieste, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4749-4258","authenticated-orcid":false,"given":"Silvia","family":"Palmisano","sequence":"additional","affiliation":[{"name":"Metabolic Liver Disease Unit, Fondazione Italiana Fegato, 34012 Trieste, Italy"},{"name":"Surgical Clinic Division, Cattinara Hospital, Azienda Sanitaria Universitaria Giuliano Isontina, 34149 Trieste, Italy"},{"name":"Department of Medical, Surgical and Health Sciences, University of Trieste, 34149 Trieste, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3346-9879","authenticated-orcid":false,"given":"Cristina","family":"Banfi","sequence":"additional","affiliation":[{"name":"Unit of Functional Proteomics, Metabolomics, and Network Analysis, Centro Cardiologico Monzino IRCCS, 20138 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2852-6648","authenticated-orcid":false,"given":"Pablo J.","family":"Giraudi","sequence":"additional","affiliation":[{"name":"Metabolic Liver Disease Unit, Fondazione Italiana Fegato, 34012 Trieste, 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