CFTR is involved in the regulation of glucagon secretion in human and rodent alpha cells
Open accessAbstract
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.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
A relatively large set of mathematical models were developed with focus on glucagon secretion at cellular level.
“A relatively large set of mathematical models were developed with focus on glucagon secretion at cellular level (12–21).”
From Mathematical Model of Glucagon Kinetics for the Assessment of Insulin-Mediated Glucagon Inhibition During an Oral Glucose Tolerance Test (2021) · cites this paper as [15]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
The unique cytoarchitecture of human pancreatic islets has implications for islet cell function
Cabrera, O., Berman, D. M., Kenyon, N. S., Ricordi, C., Berggren, P.-O., & Caicedo, A. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0510790103 · Cited by 1,312 · see citing works
Structure and Function of the CFTR Chloride Channel
Sheppard, D. N., & Welsh, M. J. (1999) · Physiological Reviews · doi:10.1152/physrev.1999.79.1.s23 · Cited by 1,025 · see citing works
Bonner, C., Kerr-Conte, J., Gmyr, V., Queniat, G., Moerman, E., Thévenet, J., Beaucamps, C., Delalleau, N., Popescu, I., Malaisse, W. J., et al. (2015) · Nature Medicine · doi:10.1038/nm.3828 · Cited by 670 · see citing works
Cystic Fibrosis–Related Diabetes: Current Trends in Prevalence, Incidence, and Mortality
Moran, A., Dunitz, J., Nathan, B. M., Saeed, A., Holme, B., & Thomas, W. T. B. (2009) · Diabetes Care · doi:10.2337/dc09-0586 · Cited by 648 · see citing works
CFTR Is a Conductance Regulator as well as a Chloride Channel
Schwiebert, E. M., Benos, D. J., Egan, M. E., et al. (1999) · Physiological Reviews · doi:10.1152/physrev.1999.79.1.s145 · Cited by 445 · see citing works
The Phenotypic Consequences of CFTR Mutations
Rowntree, R. K., & Harris, A. (2003) · Annals of Human Genetics · doi:10.1046/j.1469-1809.2003.00028.x · Cited by 339 · see citing works
Hauge-Evans, A. C., King, A. J., Carmignac, D., Richardson, C. C., Robinson, I. C. A. F., Low, M. J., Christie, M. R., Persaud, S. J., & Jones, P. M. (2009) · Diabetes · doi:10.2337/db08-0792 · Cited by 335 · see citing works
Franklin, I., Gromada, J., Gjinovci, A., Theander, S., & Wollheim, C. (2005) · Diabetes · doi:10.2337/diabetes.54.6.1808 · Cited by 291 · see citing works
Epidemiology, Pathophysiology, and Prognostic Implications of Cystic Fibrosis–Related Diabetes
Moran, A., Becker, D. J., Casella, S. J., et al. (2010) · Diabetes Care · doi:10.2337/dc10-1279 · Cited by 258 · see citing works
De Marinis, Y. Z., Salehi, A., Ward, C. E., Zhang, Q., Abdulkader, F., Bengtsson, M., Braha, O., Braun, M., Ramracheya, R., Amisten, S., et al. (2010) · Cell Metabolism · doi:10.1016/j.cmet.2010.04.007 · Cited by 257 · see citing works
Self-citationWendt, A., Birnir, B., Buschard, K., Gromada, J., Salehi, A. A., Sewing, S., Rorsman, P., & Braun, M. (2004) · Diabetes · doi:10.2337/diabetes.53.4.1038 · Cited by 257 · see citing works
Urocortin3 mediates somatostatin-dependent negative feedback control of insulin secretion
van der Meulen, T., Donaldson, C. J., Cáceres, E., Hunter, A. E., Cowing-Zitron, C., Pound, L. D., Adams, M. W., Zembrzycki, A., Grove, K. L., & Huising, M. O. (2015) · Nature Medicine · doi:10.1038/nm.3872 · Cited by 256 · see citing works
MacDonald, P. E., Marinis, Y. Z. D., Ramracheya, R. D., Salehi, A. A., Ma, X., Johnson, P., Cox, R., Eliasson, L., & Rorsman, P. (2007) · PLoS Biology · doi:10.1371/journal.pbio.0050143 · Cited by 243 · see citing works
Self-citationGöpel, S. O., Kanno, T., Barg, S., Weng, X. ‐., Gromada, J., & Rorsman, P. (2000) · The Journal of Physiology · doi:10.1111/j.1469-7793.2000.00509.x · Cited by 229 · see citing works
Zhang, Q., Ramracheya, R., Lahmann, C., Tarasov, A., Bengtsson, M., Braha, O., Braun, M., Brereton, M., Collins, S., Galvanovskis, J., et al. (2013) · Cell Metabolism · doi:10.1016/j.cmet.2013.10.014 · Cited by 225 · see citing works
Update on cystic fibrosis-related diabetes
Kelly, A. T., & Moran, A. (2013) · Journal of Cystic Fibrosis · doi:10.1016/j.jcf.2013.02.008 · Cited by 202 · see citing works
Bellin, M. D., Laguna, T. A., Leschyshyn, J., Regelmann, W. E., Dunitz, J., Billings, J. L., & Moran, A. (2013) · Pediatric Diabetes · doi:10.1111/pedi.12026 · Cited by 193 · see citing works
Pancreatic endocrine function in cystic fibrosis
Moran, A., Diem, P., Klein, D. J., Levitt, M. D., & Robertson, R. P. (1991) · The Journal of Pediatrics · doi:10.1016/s0022-3476(05)80032-0 · Cited by 190 · see citing works
Guo, J. H., Chen, H., Ruan, Y. C., Zhang, X. L., Zhang, X. H., Fok, K. L., Tsang, L. L., Yu, M. K., Huang, W. Q., Sun, X., et al. (2014) · Nature Communications · doi:10.1038/ncomms5420 · Cited by 157 · see citing works
Clinical importance of cystic fibrosis-related diabetes
Brennan, A. L., Geddes, D. M., Gyi, K. M., & Baker, E. H. (2004) · Journal of Cystic Fibrosis · doi:10.1016/j.jcf.2004.08.001 · Cited by 149 · see citing works
PATEL, Y., & Srikant, C. B. (1997) · Trends in Endocrinology and Metabolism · doi:10.1016/s1043-2760(97)00168-9 · Cited by 148 · see citing works
Insulin Sensitivity in Cystic Fibrosis
Moran, A., Pyzdrowski, K. L., Weinreb, J. E., Kahn, B. B., Smith, S. A., Adams, K. S., & Seaquist, E. R. (1994) · Diabetes · doi:10.2337/diab.43.8.1020 · Cited by 144 · see citing works
Abnormal endocrine pancreas function at birth in cystic fibrosis ferrets
Olivier, A. K., Yi, Y., Sun, X., Sui, H., Liang, B., Hu, S., Xie, W., Fisher, J. T., Keiser, N. W., Lei, D., et al. (2012) · Journal of Clinical Investigation · doi:10.1172/jci60610 · Cited by 143 · see citing works
Edlund, A., Esguerra, J. L. S., Wendt, A., Flodström‐Tullberg, M., & Eliasson, L. (2014) · BMC Medicine · doi:10.1186/1741-7015-12-87 · Cited by 138 · see citing works
Self-citationRamracheya, R., Ward, C., Shigeto, M., Walker, J. N., Amisten, S., Zhang, Q., Johnson, P. R., Rorsman, P., & Braun, M. (2010) · Diabetes · doi:10.2337/db09-1505 · Cited by 136 · see citing works
Glucagon Stimulates Exocytosis in Mouse and Rat Pancreatic α-Cells by Binding to Glucagon Receptors
Ma, X., Zhang, Y., Gromada, J., Sewing, S., Berggren, P., Buschard, K., Salehi, A. A., Vikman, J., Rorsman, P., & Eliasson, L. (2004) · Molecular Endocrinology · doi:10.1210/me.2004-0059 · Cited by 130 · see citing works
Self-citationGromada, J., Høy, M., Buschard, K., Salehi, A., & Rorsman, P. (2001) · The Journal of Physiology · doi:10.1111/j.1469-7793.2001.00519.x · Cited by 120 · see citing works
Liu, Y.-J., Vieira, E., & Gylfe, E. (2004) · Cell Calcium · doi:10.1016/j.ceca.2003.10.002 · Cited by 118 · see citing works
R-type Ca2+-channel-evoked CICR regulates glucose-induced somatostatin secretion
Zhang, Q., Bengtsson, M., Partridge, C., Salehi, A., Braun, M., Cox, R., Eliasson, L., Johnson, P. R., Renström, E., Schneider, T., et al. (2007) · Nature Cell Biology · doi:10.1038/ncb1563 · Cited by 110 · see citing works
Self-citationLanng, S., Thorsteinsson, B., Røder, M. E., Ørskov, C., Holst, J. J., Nerup, J., & Koch, C. (1993) · European Journal of Endocrinology · doi:10.1530/acta.0.1280207 · Cited by 107 · see citing works
KATP-channels and glucose-regulated glucagon secretion
Rorsman, P., Salehi, A. A., Abdulkader, F., Braun, M., & MacDonald, P. E. (2008) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2008.07.003 · Cited by 101 · see citing works
Evidence that glucagon stimulates insulin secretion through its own receptor in rats
Kawai, K., Yokota, C., Ohashi, S., Watanabe, Y., & Yamashita, K. (1995) · Diabetologia · doi:10.1007/bf00400630 · Cited by 93 · see citing works
Hepatic insulin resistance and defects in substrate utilization in cystic fibrosis.
Hardin, D. S., LeBlanc, A., Para, L. H., & Seilheimer, D. K. (1999) · Diabetes · doi:10.2337/diabetes.48.5.1082 · Cited by 86 · see citing works
Kreienkamp, H., Hönck, H., & Richter, D. (1997) · FEBS Letters · doi:10.1016/s0014-5793(97)01437-3 · Cited by 85 · see citing works
Glucose intolerance in cystic fibrosis patients
Lanng, S. (2001) · Paediatric Respiratory Reviews · doi:10.1053/prrv.2001.0148 · Cited by 80 · see citing works
Boom, A., Lybaert, P., Pollet, J.-F., et al. (2007) · Endocrine · doi:10.1007/s12020-007-9026-x · Cited by 77 · see citing works
Glucagon secretion and signaling in the development of diabetes
Gaisano, H. Y., MacDonald, P. E., & Vranić, M. (2012) · Frontiers in Physiology · doi:10.3389/fphys.2012.00349 · Cited by 75 · see citing works
Pancreatic alpha and beta cell functions in cystic fibrosis
Lippe, B. M., Sperling, M. A., & Dooley, R. R. (1977) · The Journal of Pediatrics · doi:10.1016/s0022-3476(77)81241-9 · Cited by 68 · see citing works
Submembrane ATP and Ca2+kinetics in α-cells: unexpected signaling for glucagon secretion
Li, J., Yu, Q., Ahooghalandari, P., Gribble, F. M., Reimann, F. M., Tengholm, A., & Gylfe, E. (2015) · The FASEB Journal · doi:10.1096/fj.14-265918 · Cited by 67 · see citing works
Brunicardi, F. C., Kleinman, R. M., Moldovan, S., Nguyen, T.-H. L., Watt, P. C., Walsh, J. H., & Gingerich, R. L. (2001) · Pancreas · doi:10.1097/00006676-200110000-00012 · Cited by 64 · see citing works
Pedersen, M. G., Ahlstedt, I., El Hachmane, M. F., & Göpel, S. O. (2016) · Scientific Reports · doi:10.1038/srep31214 · Cited by 64 · see citing works
Self-citationVoltage-dependent Gating of the Cystic Fibrosis Transmembrane Conductance Regulator Cl− Channel
Cai, Z., Scott‐Ward, T. S., & Sheppard, D. N. (2003) · The Journal of General Physiology · doi:10.1085/jgp.200308921 · Cited by 59 · see citing works
Modeling the pancreatic α-cell: dual mechanisms of glucose suppression of glucagon secretion
Watts, M., & Sherman, A. (2014) · Biophysical Journal · doi:10.1016/j.bpj.2013.11.4504 · Cited by 45 · see citing works
Montefusco, F., & Pedersen, M. G. (2015) · The Journal of Physiology · doi:10.1113/jp270777 · Cited by 35 · see citing works
Self-citationDelta cell secretory responses to insulin secretagogues are not mediated indirectly by insulin
Hauge-Evans, A. C., Anderson, R. L., Persaud, S. J., & Jones, P. M. (2012) · Diabetologia · doi:10.1007/s00125-012-2546-9 · Cited by 33 · see citing works
Diderichsen, P. M., & Göpel, S. (2006) · Journal of Biological Physics · doi:10.1007/s10867-006-9013-0 · Cited by 30 · see citing works
Hardin, D. S., Ahn, C. W., Rice, J., Rice, M., & Rosenblatt, R. L. (2008) · Journal of Investigative Medicine · doi:10.2310/jim.0b013e3181671788 · Cited by 30 · see citing works
Postprandial hyperglycemia and pancreatic function in cystic fibrosis patients.
Hinds, A., Ag, S., Machida, H. M., et al. (1991) · PubMed · Cited by 17 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Ramracheya, R., Chapman, C., Chibalina, M., Dou, H., Miranda, C., González, A., Moritoh, Y., Shigeto, M., Zhang, Q., Braun, M., et al. (2018) · Physiological Reports · doi:10.14814/phy2.13852 · Cited by 128 · see citing works
Putman, M. S., Norris, A. W., Hull, R. L., Rickels, M. R., Sussel, L., Blackman, S. M., Chan, C. L., Ode, K. L., Daley, T., Stecenko, A. A., et al. (2023) · Diabetes Care · doi:10.2337/dc23-0380 · Cited by 35 · see citing works
Morettini, M., Burattini, L., Göbl, C., Pacini, G., Ahrén, B., & Tura, A. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.611147 · Cited by 27 · see citing works
- Authors
- Edlund, A., Pedersen, M. G., Lindqvist, A., Wierup, N., Flodström-Tullberg, M., & Eliasson, L.
- Affiliations
- Lund University (SE)
- University of Padua (IT)
- Corresponding author
- Edlund, Anna
- Eliasson, Lena
- ORCID
- Venue
- Scientific Reports
- Published
- 2017-03-07
- Volume
- 7
- Issue
- 1
- Pages
- 90-90
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC5428348
- OpenAlex
- W2592847274
- Cited by
- 63
- References
- 48
- Citations by year
- 2026: 5 · 2025: 3 · 2024: 4 · 2023: 6 · 2022: 7 · 2021: 9 · 2020: 10 · 2019: 10 · 2018: 5 · 2017: 4
- FWCI
- 8.13
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Scientific Reports (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Tampere University Institutional Repository (Tampere University) (publishedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Lund University Publications (Lund University) (submittedVersion)
- Tampere University Institutional Repository (Tampere University) (submittedVersion, cc-by)
- Padua Research Archive (University of Padova) (submittedVersion, cc-by-nc-nd)
- Funders
- Royal Society
- Cystic Fibrosis Trust (SRC007)
- European Foundation for the Study of Diabetes
- Fredrik och Ingrid Thurings Stiftelse
- Lunds Universitet
- Università degli Studi di Padova (PRAT 2012)
- Vetenskapsrådet
- Kungliga Fysiografiska Sällskapet i Lund
- Direktör Albert Påhlssons Stiftelse
- Uppsala Universitet
- Region Skåne
- Topics
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Cystic Fibrosis Research Advances
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion Transport and Channel Regulation
- Keywords
- CFTR, cystic fibrosis transmembrane conductance regulator, glucagon secretion, alpha cells, cystic fibrosis-related diabetes, cAMP signaling, CFTR inhibition, delta cells, forskolin, glucose regulation
- MeSH terms
- Animals, Cells, Cultured, Cystic Fibrosis, Female, Colforsin, Glucagon, Glucose, Humans, Male, Membrane Potentials, Middle Aged, Mutation, Cystic Fibrosis Transmembrane Conductance Regulator, Somatostatin-Secreting Cells, Glucagon-Secreting Cells, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
