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CFTR is involved in the regulation of glucagon secretion in human and rodent alpha cells

Edlund, Anna LU ; Pedersen, Morten Gram LU ; Lindqvist, Andreas LU ; Wierup, Nils LU ; Flodström-Tullberg, Malin and Eliasson, Lena LU orcid (2017) In Scientific Reports 7. p.1-12
Abstract

Glucagon is the main counterregulatory hormone in the body. Still, the mechanism involved in the regulation of glucagon secretion from pancreatic alpha cells remains elusive. Dysregulated glucagon secretion is common in patients with Cystic Fibrosis (CF) that develop CF related diabetes (CFRD). CF is caused by a mutation in the Cl- channel Cystic fibrosis transmembrane conductance regulator (CFTR), but whether CFTR is present in human alpha cells and regulate glucagon secretion has not been investigated in detail. Here, both human and mouse alpha cells showed CFTR protein expression, whereas CFTR was absent in somatostatin secreting delta cells. CFTR-current activity induced by cAMP was measured in single alpha cells. Glucagon secretion... (More)

Glucagon is the main counterregulatory hormone in the body. Still, the mechanism involved in the regulation of glucagon secretion from pancreatic alpha cells remains elusive. Dysregulated glucagon secretion is common in patients with Cystic Fibrosis (CF) that develop CF related diabetes (CFRD). CF is caused by a mutation in the Cl- channel Cystic fibrosis transmembrane conductance regulator (CFTR), but whether CFTR is present in human alpha cells and regulate glucagon secretion has not been investigated in detail. Here, both human and mouse alpha cells showed CFTR protein expression, whereas CFTR was absent in somatostatin secreting delta cells. CFTR-current activity induced by cAMP was measured in single alpha cells. Glucagon secretion at different glucose levels and in the presence of forskolin was increased by CFTR-inhibition in human islets, whereas depolarization-induced glucagon secretion was unaffected. CFTR is suggested to mainly regulate the membrane potential through an intrinsic alpha cell effect, as supported by a mathematical model of alpha cell electrophysiology. In conclusion, CFTR channels are present in alpha cells and act as important negative regulators of cAMP-enhanced glucagon secretion through effects on alpha cell membrane potential. Our data support that loss-of-function mutations in CFTR contributes to dysregulated glucagon secretion in CFRD.

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author
; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Scientific Reports
volume
7
article number
90
pages
1 - 12
publisher
Nature Publishing Group
external identifiers
  • scopus:85030649657
  • pmid:28273890
ISSN
2045-2322
DOI
10.1038/s41598-017-00098-8
language
English
LU publication?
yes
id
71144849-e9c3-483e-b2dc-8a443867289d
date added to LUP
2018-08-21 14:12:24
date last changed
2025-01-08 13:27:41
@article{71144849-e9c3-483e-b2dc-8a443867289d,
  abstract     = {{<p>Glucagon is the main counterregulatory hormone in the body. Still, the mechanism involved in the regulation of glucagon secretion from pancreatic alpha cells remains elusive. Dysregulated glucagon secretion is common in patients with Cystic Fibrosis (CF) that develop CF related diabetes (CFRD). CF is caused by a mutation in the Cl- channel Cystic fibrosis transmembrane conductance regulator (CFTR), but whether CFTR is present in human alpha cells and regulate glucagon secretion has not been investigated in detail. Here, both human and mouse alpha cells showed CFTR protein expression, whereas CFTR was absent in somatostatin secreting delta cells. CFTR-current activity induced by cAMP was measured in single alpha cells. Glucagon secretion at different glucose levels and in the presence of forskolin was increased by CFTR-inhibition in human islets, whereas depolarization-induced glucagon secretion was unaffected. CFTR is suggested to mainly regulate the membrane potential through an intrinsic alpha cell effect, as supported by a mathematical model of alpha cell electrophysiology. In conclusion, CFTR channels are present in alpha cells and act as important negative regulators of cAMP-enhanced glucagon secretion through effects on alpha cell membrane potential. Our data support that loss-of-function mutations in CFTR contributes to dysregulated glucagon secretion in CFRD.</p>}},
  author       = {{Edlund, Anna and Pedersen, Morten Gram and Lindqvist, Andreas and Wierup, Nils and Flodström-Tullberg, Malin and Eliasson, Lena}},
  issn         = {{2045-2322}},
  language     = {{eng}},
  month        = {{03}},
  pages        = {{1--12}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Scientific Reports}},
  title        = {{CFTR is involved in the regulation of glucagon secretion in human and rodent alpha cells}},
  url          = {{http://dx.doi.org/10.1038/s41598-017-00098-8}},
  doi          = {{10.1038/s41598-017-00098-8}},
  volume       = {{7}},
  year         = {{2017}},
}