Abstract
Insulin secretion is initiated by activation of voltage-gated Ca2+ channels (VGCC) to trigger Ca2+-mediated insulin vesicle fusion with the β-cell plasma membrane. The firing of VGCC requires β-cell membrane depolarization, which is regulated by a balance of depolarizing and hyperpolarizing ionic currents. Here, we show that SWELL1 mediates a swell-activated, depolarizing chloride current (ICl,SWELL) in both murine and human β-cells. Hypotonic and glucose-stimulated β-cell swelling activates SWELL1-mediated ICl,SWELL and this contributes to membrane depolarization and activation of VGCC-dependent intracellular calcium signaling. SWELL1 depletion in MIN6 cells and islets significantly impairs glucose-stimulated insulin secretion. Tamoxifen-inducible β-cell-targeted Swell1 KO mice have normal fasting serum glucose and insulin levels but impaired glucose-stimulated insulin secretion and glucose tolerance; and this is further exacerbated in mild obesity. Our results reveal that β-cell SWELL1 modulates insulin secretion and systemic glycaemia by linking glucose-mediated β-cell swelling to membrane depolarization and activation of VGCC-triggered calcium signaling.
Highlights
Insulin secretion is initiated by activation of voltage-gated Ca2+ channels (VGCC) to trigger Ca2+-mediated insulin vesicle fusion with the β-cell plasma membrane
We find that basal serum insulin values are similar between genotypes (Fig. 8g), with glucose stimulation insulin secretion is significantly impaired in Tm-induced Ins1CreERT2;Swell1fl/fl (+) mice compared to Tminduced Swell1fl/fl mice (+) (Fig. 8g, h), and this is associated with impaired glucose tolerance (Fig. 8i)
volume regulatory anion current (VRAC) or ICl, SWELL is a swell-activated ionic current that has been studied for decades through electrophysiological recordings in numerous cell types[42,43,44], but only recently has it been discovered that SWELL1/
Summary
Insulin secretion is initiated by activation of voltage-gated Ca2+ channels (VGCC) to trigger Ca2+-mediated insulin vesicle fusion with the β-cell plasma membrane. There is a longstanding hypothesis, first proposed in the 1990s, that an elusive chloride (Cl−) conductance known as the volume regulatory anion current (VRAC) or swell-activated Cl− current (ICl,SWELL) is responsible for an important glucose sensitive, swellactivated depolarizing current that is required for β-cell depolarization and subsequent activation of VGCC-mediated Ca2+ signaling, insulin vesicle fusion and insulin secretion[13,14,15,16,17,18,19,20]. These data highlight SWELL1-mediated “swellsecretion” coupling as required for glucose-stimulated insulin secretion (GSIS) and for regulation of systemic glycaemia
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
