Extracellular Matrix Stiffness Mediates Insulin Secretion in Pancreatic Islets Via Phosphofructokinase Activity and Piezo1 Activation

The pancreatic islet is surrounded by ECM that provides both biochemical and mechanical cues to the islet β-cell to regulate cell survival and insulin secretion. Changes in ECM composition and mechanical properties drive β-cell dysfunction in many pancreatic diseases. While several studies have characterized changes in islet dysfunction with changes in substrate stiffness, little is known about the mechanotransduction signaling driving altered islet function in response to mechanical cues. The goal of this study is to determine how matrix stiffness regulates insulin secretion in mouse and human islets. We hypothesized that increasing matrix stiffness will increase islet glucose sensitivity by activating the mechanosensing Piezo1 channel and increasing phosphofructokinase (PFK) activity in pancreatic islets. To test our hypothesis, mouse and human cadaveric islets were encapsulated in a synthetic reverse thermal gel (RTG) scaffold with tailorable stiffness that allowed us to isolate the impact of scaffold stiffness on islet function. Our results indicate that increased scaffold stiffness causes dysfunction to insulin secretion at low glucose levels mediated by closure of Piezo1 channels and increased PFK activity. Additionally, inhibition of Piezo1 rescued glucose-stimulated insulin secretion in islets in stiff scaffolds. Overall, our results emphasize the role β-cell mechanosensing plays in regulating function and supports further investigation into the modulation of Piezo1 channel activity to restore islet function in diseases like type 2 diabetes (T2D) and pancreatic cancer where fibrosis of the peri-islet ECM leads to increased tissue stiffness and islet dysfunction.