Abstract

Pancreatic islets respond to obesity-related insulin resistance by increasing β cell mass and insulin secretion. However, the molecular mechanisms behind this vital compensation are not fully understood. This study shows that adaptive islet–derived small extracellular vesicles (aid-sEVs) play a key role in β cell adaptation in obesity. Aid-sEV production rises under hyperlipidemic conditions, and uptake by adjacent cells occurs via F11R-mediated recognition. Mesenchymal stem cells (MSCs) act as downstream effectors after they internalize aid-sEVs, promoting β cell–adaptive responses. These vesicles deliver miR-151 to MSCs, triggering miR-151– dependent cellular reprogramming toward a Wnt-secreting phenotype. Restoration of miR-151 in microRNA-deficient aid-sEVs restores their proadaptive effects on β cells. Klf9 , a direct target of miR-151 , is involved in regulating MSC proliferation and WNT secretion by controlling Wnt3a and Ccnd1 transcription. These findings reveal a critical pathway controlling β cell compensation in diet-induced obesity and indicate that targeted enhancement of aid-sEV secretion could be a therapeutic strategy to counteract β cell dysfunction in diabetic patients.