{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T00:31:44Z","timestamp":1789518704859,"version":"build-2803163510"},"reference-count":66,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T00:00:00Z","timestamp":1785715200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Insulin resistance (IR) remains the central pathophysiological driver of type 2 diabetes mellitus (T2DM) and is inadequately targeted by current pharmacotherapies. Emerging evidence in immunometabolism identifies metabolic inflammation (meta-inflammation) as a critical mechanistic bridge between chronic nutrient excess and IR progression, primarily through IKK\u03b2\/NF-\u03baB and JNK signaling cascades, NLRP3 inflammasome activation, mitochondrial dysfunction, and lipotoxicity. Exercise intervention counteracts these processes via coordinated multi-tiered mechanisms, including AMPK-mediated insulin sensitization, myokine-driven anti-inflammatory modulation, mitophagy-based mitochondrial quality control, liver\u2013muscle\u2013adipose metabolic crosstalk, and epigenetic reprogramming of inflammatory transcriptional responses. However, clinically significant interindividual variability in exercise responsiveness\u2014termed exercise non-response\u2014limits the effectiveness of population-averaged prescription guidelines. This heterogeneity is attributable to genetic polymorphisms, baseline inflammatory burden, gut microbiota composition, and suboptimal exercise protocol design. This review synthesizes mechanistic evidence linking meta-inflammation, exercise, and IR, and proposes a precision exercise medicine framework integrating multi-omics phenotyping (genomics, metabolomics, and microbiome profiling) with data-driven clinical decision-support tools. This approach aims to translate mechanistic insights into individualized therapeutic strategies for the long-term management of T2DM.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1886943","type":"journal-article","created":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T10:10:35Z","timestamp":1785751835000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Targeting metabolic inflammation in type 2 diabetes mellitus through exercise: multi-level mechanisms of insulin resistance reversal and precision clinical translation \u2014 a review"],"prefix":"10.3389","volume":"17","author":[{"given":"Li","family":"Wu","sequence":"first","affiliation":[{"name":"College of Sports Science, Jishou University","place":["Jishou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,3]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1002\/hsr2.2004","article-title":"Diabetes mellitus, the fastest growing global public health concern: Early detection should be focused","volume":"7","author":"Hossain","year":"2024","journal-title":"Health Sci Rep"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1002\/edm2.321","article-title":"Impact of micro- and macrovascular complications of type 2 diabetes on quality of life: Insights from the DISCOVER prospective cohort study","volume":"5","author":"Arnold","year":"2022","journal-title":"Endocrinol Diabetes Metab"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrep.2025.102037","article-title":"Type 2 diabetes mellitus - conventional therapies and future perspectives in innovative treatment","volume":"42","author":"Gieroba","year":"2025","journal-title":"Biochem Biophys Rep"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1042\/BST20221066","article-title":"Insulin signalling and GLUT4 trafficking in insulin resistance","volume":"51","author":"van Gerwen","year":"2023","journal-title":"Biochem Soc Trans"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2023.1149239","article-title":"The crucial role and mechanism of insulin resistance in metabolic disease","volume":"14","author":"Zhao","year":"2023","journal-title":"Front Endocrinol (Lausanne)"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.3390\/ijms262110445","article-title":"Metaflammation's role in systemic dysfunction in obesity: A comprehensive review","volume":"26","author":"Crasan","year":"2025","journal-title":"Int J Mol Sci"},{"key":"B7","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1007\/s11010-016-2878-8","article-title":"Protein kinases: Mechanisms and downstream targets in inflammation-mediated obesity and insulin resistance","volume":"426","author":"Nandipati","year":"2016","journal-title":"Mol Cell Biochem"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.3390\/metabo16040269","article-title":"Precision exercise in type 2 diabetes mellitus: targeting signaling networks for lipid homeostasis","volume":"16","author":"Tian","year":"2026","journal-title":"Metabolites"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2025.118846","article-title":"The role of gut dysbiosis and mitochondrial dysfunction in type 2 diabetes: insights on pathogenesis, intervention and future perspective","volume":"193","author":"Yu","year":"2025","journal-title":"BioMed Pharmacother"},{"key":"B10","doi-asserted-by":"publisher","first-page":"3615","DOI":"10.3390\/nu17223615","article-title":"Can myokines serve as supporters of muscle-brain connectivity in obesity and type 2 diabetes? 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