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Following the 16\u2010week moderate\u2010intensity exercise intervention, db\/db mice showed reduced body weight and improved glucose tolerance and insulin sensitivity. This exercise intervention also decreased collagen\u2010I (Col\u2010I), fibronectin (FN), and \u03b1\u2010smooth muscle actin (\u03b1\u2010SMA); reduced islet fibrosis area (assessed by Masson staining); and lowered the numbers of \u03b1\u2010SMA\u2010positive ISCs in the pancreas. Serum irisin was increased after a single bout of moderate\u2010intensity exercise but decreased following the 16\u2010week exercise intervention. In\u00a0vitro experiments showed that irisin suppressed ISC activation by delaying lipid droplet loss, inhibiting migration, and reducing expression of \u03b1\u2010SMA, Col\u2010I, and FN. Irisin also attenuated advanced glycation end products\u2014or transforming growth factor\u2010\u03b2 (TGF\u2010\u03b2)\u2014induced ISC activation and extracellular matrix production and competitively bound to TGF\u2010\u03b2 receptor 2 (TGFBR2), inhibiting TGF\u2010\u03b2\/Smad pathway phosphorylation. These findings suggest that exercise may help to alleviate diabetes\u2010related islet fibrosis, in part by suppressing ISC activation via irisin\u2010mediated inhibition of TGF\u2010\u03b2\/Smad signaling.<\/jats:p>","DOI":"10.1096\/fj.202601380rr","type":"journal-article","created":{"date-parts":[[2026,6,13]],"date-time":"2026-06-13T15:11:56Z","timestamp":1781363516000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Exercise\u2010Induced Irisin Antagonizes\n                    <scp>TGFBR2<\/scp>\n                    to Attenuate Islet Fibrosis and Improve Glucose Homeostasis in Type 2 Diabetes"],"prefix":"10.1096","volume":"40","author":[{"given":"Qianqian","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Endocrinology, Zhongda Hospital, Institute of Diabetes, School of Medicine Southeast University  Nanjing Jiangsu 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