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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, Germán.
Afiliación
  • Villa-Pérez P; Instituto de Biología y Genética Molecular, University of Valladolid-CSIC, Valladolid, Spain.
  • Merino B; Instituto de Biología y Genética Molecular, University of Valladolid-CSIC, Valladolid, Spain.
  • Fernández-Díaz CM; Instituto de Biología y Genética Molecular, University of Valladolid-CSIC, Valladolid, Spain.
  • Cidad P; Instituto de Biología y Genética Molecular, University of Valladolid-CSIC, Valladolid, Spain.
  • Lobatón CD; Instituto de Biología y Genética Molecular, University of Valladolid-CSIC, Valladolid, Spain.
  • Moreno A; Instituto de Biología y Genética Molecular, University of Valladolid-CSIC, Valladolid, Spain.
  • Muturi HT; Department of Biomedical Sciences, Ohio University, USA; Diabetes Institute, Heritage College of Osteopathic Medicine, Ohio University, USA.
  • Ghadieh HE; Department of Biomedical Sciences, Ohio University, USA; Diabetes Institute, Heritage College of Osteopathic Medicine, Ohio University, USA.
  • Najjar SM; Department of Biomedical Sciences, Ohio University, USA; Diabetes Institute, Heritage College of Osteopathic Medicine, Ohio University, USA.
  • Leissring MA; Institute for Memory Impairments and Neurological Disorders, University of California, UCI MIND, Irvine, CA, USA.
  • Cózar-Castellano I; Instituto de Biología y Genética Molecular, University of Valladolid-CSIC, Valladolid, Spain.
  • Perdomo G; Departamento de Ciencias de la Salud, Universidad de Burgos, Burgos, Spain. Electronic address: gmperdomo@ubu.es.
Metabolism ; 88: 1-11, 2018 11.
Article en En | MEDLINE | ID: mdl-30098324
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Resistencia a la Insulina / Prueba de Tolerancia a la Glucosa / Insulina / Insulisina / Hígado Tipo de estudio: Etiology_studies Límite: Animals Idioma: En Revista: Metabolism Año: 2018 Tipo del documento: Article País de afiliación: España Pais de publicación: Estados Unidos
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Resistencia a la Insulina / Prueba de Tolerancia a la Glucosa / Insulina / Insulisina / Hígado Tipo de estudio: Etiology_studies Límite: Animals Idioma: En Revista: Metabolism Año: 2018 Tipo del documento: Article País de afiliación: España Pais de publicación: Estados Unidos