Diabetes mellitus remains a growing global health burden, yet advances in mechanobiology highlight a pivotal role for mechanical cues in regulating pancreatic β-cell function. This review summarizes evidence that the extracellular matrix (ECM) surrounding pancreatic islets is not merely structural support but a dynamic mechanosignaling platform integrating biochemical and physical stimuli to govern β-cell fate. In healthy tissue, a compliant ECM enriched in collagen IV and laminin supports optimal insulin secretion and glucose responsiveness. In contrast, obesity- and diabetes-associated fibrosis induces excessive ECM deposition, aberrant crosslinking, and pathological stiffening, disrupting mechanosensing, glucose signaling, and β-cell maturation. Mechanical forces are transmitted through integrin-mediated focal adhesions and FAK activation, triggering MAPK, PI3K–AKT, and Rho GTPase pathways that regulate cytoskeletal tension, transcriptional programming, and survival. Mechanosensitive Piezo1 channels convert membrane stretch into Ca 2+ influx, modulating insulin exocytosis, while the Hippo–YAP/TAZ axis interprets matrix stiffness to control β-cell proliferation and phenotypic stability. Chronic hyperglycemia further induces nuclear deformation and chromatin remodeling, impairing transcription factors such as PDX1 and accelerating β-cell dysfunction. These pathways intersect with inflammatory and oxidative stress signaling, driving apoptosis and progressive β-cell loss in type 2 diabetes. By reframing diabetes as a disorder of aberrant cell–matrix communication, this review highlights mechanobiology-guided strategies including stiffness-tunable matrices, viscoelastic hydrogels, and mechano-responsive scaffolds to restore a functional microenvironment. Targeting ECM remodeling, modulating Piezo1 activity, and fine-tuning YAP signaling, particularly with stem cell-derived β-cell replacement, offers a promising approach for restoring β-cell mass and achieving durable glycemic control.
Swaminadhan et al. (Tue,) studied this question.