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


ABSTRACT: 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.

SUBMITTER: Villa-Perez P 

PROVIDER: S-EPMC6185772 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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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 P   Merino Beatriz B   Fernández-Díaz Cristina M CM   Cidad Pilar P   Lobatón Carmen D CD   Moreno Alfredo A   Muturi Harrison T HT   Ghadieh Hilda E HE   Najjar Sonia M SM   Leissring Malcolm A MA   Cózar-Castellano Irene I   Perdomo Germán G  

Metabolism: clinical and experimental 20180808


The role of insulin-degrading enzyme (IDE), a metalloprotease with high affinity for insulin, in insulin clearance remains poorly understood.<h4>Objective</h4>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.<h4>Methods</h4>We generated mice with liver-specific deletion of Ide (L-IDE-KO) and assessed insulin clearance and action.<h4>Results</h4>L-IDE-KO mice exhibited higher (~20%) fasting and n  ...[more]

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