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

2026-10-12T23:39:13Zhttps://riubu.ubu.es/oai/request

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

Liver-specific ablation of insulin-degrading enzyme causes hepatic insulin resistance and glucose intolerance, without affecting insulin clearance in mice Villa Pérez, Pablo . Merino, Beatriz Fernández Díaz, Cristina M. . Cidad, Pilar Lobatón, Carmen D. Moreno, Alfredo Muturi, Harrison T. . Ghadieh, Hilda E. . Najjar, Sonia M. . Leissring, Malcolm A. Cózar Castellano, Irene Perdomo Hernández, Germán M. nsulin-degrading enzyme Hepatic insulin resistance Insulin recepto Carcinoembryonic antigen-related cell adhesion molecule 1 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 2018-10-11 2018-10-11 2018-11 info:eu-repo/semantics/article 0026-0495 http://hdl.handle.net/10259/4965 10.1016/j.metabol.2018.08.001 eng 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 http://creativecommons.org/licenses/by/4.0/ info:eu-repo/semantics/openAccess Attribution 4.0 International Elsevier