Exercise-Induced Irisin Antagonizes TGFBR2 to Attenuate Islet Fibrosis and Improve Glucose Homeostasis in Type 2 Diabetes.

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.