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

Beatriz Merino,Malcolm A Leissring,Harrison T Muturi,Cristina M Fernández-Díaz,Hilda E Ghadieh,Germán Perdomo,Sonia M Najjar,Pilar Cidad,Carmen D Lobatón,Alfredo Moreno,Irene Cózar-Castellano,Pablo Villa-Pérez

doi:10.1016/j.metabol.2018.08.001

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. MethodsWe generated mice with liver-specific deletion of Ide (L-IDE-KO) and assessed insulin clearance and action. ResultsL-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. ConclusionIDE is not a rate-limiting regulator of plasma insulin levels in vivo.

Highlights

Insulin-degrading enzyme (IDE) is a 110-kDa zincmetalloendopeptidase first identified and named based on its ability to bind to and degrade insulin [1]
No differences in IDE expression were observed in other tissues, except for a ~20% reduction in Ide mRNA levels without changes in IDE protein levels in skeletal muscle
Hepatic IDE Deletion Leads to Glucose Intolerance and Insulin Resistance, but without Altered Insulin Metabolism

Summary

Introduction

Insulin-degrading enzyme (IDE) is a 110-kDa zincmetalloendopeptidase first identified and named based on its ability to bind to and degrade insulin [1]. The protease is primarily cytosolic, but it has been reported to exist within a number of intracellular vesicles, and organelles, as well as being associated with membranes, and secreted into the extracellular space [1,3,4,5,6]. This wide distribution suggests a dynamic and multifunctional role for IDE.

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