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dc.contributor.authorMerino Antolín, Beatriz 
dc.contributor.authorCasanueva Álvarez, Elena
dc.contributor.authorQuesada, Iván
dc.contributor.authorGonzález Casimiro, Carlos Manuel 
dc.contributor.authorFernández Díaz, Cristina María 
dc.contributor.authorPostigo Casado, Tamara
dc.contributor.authorLeissring, Malcolm A.
dc.contributor.authorKaestner, Klaus H.
dc.contributor.authorPerdomo Hernández, Germán
dc.contributor.authorCózar Castellano, Irene 
dc.date.accessioned2022-07-06T09:00:40Z
dc.date.available2022-07-06T09:00:40Z
dc.date.issued2022
dc.identifier.citationDiabetologia volume 65, 2022, pages 1375–1389es
dc.identifier.issn0012-186Xes
dc.identifier.urihttps://uvadoc.uva.es/handle/10324/53866
dc.descriptionProducción Científicaes
dc.description.abstractAims/hypothesis Type 2 diabetes is characterised by hyperglucagonaemia and perturbed function of pancreatic glucagon secreting alpha cells but the molecular mechanisms contributing to these phenotypes are poorly understood. Insulin-degrading enzyme (IDE) is present within all islet cells, mostly in alpha cells, in both mice and humans. Furthermore, IDE can degrade glucagon as well as insulin, suggesting that IDE may play an important role in alpha cell function in vivo. Methods We have generated and characterised a novel mouse model with alpha cell-specific deletion of Ide, the A-IDE-KO mouse line. Glucose metabolism and glucagon secretion in vivo was characterised; isolated islets were tested for glucagon and insulin secretion; alpha cell mass, alpha cell proliferation and α-synuclein levels were determined in pancreas sections by immunostaining. Results Targeted deletion of Ide exclusively in alpha cells triggers hyperglucagonaemia and alpha cell hyperplasia, resulting in elevated constitutive glucagon secretion. The hyperglucagonaemia is attributable in part to dysregulation of glucagon secretion, specifically an impaired ability of IDE-deficient alpha cells to suppress glucagon release in the presence of high glucose or insulin. IDE deficiency also leads to α-synuclein aggregation in alpha cells, which may contribute to impaired glucagon secretion via cytoskeletal dysfunction. We showed further that IDE deficiency triggers impairments in cilia formation, inducing alpha cell hyperplasia and possibly also contributing to dysregulated glucagon secretion and hyperglucagonaemia. Conclusions/interpretation We propose that loss of IDE function in alpha cells contributes to hyperglucagonaemia in type 2 diabeteses
dc.format.mimetypeapplication/pdfes
dc.language.isoenges
dc.publisherSpringeres
dc.rights.accessRightsinfo:eu-repo/semantics/openAccesses
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/*
dc.subject.classificationAlpha cellses
dc.subject.classificationCytoskeletones
dc.subject.classificationHyperglucagonaemiaes
dc.subject.classificationInsulin-degrading enzymees
dc.subject.classificationPrimary ciliaes
dc.subject.classificationProliferationes
dc.subject.classificationType 2 diabeteses
dc.titleInsulin-degrading enzyme ablation in mouse pancreatic alpha cells triggers cell proliferation, hyperplasia and glucagon secretion dysregulationes
dc.typeinfo:eu-repo/semantics/articlees
dc.rights.holder© The Author(s) 2022es
dc.identifier.doi10.1007/s00125-022-05729-yes
dc.relation.publisherversionhttps://link.springer.com/article/10.1007/s00125-022-05729-yes
dc.identifier.publicationtitleDiabetologiaes
dc.peerreviewedSIes
dc.description.projectMinisterio de Economía, Industria y Competitividad (SAF2016-77871-C2-1-R to IC and BFU2016-77125-R to IQ)es
dc.description.projectMinisterio de Ciencia, Innovación y Universidades (PID2019-110496RB-C21 to IC and PID2019-110496RB-C22 to GP)es
dc.description.projectLa Caixa Foundation (grant LCF/PR/PR18/51130007 to GP)es
dc.description.projectNational Institutes of Health from USA (GM115617)es
dc.description.projectPublicación en abierto financiada por el Consorcio de Bibliotecas Universitarias de Castilla y León (BUCLE), con cargo al Programa Operativo 2014ES16RFOP009 FEDER 2014-2020 DE CASTILLA Y LEÓN, Actuación:20007-CL - Apoyo Consorcio BUCLEes
dc.identifier.essn1432-0428es
dc.rightsAtribución 4.0 Internacional*
dc.type.hasVersioninfo:eu-repo/semantics/publishedVersiones
dc.subject.unesco32 Ciencias Médicases


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