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dc.contributor.authorKnudsen, Jakob G
dc.contributor.authorHamilton, Alexander
dc.contributor.authorRamracheya, Reshma
dc.contributor.authorTarasov, Andrei I
dc.contributor.authorBrereton, Melissa
dc.contributor.authorHaythorne, Elizabeth
dc.contributor.authorChibalina, Margarita V
dc.contributor.authorSpégel, Peter
dc.contributor.authorMulder, Hindrik
dc.contributor.authorZhang, Quan
dc.contributor.authorAshcroft, Frances M
dc.contributor.authorAdam, Julie
dc.contributor.authorRorsman, Patrik
dc.date.accessioned2019-03-05T11:17:57Z
dc.date.available2019-03-05T11:17:57Z
dc.date.issued2019-02-05
dc.identifier.citationKnudsen , J G , Hamilton , A , Ramracheya , R , Tarasov , A I , Brereton , M , Haythorne , E , Chibalina , M V , Spégel , P , Mulder , H , Zhang , Q , Ashcroft , F M , Adam , J & Rorsman , P 2019 , ' Dysregulation of Glucagon Secretion by Hyperglycemia-Induced Sodium-Dependent Reduction of ATP Production ' , Cell metabolism , vol. 29 , no. 2 , pp. 430-442 . https://doi.org/10.1016/j.cmet.2018.10.003
dc.identifier.issn1550-4131
dc.identifier.otherPURE: 15684995
dc.identifier.otherPURE UUID: 37da99c6-8a36-445b-9e93-fd5fc317f113
dc.identifier.otherPubMed: 30415925
dc.identifier.otherScopus: 85059061884
dc.identifier.urihttp://hdl.handle.net/2299/21164
dc.description© 2018 The Author(s). Published by Elsevier Inc.
dc.description.abstractDiabetes is a bihormonal disorder resulting from combined insulin and glucagon secretion defects. Mice lacking fumarase (Fh1) in their β cells (Fh1βKO mice) develop progressive hyperglycemia and dysregulated glucagon secretion similar to that seen in diabetic patients (too much at high glucose and too little at low glucose). The glucagon secretion defects are corrected by low concentrations of tolbutamide and prevented by the sodium-glucose transport (SGLT) inhibitor phlorizin. These data link hyperglycemia, intracellular Na+ accumulation, and acidification to impaired mitochondrial metabolism, reduced ATP production, and dysregulated glucagon secretion. Protein succination, reflecting reduced activity of fumarase, is observed in α cells from hyperglycemic Fh1βKO and β-V59M gain-of-function KATP channel mice, diabetic Goto-Kakizaki rats, and patients with type 2 diabetes. Succination is also observed in renal tubular cells and cardiomyocytes from hyperglycemic Fh1βKO mice, suggesting that the model can be extended to other SGLT-expressing cells and may explain part of the spectrum of diabetic complications.en
dc.language.isoeng
dc.relation.ispartofCell metabolism
dc.rightsOpen
dc.subjectFh1
dc.subjectdiabetes
dc.subjectglucagon
dc.subjectsodium-glucose co-transport
dc.subjectsuccination
dc.subjectPhysiology
dc.subjectMolecular Biology
dc.subjectCell Biology
dc.titleDysregulation of Glucagon Secretion by Hyperglycemia-Induced Sodium-Dependent Reduction of ATP Productionen
dc.contributor.institutionDepartment of Biological and Environmental Sciences
dc.contributor.institutionBiosciences Research Group
dc.contributor.institutionSchool of Life and Medical Sciences
dc.description.statusPeer reviewed
dc.identifier.urlhttp://www.scopus.com/inward/record.url?scp=85059061884&partnerID=8YFLogxK
dc.relation.schoolSchool of Life and Medical Sciences
dc.description.versiontypeFinal Published version
dcterms.dateAccepted2019-02-05
rioxxterms.versionVoR
rioxxterms.versionofrecordhttps://doi.org/10.1016/j.cmet.2018.10.003
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/
rioxxterms.typeJournal Article/Review
herts.preservation.rarelyaccessedtrue
herts.rights.accesstypeOpen


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