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Cited by 50Pancreatic function and diabetesIon channel regulation and functionCardiac electrophysiology and arrhythmias

BK channels affect glucose homeostasis and cell viability of murine pancreatic beta cells

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Düfer, M., Neye, Y., Hörth, K., Krippeit-Drews, P., Hennige, A., Widmer, H., McClafferty, H., Shipston, M. J. +3 more·2011·Diabetologia
DOI 10.1007/s00125-010-1936-0PMC PMC4005923
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Abstract

Aims/hypothesis Evidence is accumulating that Ca(2+)-regulated K(+) (K(Ca)) channels are important for beta cell function. We used BK channel knockout (BK-KO) mice to examine the role of these K(Ca) channels for glucose homeostasis, beta cell function and viability. Methods Glucose and insulin tolerance were tested with male wild-type and BK-KO mice. BK channels were detected by single-cell RT-PCR, cytosolic Ca(2+) concentration ([Ca(2+)](c)) by fura-2 fluorescence, and insulin secretion by radioimmunoassay. Electrophysiology was performed with the patch-clamp technique. Apoptosis was detected via caspase 3 or TUNEL assay. Results BK channels were expressed in murine pancreatic beta cells. BK-KO mice were normoglycaemic but displayed markedly impaired glucose tolerance. Genetic or pharmacological deletion of the BK channel reduced glucose-induced insulin secretion from isolated islets. BK-KO and BK channel inhibition (with iberiotoxin, 100 nmol/l) broadened action potentials and abolished the after-hyperpolarisation in glucose-stimulated beta cells. However, BK-KO did not affect action potential frequency, the plateau potential at which action potentials start or glucose-induced elevation of [Ca(2+)](c). BK-KO had no direct influence on exocytosis. Importantly, in BK-KO islet cells the fraction of apoptotic cells and the rate of cell death induced by oxidative stress (H(2)O(2), 10-100 μmol/l) were significantly increased compared with wild-type controls. Similar effects were obtained with iberiotoxin. Determination of H(2)O(2)-induced K(+) currents revealed that BK channels contribute to the hyperpolarising K(+) current activated under conditions of oxidative stress. Conclusions/interpretation Ablation or inhibition of BK channels impairs glucose homeostasis and insulin secretion by interfering with beta cell stimulus-secretion coupling. In addition, BK channels are part of a defence mechanism against apoptosis and oxidative stress.

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Authors
Düfer, M., Neye, Y., Hörth, K., Krippeit-Drews, P., Hennige, A., Widmer, H., McClafferty, H., Shipston, M. J., Häring, H.-U., Ruth, P., & Drews, G.
Affiliations
  • University of Tübingen (DE)
  • Glasgow Caledonian University (GB)
  • University of Edinburgh (GB)
Corresponding author
Drews, G.
ORCID
Venue
Diabetologia
Publisher
Springer Science and Business Media LLC
Published
2010-10-28
Volume
54
Issue
2
Pages
423-432
ISSN
  • 0012-186X (ISSN-L)
  • 1432-0428
DOI
10.1007/s00125-010-1936-0
PMC
PMC4005923
OpenAlex
W2132820399
Cited by
50
References
3
Citations by year
2025: 3 · 2023: 1 · 2022: 2 · 2021: 4 · 2020: 3 · 2019: 2 · 2018: 2 · 2017: 4 · 2016: 4 · 2015: 5 · 2014: 5 · 2013: 4 · 2012: 8
FWCI
5.07
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Diabetologia (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • ResearchOnline (acceptedVersion)
  • Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
Funders
  • Wellcome Trust (082407)
  • Deutsche Forschungsgemeinschaft
Topics
  • Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
Keywords
BK channels, pancreatic beta cells, glucose homeostasis, glucose tolerance, insulin secretion, stimulus-secretion coupling, beta-cell apoptosis, oxidative stress, iberiotoxin, potassium currents
MeSH terms
Animals, Cell Survival, Cells, Cultured, Electrophysiology, Glucose, Homeostasis, Male, Potassium Channels, Polymerase Chain Reaction, Apoptosis, Mice, Knockout, Mice

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