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Liver-specific ablation of insulin-degrading enzyme causes hepatic insulin resistance and glucose intolerance, without affecting insulin clearance in mice
|Authors:||Villa-Pérez, Pablo; Merino, Cristina; Fernández-Díaz, C. CSIC ORCID; Cidad, Pilar CSIC ORCID; Lobatón, Carmen D.; Moreno, Alfredo; Muturi, Harrison T.; Ghadieh, Hilda E.; Najjarb, Sonia M.; Leissring, Malcolm A.; Cózar-Castellano, Irene CSIC ORCID CVN; Perdomo, Germán|
Hepatic insulin resistance
Carcinoembryonic antigen-related cell adhesion molecule 1
|Citation:||Metabolism 88: 1-11 (2018)|
|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.
|Description:||The study was partially presented as a poster in the 53rd Annual Meeting of the European Association for the Study of Diabetes, Lisbon 2017.|
|Publisher version (URL):||https://doi.org/10.1016/j.metabol.2018.08.001|
|Appears in Collections:||(IBGM) Artículos|