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Cited by 157Pancreatic function and diabetesCystic Fibrosis Research AdvancesDiabetes and associated disorders

Glucose-induced electrical activities and insulin secretion in pancreatic islet β-cells are modulated by CFTR

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Guo, Jing Hui, Chen, Hui, Ruan, Ye Chun, Zhang, Xue Lian, Zhang, Xiao Hu, Fok, Kin Lam, Tsang, Lai Ling, Yu, Mei Kuen +6 more·2014·Nature Communications
DOI 10.1038/ncomms5420PMC PMC4104438
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Abstract

The cause of insulin insufficiency remains unknown in many diabetic cases. Up to 50% adult patients with cystic fibrosis (CF), a disease caused by mutations in the gene encoding the CF transmembrane conductance regulator (CFTR), develop CF-related diabetes (CFRD) with most patients exhibiting insulin insufficiency. Here we show that CFTR is a regulator of glucose-dependent electrical acitivities and insulin secretion in β-cells. We demonstrate that glucose elicited whole-cell currents, membrane depolarization, electrical bursts or action potentials, Ca 2+oscillations and insulin secretion are abolished or reduced by inhibitors or knockdown of CFTR in primary mouse β-cells or RINm5F β-cell line, or significantly attenuated in CFTR mutant (DF508) mice compared with wild-type mice. VX-809, a newly discovered corrector of DF508 mutation, successfully rescues the defects in DF508 β-cells. Our results reveal a role of CFTR in glucose-induced electrical activities and insulin secretion in β-cells, shed light on the pathogenesis of CFRD and possibly other idiopathic diabetes, and present a potential treatment strategy.

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  • The reported glucose-activated CFTR current in mouse β-cells corresponds to a whole-cell conductance of 20 nS, which is too large: it would clamp the membrane potential at the Cl- equilibrium potential and prevent action potential firing.

    “The reported (244) current-voltage relationship of the glucose-activated CFTR current in metabolically intact mouse β-cells corresponds to a whole-cell conductance of 20 nS. This is 5-fold larger than the resting conductance recorded from metabolically intact β-cells in the absence of glucose (221), and 10-fold larger than the peak voltage-gated Ca2+ current (see legend to Figure 9) (221). With CF”

    From Pancreatic β-Cell Electrical Activity and Insulin Secretion: Of Mice and Men (2018) · cites this paper as [244]

    The Results section on glucose-sensitive CFTR-mediated Cl− currents reports a glucose-activated whole-cell current in primary mouse β-cells and refers to its current–voltage data in Fig. 1c. Our text copy does not give a 20 nS conductance. The claim that this conductance would clamp the membrane potential and prevent firing is the citing authors’ critique, not a conclusion reported by this source; its Results instead report glucose-induced action potentials. (LLM, conf=0.82)

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Authors
Guo, J. H., Chen, H., Ruan, Y. C., Zhang, X. L., Zhang, X. H., Fok, K. L., Tsang, L. L., Yu, M. K., Huang, W. Q., Sun, X., Chung, Y. W., Jiang, X., Sohma, Y., & Chan, H. C.
Affiliations
  • Chinese University of Hong Kong (HK)
  • Beijing Tongren Hospital (CN)
  • Keio University (JP)
Corresponding author
Chan, Hsiao Chang
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2014-07-15
Volume
5
Issue
1
Pages
4420-4420
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/ncomms5420
PMC
PMC4104438
OpenAlex
W2147821592
Cited by
157
References
4
Citations by year
2026: 6 · 2025: 10 · 2024: 7 · 2023: 7 · 2022: 9 · 2021: 25 · 2020: 10 · 2019: 18 · 2018: 20 · 2017: 19 · 2016: 10 · 2015: 10 · 2014: 6
FWCI
14.88
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
Funders
  • Chinese University of Hong Kong
  • Japan Society for the Promotion of Science (25293049)
Topics
  • Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Cystic Fibrosis Research Advances
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
Keywords
CFTR, cystic fibrosis-related diabetes, pancreatic beta cells, insulin secretion, calcium oscillations, lumacaftor, CFTR correctors, membrane depolarization, action potential
MeSH terms
Insulin Secretion, Animals, Enzyme-Linked Immunosorbent Assay, Glucose, Insulin, Male, Membrane Potentials, Mice, Inbred C57BL, Patch-Clamp Techniques, Cystic Fibrosis Transmembrane Conductance Regulator, Insulin-Secreting Cells, Mice

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