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dc.contributor.authorVilla Pérez, Pablo .
dc.contributor.authorMerino, Beatriz
dc.contributor.authorFernández Díaz, Cristina M. .
dc.contributor.authorCidad, Pilar
dc.contributor.authorLobatón, Carmen D.
dc.contributor.authorMoreno, Alfredo
dc.contributor.authorMuturi, Harrison T. .
dc.contributor.authorGhadieh, Hilda E. .
dc.contributor.authorNajjar, Sonia M. .
dc.contributor.authorLeissring, Malcolm A.
dc.contributor.authorCózar Castellano, Irene
dc.contributor.authorPerdomo Hernández, Germán M. 
dc.date.accessioned2018-10-11T10:26:09Z
dc.date.available2018-10-11T10:26:09Z
dc.date.issued2018-11
dc.identifier.issn0026-0495
dc.identifier.urihttp://hdl.handle.net/10259/4965
dc.description.abstractThe role of insulin-degrading enzyme (IDE), a metalloprotease with high affinity for insulin, in insulin clearance remains poorly understood. OBJECTIVE: This study aimed to clarify whether IDE is a major mediator of insulin clearance, and to define its role in the etiology of hepatic insulin resistance. Methods We generated mice with liver-specific deletion of Ide (L-IDE-KO) and assessed insulin clearance and action. Results L-IDE-KO mice exhibited higher (~20%) fasting and non-fasting plasma glucose levels, glucose intolerance and insulin resistance. This phenotype was associated with ~30% lower plasma membrane insulin receptor levels in liver, as well as ~55% reduction in insulin-stimulated phosphorylation of the insulin receptor, and its downstream signaling molecules, AKT1 and AKT2 (reduced by ~40%). In addition, FoxO1 was aberrantly distributed in cellular nuclei, in parallel with up-regulation of the gluconeogenic genes Pck1 and G6pc. Surprisingly, L-IDE-KO mice showed similar plasma insulin levels and hepatic insulin clearance as control mice, despite reduced phosphorylation of the carcinoembryonic antigen-related cell adhesion molecule 1, which upon its insulin-stimulated phosphorylation, promotes receptor-mediated insulin uptake to be degraded. Conclusion IDE is not a rate-limiting regulator of plasma insulin levels in vivoen
dc.description.sponsorshipMinisterio de Economía, Industria y Competitividad: SAF2014-58702-C2-1-R and SAF2016-77871-C2-1-R to ICC; SAF2014-58702-C2-2-R and SAF2016-77871-C2-2-R to GP; supported by the EFSD European Research Programme on New Targets for Type 2 Diabetes supported by an educational research grant from MSD to ICC and GP; the National Institutes of Health: R01-DK054254, R01-DK083850 and RO1-HL-112248 to SMN, and R01-GM115617 to MAL; and the American Diabetes Association: Career Development Award 7-11-CD-13 to MAL.en
dc.format.mimetypeapplication/pdf
dc.language.isoenges
dc.publisherElsevieren
dc.relation.ispartofMetabolism. 2018, V. 88, p. 1-11en
dc.rightsAttribution 4.0 International
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectnsulin-degrading enzymeen
dc.subjectHepatic insulin resistanceen
dc.subjectInsulin receptoen
dc.subjectCarcinoembryonic antigen-related cell adhesion molecule 1en
dc.subject.otherEndocrinologíaes
dc.subject.otherEndocrinologyen
dc.titleLiver-specific ablation of insulin-degrading enzyme causes hepatic insulin resistance and glucose intolerance, without affecting insulin clearance in miceen
dc.typeinfo:eu-repo/semantics/article
dc.rights.accessRightsinfo:eu-repo/semantics/openAccess
dc.relation.publisherversionhttps://doi.org/10.1016/j.metabol.2018.08.001
dc.identifier.doi10.1016/j.metabol.2018.08.001
dc.relation.projectIDinfo:eu-repo/grantAgreement/MINECO/SAF2014-58702-C2-1-R
dc.relation.projectIDinfo:eu-repo/grantAgreement/MINECO/SAF2016-77871-C2-1-R
dc.relation.projectIDinfo:eu-repo/grantAgreement/MINECO/SAF2014-58702-C2-2-R
dc.relation.projectIDinfo:eu-repo/grantAgreement/MINECO/SAF2016-77871-C2-2-R
dc.relation.projectIDinfo:eu-repo/grantAgreement/NationalInstitutesofHealth/R01-DK054254
dc.relation.projectIDinfo:eu-repo/grantAgreement/NationalInstitutesofHealth/R01-DK083850
dc.relation.projectIDinfo:eu-repo/grantAgreement/NationalInstitutesofHealth/RO1-HL-112248
dc.relation.projectIDinfo:eu-repo/grantAgreement/NationalInstitutesofHealth/R01-GM115617
dc.type.hasVersioninfo:eu-repo/semantics/publishedVersionen


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