Piezo1 channel agonist mimics high glucose as a stimulator of insulin release

Objective: Glucose and hypotonicity induced cell swelling stimulate insulin release from pancreatic β-cells but the mechanisms are poorly understood. Recently, Piezo1 was identified as a mechanically-activated nonselective Ca 2+ permeable cationic channel in a range of mammalian cells. As cell swelling induced insulin release could be through stimulation of Ca 2+ permeable stretch activated channels, we hypothesised a role for Piezo1 in cell swelling induced insulin release.Methods: Two rat β-cell lines (INS-1 and BRIN-BD11) and freshly-isolated mouse pancreatic islets were studied. Intracellular Ca 2+ measurements were performed using the fura-2 Ca 2+ indicator dye. Piezo1 agonist Yoda1, a competitive antagonist of Yoda1 (Dooku1) and an inactive analogue of Yoda1 (2e) were used as chemical probes. Piezo1 mRNA and insulin secretion were measured by RT-PCR and ELISA respectively. Results: Piezo1 mRNA was detected in both β-cell lines and mouse islets. Yoda1 evoked Ca 2+ entry which was inhibited by Yoda1 antagonist Dooku1 as well as other Piezo1 inhibitors gadolinium and ruthenium red, and not mimicked by 2e. Yoda1, but not 2e, stimulated Dooku1-sensitive insulin release from β-cells and pancreatic islets. Hypotonicity and high glucose increased intracellular Ca 2+ and enhanced Yoda1 Ca 2+ influx responses. Pre-treatment with ruthenium red significantly reduced hypotonicity induced insulin release from β-cells and pancreatic islets.Conclusion: The data show that Piezo1 channel agonist induces insulin release from β-cell lines and mouse pancreatic islets suggesting a role for Piezo1 in cell swelling induced insulin release. Hence Piezo1 agonists have a potential to be used as enhancers of insulin release.