Elsevier

Metabolism

Volume 88, November 2018, Pages 1-11
Metabolism

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

https://doi.org/10.1016/j.metabol.2018.08.001Get rights and content
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Highlights

  • IDE is a metalloprotease which role in insulin clearance remains poorly understood.

  • L-IDE-KO mice resulted in glucose intolerance and hepatic insulin resistance.

  • IDE is not a principal or rate-limiting regulator of plasma insulin levels in vivo.

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.

Keywords

Insulin-degrading enzyme
Hepatic insulin resistance
Insulin receptor
Carcinoembryonic antigen-related cell adhesion molecule 1

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