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Nat Commun. 2018 Jan 25;9(1):367. doi: 10.1038/s41467-017-02664-0.

SWELL1 is a glucose sensor regulating β-cell excitability and systemic glycaemia.

Author information

1
Department of Internal Medicine, Division of Cardiovascular Medicine, University of Iowa, Carver College of Medicine, Iowa City, IA, 52242, USA.
2
Department of Pediatrics, University of Iowa, Carver College of Medicine, Iowa City, IA, 52242, USA.
3
Fraternal Order of the Eagles Diabetes Research Center, Iowa City, IA, 52242, USA.
4
Department of Internal Medicine, Division of Cardiovascular Medicine, University of Iowa, Carver College of Medicine, Iowa City, IA, 52242, USA. rajan-sah@uiowa.edu.
5
Fraternal Order of the Eagles Diabetes Research Center, Iowa City, IA, 52242, USA. rajan-sah@uiowa.edu.
6
Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine, Iowa City, IA, 52242, USA. rajan-sah@uiowa.edu.

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.

PMID:
29371604
PMCID:
PMC5785485
DOI:
10.1038/s41467-017-02664-0
[Indexed for MEDLINE]
Free PMC Article

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