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oai:riubu.ubu.es:10259/49652021-11-10T09:38:25Zcom_10259_4725com_10259_5086com_10259_2604col_10259_4726

Villa Pérez, Pablo . 3513e97f-2ba9-4b82-a9b1-325531b44fc3 500 Merino, Beatriz 495e29d2-20b6-4c40-bf6a-c80b0c3b2cc5 500 Fernández Díaz, Cristina M. . 85487389-124d-4d58-9144-f9eb09bb9028 500 Cidad, Pilar d74c82a7-02fc-4943-af46-58047124e2e3 500 Lobatón, Carmen D. 34ae5e7d-c828-4fae-a691-eb28cce143b7 500 Moreno, Alfredo 92809a8e-4bc4-4f5f-a226-66743932a929 500 Muturi, Harrison T. . 98996a65-47bd-4b43-9df1-34879b1329f8 500 Ghadieh, Hilda E. . de0f101e-d8ec-45fb-9848-1380b9262401 500 Najjar, Sonia M. . adabd5c9-9ebc-4f02-9039-89faa13fb570 500 Leissring, Malcolm A. 225f86a0-b28a-46fc-b122-069ba4734a19 500 Cózar Castellano, Irene 3f72cbc3-d322-4e0a-a780-4e0fc4965813 500 Perdomo Hernández, Germán M. 433 500 2018-10-11T10:26:09Z 2018-10-11T10:26:09Z 2018-11 0026-0495 http://hdl.handle.net/10259/4965 10.1016/j.metabol.2018.08.001 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 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. application/pdf eng Elsevier Metabolism. 2018, V. 88, p. 1-11 https://doi.org/10.1016/j.metabol.2018.08.001 info:eu-repo/grantAgreement/MINECO/SAF2014-58702-C2-1-R info:eu-repo/grantAgreement/MINECO/SAF2016-77871-C2-1-R info:eu-repo/grantAgreement/MINECO/SAF2014-58702-C2-2-R info:eu-repo/grantAgreement/MINECO/SAF2016-77871-C2-2-R info:eu-repo/grantAgreement/NationalInstitutesofHealth/R01-DK054254 info:eu-repo/grantAgreement/NationalInstitutesofHealth/R01-DK083850 info:eu-repo/grantAgreement/NationalInstitutesofHealth/RO1-HL-112248 info:eu-repo/grantAgreement/NationalInstitutesofHealth/R01-GM115617 Attribution 4.0 International http://creativecommons.org/licenses/by/4.0/ info:eu-repo/semantics/openAccess nsulin-degrading enzyme Hepatic insulin resistance Insulin recepto Carcinoembryonic antigen-related cell adhesion molecule 1 Endocrinología Endocrinology Liver-specific ablation of insulin-degrading enzyme causes hepatic insulin resistance and glucose intolerance, without affecting insulin clearance in mice info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion CC-LICENSE license_rdf license_rdf application/rdf+xml; charset=utf-8 908 https://riubu.ubu.es/bitstream/10259/4965/8/license_rdf 0175ea4a2d4caec4bbcc37e300941108 MD5 8 THUMBNAIL Villa-Metabolism_2018.pdf.jpg Villa-Metabolism_2018.pdf.jpg IM Thumbnail image/jpeg 3980 https://riubu.ubu.es/bitstream/10259/4965/7/Villa-Metabolism_2018.pdf.jpg e5a91dae496c0b4371c0cc96e52eb8b1 MD5 7 ORIGINAL Villa-Metabolism_2018.pdf Villa-Metabolism_2018.pdf application/pdf 1403438 https://riubu.ubu.es/bitstream/10259/4965/1/Villa-Metabolism_2018.pdf 93f98211445a0a484770dc792fa725f8 MD5 1 LICENSE license.txt license.txt text/plain; charset=utf-8 999 https://riubu.ubu.es/bitstream/10259/4965/5/license.txt b295bcbce42e2caabeb0c623d3860c06 MD5 5 TEXT Villa-Metabolism_2018.pdf.txt Villa-Metabolism_2018.pdf.txt Extracted text text/plain 50452 https://riubu.ubu.es/bitstream/10259/4965/6/Villa-Metabolism_2018.pdf.txt dcfbc01ddef200769a15037c12198c9d MD5 6 10259/4965 oai:riubu.ubu.es:10259/4965 2021-11-10 10:38:25.961 Repositorio Institucional de la Universidad de Burgos bubrep@ubu.es RWwgYXV0b3IgY29tbyDDum5pY28gdGl0dWxhciBkZSBsb3MgZGVyZWNob3MgZGUgcHJvcGllZGFkIGludGVsZWN0dWFsIGRlIGxhIG9icmEsIG8gZGlzcG9uaWVuZG8gZGUgbG9zIGRlYmlkb3MgcGVybWlzb3MgZGUgbG9zIG90cm9zIHRpdHVsYXJlcywgc2kgbG9zIGh1YmllcmEsIHkgZW4gdmlydHVkIGRlIGxvcyBkZXJlY2hvcyBxdWUgbGUgY29uZmllcmUgbGEgbGVnaXNsYWNpw7NuIHZpZ2VudGUgc29icmUgcHJvcGllZGFkIGludGVsZWN0dWFsIHkgZGVyZWNob3MgZGUgYXV0b3IsIA0KQVVUT1JJWkEgYSBsYSBVbml2ZXJzaWRhZCBkZSBCdXJnb3MgYSBkaWZ1bmRpciwgZGUgbWFuZXJhIGdyYXR1aXRhLCBlbCBjb250ZW5pZG8gZGUgbG9zIGFyY2hpdm9zIGRpZ2l0YWxlcyBxdWUgY29ycmVzcG9uZGVuIGFsIGRvY3VtZW50byBkZXNjcml0byBhbnRlcmlvcm1lbnRlLCBjb24gY2Fyw6FjdGVyIG5vIGV4Y2x1c2l2byB5IGRlIG1hbmVyYSBww7pibGljYSBlbiBhY2Nlc28gYWJpZXJ0byBhIHRyYXbDqXMgZGUgSW50ZXJuZXQsIHBhcmEgbG8gcXVlIGxhIEJpYmxpb3RlY2EgcHJvY2VkZXLDoSBhIGFyY2hpdmFybG9zIGVuIGVsIFJlcG9zaXRvcmlvIEluc3RpdHVjaW9uYWwuIEFzaW1pc21vIGF1dG9yaXphIGEgbGEgVW5pdmVyc2lkYWQgZGUgQnVyZ29zIGEgcmVhbGl6YXIgbGFzIHRyYW5zZm9ybWFjaW9uZXMgbmVjZXNhcmlhcyBkZSBmb3JtYXRvLCBubyBkZSBjb250ZW5pZG8sIHBhcmEgZ2FyYW50aXphciBsYSBwcmVzZXJ2YWNpw7NuIHkgZWwgYWNjZXNvIGVuIGVsIGZ1dHVyby4NCg0KRWwgYXV0b3IgZGlzcG9uZSwgZW4gdG9kbyBjYXNvLCBkZWwgZGVyZWNobyBhIHJldm9jYXIgZXN0YSBhdXRvcml6YWNpw7NuLg0KDQpMYSBjZXNpw7NuIGRlIGRlcmVjaG9zIGRlIGVzdGEgb2JyYSBzZSBlbmN1ZW50cmEgc3VqZXRhIGEgbGEgbGVnaXNsYWNpw7NuIHZpZ2VudGUgc29icmUgcHJvcGllZGFkIGludGVsZWN0dWFsIHkgZGVyZWNob3MgZGUgYXV0b3Iu