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Defective exocytosis and processing of insulin in a cystic fibrosis mouse model

Edlund, Anna LU ; Barghouth, Mohammad LU ; Huhn, Michael ; Abels, Mia LU ; Esguerra, Jonathan LU ; Mollet, Ines LU ; Svedin, Emma LU ; Wendt, Anna LU ; Renström, Erik LU and Zhang, Enming LU , et al. (2019) In Journal of Endocrinology 241(1). p.45-57
Abstract

Cystic fibrosis-related diabetes (CFRD) is a common complication for patients with cystic fibrosis (CF), a disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR). The cause of CFRD is unclear, but a commonly observed reduction in first-phase insulin secretion suggests defects at the beta cell level. Here we aimed to examine beta- and alpha-cell function in the Cftrtm1EUR/F508del mouse model (C57BL/6J), which carries the most common human mutation in CFTR, the F508del mutation. CFTR expression, beta cell mass, insulin granule distribution, hormone secretion and single cell capacitance changes were evaluated using islets (or beta cells) from F508del mice and age-matched wild-type mice aged 7-10... (More)

Cystic fibrosis-related diabetes (CFRD) is a common complication for patients with cystic fibrosis (CF), a disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR). The cause of CFRD is unclear, but a commonly observed reduction in first-phase insulin secretion suggests defects at the beta cell level. Here we aimed to examine beta- and alpha-cell function in the Cftrtm1EUR/F508del mouse model (C57BL/6J), which carries the most common human mutation in CFTR, the F508del mutation. CFTR expression, beta cell mass, insulin granule distribution, hormone secretion and single cell capacitance changes were evaluated using islets (or beta cells) from F508del mice and age-matched wild-type mice aged 7-10 weeks. Granular pH was measured with DND-189 fluorescence. Serum glucose, insulin and glucagon levels were measured in vivo, and glucose tolerance was assessed using IPGTT. We show increased secretion of proinsulin and concomitant reduced secretion of C-peptide in islets from F508del mice compared to WT mice. Exocytosis and number of docked granules was reduced. We confirmed reduced granular pH by CFTR stimulation. We detected decreased pancreatic beta cell area, but unchanged beta cell number. Moreover, the F508del mutation caused failure to suppress glucagon secretion leading to hyperglucagonemia. In conclusion, F508del mice have beta cell defects resulting in 1) reduced number of docked insulin granules and reduced exocytosis, and 2) potential defective proinsulin cleavage and secretion of immature insulin. These observations provide insight into the functional role of CFTR in pancreatic islets and contribute to increased understanding of the pathogenesis of CFRD.

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published
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Journal of Endocrinology
volume
241
issue
1
pages
45 - 57
publisher
Society for Endocrinology
external identifiers
  • pmid:30721137
  • scopus:85063933976
ISSN
1479-6805
DOI
10.1530/JOE-18-0570
language
English
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yes
id
44675df5-1a93-45f3-ac24-4f724c948d80
date added to LUP
2019-04-09 11:32:38
date last changed
2020-01-26 05:32:16
@article{44675df5-1a93-45f3-ac24-4f724c948d80,
  abstract     = {<p>Cystic fibrosis-related diabetes (CFRD) is a common complication for patients with cystic fibrosis (CF), a disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR). The cause of CFRD is unclear, but a commonly observed reduction in first-phase insulin secretion suggests defects at the beta cell level. Here we aimed to examine beta- and alpha-cell function in the Cftrtm1EUR/F508del mouse model (C57BL/6J), which carries the most common human mutation in CFTR, the F508del mutation. CFTR expression, beta cell mass, insulin granule distribution, hormone secretion and single cell capacitance changes were evaluated using islets (or beta cells) from F508del mice and age-matched wild-type mice aged 7-10 weeks. Granular pH was measured with DND-189 fluorescence. Serum glucose, insulin and glucagon levels were measured in vivo, and glucose tolerance was assessed using IPGTT. We show increased secretion of proinsulin and concomitant reduced secretion of C-peptide in islets from F508del mice compared to WT mice. Exocytosis and number of docked granules was reduced. We confirmed reduced granular pH by CFTR stimulation. We detected decreased pancreatic beta cell area, but unchanged beta cell number. Moreover, the F508del mutation caused failure to suppress glucagon secretion leading to hyperglucagonemia. In conclusion, F508del mice have beta cell defects resulting in 1) reduced number of docked insulin granules and reduced exocytosis, and 2) potential defective proinsulin cleavage and secretion of immature insulin. These observations provide insight into the functional role of CFTR in pancreatic islets and contribute to increased understanding of the pathogenesis of CFRD.</p>},
  author       = {Edlund, Anna and Barghouth, Mohammad and Huhn, Michael and Abels, Mia and Esguerra, Jonathan and Mollet, Ines and Svedin, Emma and Wendt, Anna and Renström, Erik and Zhang, Enming and Wierup, Nils and Scholte, Bob J and Flodström-Tullberg, Malin and Eliasson, Lena},
  issn         = {1479-6805},
  language     = {eng},
  number       = {1},
  pages        = {45--57},
  publisher    = {Society for Endocrinology},
  series       = {Journal of Endocrinology},
  title        = {Defective exocytosis and processing of insulin in a cystic fibrosis mouse model},
  url          = {http://dx.doi.org/10.1530/JOE-18-0570},
  doi          = {10.1530/JOE-18-0570},
  volume       = {241},
  year         = {2019},
}