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

Chen Kang; Litao Xie; Susheel K Gunasekar; Anil Mishra; Yanhui Zhang; Saachi Pai; Yiwen Gao; Ashutosh Kumar; Andrew W Norris; Samuel B Stephens; Rajan Sah

doi:10.1038/s41467-017-02664-0

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

Journal article

Open access

Peer reviewed

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

Chen Kang, Litao Xie, Susheel K Gunasekar, Anil Mishra, Yanhui Zhang, Saachi Pai, Yiwen Gao, Ashutosh Kumar, Andrew W Norris, Samuel B Stephens, …

Nature communications, Vol.9(1), 367

01/25/2018

DOI: 10.1038/s41467-017-02664-0

PMCID: PMC5785485

PMID: 29371604

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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.

Islets of Langerhans - drug effects

Calcium Channels - metabolism

Calcium - metabolism

Membrane Proteins - genetics

Humans

Male

Mice, Transgenic

Glucose - pharmacology

Mice, Knockout

Insulin - metabolism

Insulin-Secreting Cells - metabolism

Animals

Insulin-Secreting Cells - drug effects

Islets of Langerhans - metabolism

CRISPR-Cas Systems

Cell Line, Tumor

Glucose - metabolism

Female

Membrane Proteins - metabolism

Blood Glucose - metabolism

Insulin Secretion

Details

Title: Subtitle: SWELL1 is a glucose sensor regulating β-cell excitability and systemic glycaemia
Creators: Chen Kang - Department of Internal Medicine, Division of Cardiovascular Medicine, University of Iowa, Carver College of Medicine, Iowa City, IA, 52242, USA
Litao Xie - Department of Internal Medicine, Division of Cardiovascular Medicine, University of Iowa, Carver College of Medicine, Iowa City, IA, 52242, USA
Susheel K Gunasekar - Department of Internal Medicine, Division of Cardiovascular Medicine, University of Iowa, Carver College of Medicine, Iowa City, IA, 52242, USA
Anil Mishra - Department of Internal Medicine, Division of Cardiovascular Medicine, University of Iowa, Carver College of Medicine, Iowa City, IA, 52242, USA
Yanhui Zhang - Department of Internal Medicine, Division of Cardiovascular Medicine, University of Iowa, Carver College of Medicine, Iowa City, IA, 52242, USA
Saachi Pai - Department of Internal Medicine, Division of Cardiovascular Medicine, University of Iowa, Carver College of Medicine, Iowa City, IA, 52242, USA
Yiwen Gao - Department of Internal Medicine, Division of Cardiovascular Medicine, University of Iowa, Carver College of Medicine, Iowa City, IA, 52242, USA
Ashutosh Kumar - Department of Internal Medicine, Division of Cardiovascular Medicine, University of Iowa, Carver College of Medicine, Iowa City, IA, 52242, USA
Andrew W Norris - Fraternal Order of the Eagles Diabetes Research Center, Iowa City, IA, 52242, USA
Samuel B Stephens - Fraternal Order of the Eagles Diabetes Research Center, Iowa City, IA, 52242, USA
Rajan Sah - Abboud Cardiovascular Research Center, University of Iowa Carver College of Medicine, Iowa City, IA, 52242, USA. rajan-sah@uiowa.edu
Resource Type: Journal article
Publication Details: Nature communications, Vol.9(1), 367
DOI: 10.1038/s41467-017-02664-0
PMID: 29371604
PMCID: PMC5785485
NLM abbreviation: Nat Commun
ISSN: 2041-1723
eISSN: 2041-1723
Publisher: England
Grant note: R01 DK106009 / NIDDK NIH HHS R01 DK097820 / NIDDK NIH HHS R24 DK096518 / NIDDK NIH HHS P30 DK054759 / NIDDK NIH HHS
Language: English
Date published: 01/25/2018
Academic Unit: Endocrinology and Diabetes; Stead Family Department of Pediatrics; Biochemistry and Molecular Biology; Endocrinology and Metabolism; Internal Medicine
Record Identifier: 9984024524702771

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