Exercise‐Induced Irisin Antagonizes <scp>TGFBR2</scp> to Attenuate Islet Fibrosis and Improve Glucose Homeostasis in Type 2 Diabetes

ABSTRACT This study examined the effects of exercise on islet fibrosis in mice with type 2 diabetes and investigated the role of irisin in the regulation of islet stellate cell (ISC) activation. Following the 16‐week moderate‐intensity exercise intervention, db/db mice showed reduced body weight and improved glucose tolerance and insulin sensitivity. This exercise intervention also decreased collagen‐I (Col‐I), fibronectin (FN), and α‐smooth muscle actin (α‐SMA); reduced islet fibrosis area (assessed by Masson staining); and lowered the numbers of α‐SMA‐positive ISCs in the pancreas. Serum irisin was increased after a single bout of moderate‐intensity exercise but decreased following the 16‐week exercise intervention. In vitro experiments showed that irisin suppressed ISC activation by delaying lipid droplet loss, inhibiting migration, and reducing expression of α‐SMA, Col‐I, and FN. Irisin also attenuated advanced glycation end products—or transforming growth factor‐β (TGF‐β)—induced ISC activation and extracellular matrix production and competitively bound to TGF‐β receptor 2 (TGFBR2), inhibiting TGF‐β/Smad pathway phosphorylation. These findings suggest that exercise may help to alleviate diabetes‐related islet fibrosis, in part by suppressing ISC activation via irisin‐mediated inhibition of TGF‐β/Smad signaling.