Liver-specific ablation of insulin-degrading enzyme causes hepatic insulin resistance and glucose intolerance, without affecting insulin clearance in mice

The study was partially presented as a poster in the 53rd Annual Meeting of the European Association for the Study of Diabetes, Lisbon 2017.

Detalles Bibliográficos
Autores: Villa-Pérez, Pablo, Merino, Cristina, Fernández-Díez, Cristina, Cidad, Pilar, Lobatón, Carmen D., Moreno, Alfredo, Muturi, Harrison T., Ghadieh, Hilda E., Najjarb, Sonia M., Leissring, Malcolm A., Cózar-Castellano, Irene, Perdomo, Germán
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2018
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/196713
Acceso en línea:http://hdl.handle.net/10261/196713
Access Level:acceso abierto
Palabra clave:Insulin-degrading enzyme
Hepatic insulin resistance
Insulin receptor
Carcinoembryonic antigen-related cell adhesion molecule 1
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spelling Liver-specific ablation of insulin-degrading enzyme causes hepatic insulin resistance and glucose intolerance, without affecting insulin clearance in miceVilla-Pérez, PabloMerino, CristinaFernández-Díez, CristinaCidad, PilarLobatón, Carmen D.Moreno, AlfredoMuturi, Harrison T.Ghadieh, Hilda E.Najjarb, Sonia M.Leissring, Malcolm A.Cózar-Castellano, IrenePerdomo, GermánInsulin-degrading enzymeHepatic insulin resistanceInsulin receptorCarcinoembryonic antigen-related cell adhesion molecule 1The study was partially presented as a poster in the 53rd Annual Meeting of the European Association for the Study of Diabetes, Lisbon 2017.The 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 vivo.This work was supported by grants from the Ministerio 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.Peer reviewedElsevierMinisterio de Economía, Industria y Competitividad (España)Ministerio de Economía y Competitividad (España)European CommissionNational Institutes of Health (US)American Diabetes AssociationConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]201920192018info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/196713reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2014-58702-C2-1-Rinfo:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2016-77871-C2-1-Rinfo:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2014-58702-C2-2-Rinfo:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2016-77871-C2-2-Rhttps://doi.org/10.1016/j.metabol.2018.08.001Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/1967132026-05-22T06:33:51Z
dc.title.none.fl_str_mv Liver-specific ablation of insulin-degrading enzyme causes hepatic insulin resistance and glucose intolerance, without affecting insulin clearance in mice
title Liver-specific ablation of insulin-degrading enzyme causes hepatic insulin resistance and glucose intolerance, without affecting insulin clearance in mice
spellingShingle Liver-specific ablation of insulin-degrading enzyme causes hepatic insulin resistance and glucose intolerance, without affecting insulin clearance in mice
Villa-Pérez, Pablo
Insulin-degrading enzyme
Hepatic insulin resistance
Insulin receptor
Carcinoembryonic antigen-related cell adhesion molecule 1
title_short Liver-specific ablation of insulin-degrading enzyme causes hepatic insulin resistance and glucose intolerance, without affecting insulin clearance in mice
title_full Liver-specific ablation of insulin-degrading enzyme causes hepatic insulin resistance and glucose intolerance, without affecting insulin clearance in mice
title_fullStr Liver-specific ablation of insulin-degrading enzyme causes hepatic insulin resistance and glucose intolerance, without affecting insulin clearance in mice
title_full_unstemmed Liver-specific ablation of insulin-degrading enzyme causes hepatic insulin resistance and glucose intolerance, without affecting insulin clearance in mice
title_sort Liver-specific ablation of insulin-degrading enzyme causes hepatic insulin resistance and glucose intolerance, without affecting insulin clearance in mice
dc.creator.none.fl_str_mv Villa-Pérez, Pablo
Merino, Cristina
Fernández-Díez, Cristina
Cidad, Pilar
Lobatón, Carmen D.
Moreno, Alfredo
Muturi, Harrison T.
Ghadieh, Hilda E.
Najjarb, Sonia M.
Leissring, Malcolm A.
Cózar-Castellano, Irene
Perdomo, Germán
author Villa-Pérez, Pablo
author_facet Villa-Pérez, Pablo
Merino, Cristina
Fernández-Díez, Cristina
Cidad, Pilar
Lobatón, Carmen D.
Moreno, Alfredo
Muturi, Harrison T.
Ghadieh, Hilda E.
Najjarb, Sonia M.
Leissring, Malcolm A.
Cózar-Castellano, Irene
Perdomo, Germán
author_role author
author2 Merino, Cristina
Fernández-Díez, Cristina
Cidad, Pilar
Lobatón, Carmen D.
Moreno, Alfredo
Muturi, Harrison T.
Ghadieh, Hilda E.
Najjarb, Sonia M.
Leissring, Malcolm A.
Cózar-Castellano, Irene
Perdomo, Germán
author2_role author
author
author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Ministerio de Economía, Industria y Competitividad (España)
Ministerio de Economía y Competitividad (España)
European Commission
National Institutes of Health (US)
American Diabetes Association
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Insulin-degrading enzyme
Hepatic insulin resistance
Insulin receptor
Carcinoembryonic antigen-related cell adhesion molecule 1
topic Insulin-degrading enzyme
Hepatic insulin resistance
Insulin receptor
Carcinoembryonic antigen-related cell adhesion molecule 1
description The study was partially presented as a poster in the 53rd Annual Meeting of the European Association for the Study of Diabetes, Lisbon 2017.
publishDate 2018
dc.date.none.fl_str_mv 2018
2019
2019
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/196713
url http://hdl.handle.net/10261/196713
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv #PLACEHOLDER_PARENT_METADATA_VALUE#
#PLACEHOLDER_PARENT_METADATA_VALUE#
#PLACEHOLDER_PARENT_METADATA_VALUE#
#PLACEHOLDER_PARENT_METADATA_VALUE#
info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2014-58702-C2-1-R
info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2016-77871-C2-1-R
info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2014-58702-C2-2-R
info:eu-repo/grantAgreement/MINECO/Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016/SAF2016-77871-C2-2-R
https://doi.org/10.1016/j.metabol.2018.08.001
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
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repository.mail.fl_str_mv
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