title: CFTR is involved in the regulation of glucagon secretion in human and rodent alpha cells.
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 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.
authors.affiliation: Unit of Islet Cell Exocytosis, Lund University Diabetes Centre, Department of Clinical Sciences in Malmö, Lund University, CRC, SUS Malmö, Malmö, Sweden. anna.edlund@med.lu.se.
authors.forename: Anna
authors.initials: A
authors.lastname: Edlund
authors.affiliation: Department of Information Engineering, University of Padova, Via Gradenigo 6/B, 35131, Padova, Italy.
authors.forename: Morten Gram
authors.identifier: 0000-0002-2639-2394
authors.initials: MG
authors.lastname: Pedersen
authors.affiliation: Unit of Neuroendocrine Cell Biology, Lund University Diabetes Centre, Department of Clinical Sciences in Malmö, Lund University, CRC, SUS Malmö, Malmö, Sweden.
authors.forename: Andreas
authors.initials: A
authors.lastname: Lindqvist
authors.affiliation: Unit of Neuroendocrine Cell Biology, Lund University Diabetes Centre, Department of Clinical Sciences in Malmö, Lund University, CRC, SUS Malmö, Malmö, Sweden.
authors.forename: Nils
authors.initials: N
authors.lastname: Wierup
authors.affiliation: Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Huddinge University Hospital, Stockholm, Sweden.
authors.forename: Malin
authors.identifier: 0000-0003-2685-2052
authors.initials: M
authors.lastname: Flodström-Tullberg
authors.affiliation: Unit of Islet Cell Exocytosis, Lund University Diabetes Centre, Department of Clinical Sciences in Malmö, Lund University, CRC, SUS Malmö, Malmö, Sweden. lena.eliasson@med.lu.se.
authors.forename: Lena
authors.identifier: 0000-0002-6467-5029
authors.initials: L
authors.lastname: Eliasson
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D005576:Colforsin / Q000378:metabolism; D003550:Cystic Fibrosis / Q000235:genetics; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005934:Glucagon / Q000378:metabolism*; D050416:Glucagon-Secreting Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D005947:Glucose / Q000494:pharmacology; D006801:Humans; D008297:Male; D008564:Membrane Potentials; D051379:Mice; D008875:Middle Aged; D009154:Mutation; D019864:Somatostatin-Secreting Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism
chemical_list: C505032:CFTR protein, human; C000628140:Cftr protein, mouse; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D005576:Colforsin; D005934:Glucagon; D005947:Glucose