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ludc web

Anna Wendt

Assistant researcher

ludc web

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

Author

  • Anna Edlund
  • Mohammad Barghouth
  • Michael Huhn
  • Mia Abels
  • Jonathan Esguerra
  • Ines Mollet
  • Emma Svedin
  • Anna Wendt
  • Erik Renström
  • Enming Zhang
  • Nils Wierup
  • Bob J Scholte
  • Malin Flodström-Tullberg
  • Lena Eliasson

Summary, in English

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.

Department/s

  • Diabetes - Islet Cell Exocytosis
  • Diabetes - Islet Patophysiology
  • Neuroendocrine Cell Biology
  • Cardiovascular Research - Immunity and Atherosclerosis
  • EXODIAB: Excellence of Diabetes Research in Sweden
  • Department of Clinical Sciences, Malmö

Publishing year

2019

Language

English

Pages

45-57

Publication/Series

Journal of Endocrinology

Volume

241

Issue

1

Document type

Journal article

Publisher

Society for Endocrinology

Topic

  • Endocrinology and Diabetes

Status

Published

Research group

  • Diabetes - Islet Cell Exocytosis
  • Diabetes - Islet Patophysiology
  • Neuroendocrine Cell Biology
  • Cardiovascular Research - Immunity and Atherosclerosis

ISBN/ISSN/Other

  • ISSN: 1479-6805