{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T12:12:38Z","timestamp":1789042358789,"version":"build-2803163510"},"reference-count":185,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T00:00:00Z","timestamp":1788998400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Type 2 diabetes (T2D) is increasingly understood as a chronic, low-grade inflammatory disease in which immune and metabolic signalling are bidirectionally coupled. Nutrient excess drives glucolipotoxic stress in adipose tissue, liver, skeletal muscle and pancreatic islets, engaging innate immune sensors. Responding immune cells then reconfigure their own intermediary metabolism, and the resulting metabolites\u2014succinate, which stabilises hypoxia-inducible factor-1\u03b1, and the itaconate that opposes it\u2014themselves specify inflammatory output. These signals converge on NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome assembly, gasdermin D-mediated pyroptosis and interleukin-1\u03b2 (IL-1\u03b2) release, which interrupt insulin signalling through inhibitory serine phosphorylation of insulin receptor substrate-1. Mitochondrial dysfunction, impaired mitophagy and cytosolic mitochondrial DNA sensing sustain the loop, while gut barrier failure supplies a parallel systemic input that converges on beta-cell dysfunction. This narrative review synthesises these mechanisms and examines how metformin, glucagon-like peptide-1 receptor agonists, sodium\u2013glucose cotransporter 2 inhibitors and inflammasome-directed agents intersect with them. The chain described is that of obesity-associated T2D, and the heterogeneity that limits its generalisation across the recognised subgroups of the disease is addressed explicitly rather than assumed away. We give particular weight to a dissociation that constrains the field: sustained IL-1\u03b2 neutralisation reduced cardiovascular events without preventing incident diabetes. Establishing why is, in our view, the central question for immunometabolic therapeutics in T2D.<\/jats:p>","DOI":"10.3390\/ijms27188063","type":"journal-article","created":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T11:38:39Z","timestamp":1789040319000},"page":"8063","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Immunometabolism in Obesity-Associated Type 2 Diabetes: Molecular Mechanisms and Emerging Therapeutic Targets"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1239-7012","authenticated-orcid":false,"given":"Carlo","family":"Acierno","sequence":"first","affiliation":[{"name":"Department of Health Sciences (DiSS), University of Basilicata, Via dell\u2019Ateneo Lucano 10, 85100 Potenza, Italy"},{"name":"Department of Infectious Diseases, Azienda Ospedaliera Regionale San Carlo, 85100 Potenza, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Massimiliano","family":"Cavallo","sequence":"additional","affiliation":[{"name":"Internal Medicine Unit, Degli Infermi Hospital of Narni, USL Umbria 2, 05035 Narni, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5573-4536","authenticated-orcid":false,"given":"Damiano","family":"D\u2019Ardes","sequence":"additional","affiliation":[{"name":"Department of Medicine and Aging Sciences, University of G. d\u2019Annunzio Chieti and Pescara, 66100 Chieti, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9303-7790","authenticated-orcid":false,"given":"Andrea","family":"Boccatonda","sequence":"additional","affiliation":[{"name":"Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-9617-4491","authenticated-orcid":false,"given":"Davide","family":"Nilo","sequence":"additional","affiliation":[{"name":"Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7761-7533","authenticated-orcid":false,"given":"Alfredo","family":"Caturano","sequence":"additional","affiliation":[{"name":"Department of Human Sciences and Promotion of the Quality of Life, San Raffaele Roma University, 00166 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"166425","DOI":"10.1016\/j.bbadis.2022.166425","article-title":"Immunometabolism and the modulation of immune responses and host defense: A role for methylglyoxal?","volume":"1868","author":"Zhang","year":"2022","journal-title":"Biochim. 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