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

• Published in: Metabolism, clinical and experimental Vol. 88; pp. 1 - 11
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-11-2018
• Subjects: Animals; Carcinoembryonic antigen-related cell adhesion molecule 1; Gluconeogenesis - genetics; Glucose Tolerance Test; Hepatic insulin resistance; Insulin - blood; Insulin receptor; Insulin Resistance; Insulin-degrading enzyme; Insulin-Secreting Cells - pathology; Insulysin - genetics; Insulysin - metabolism; Liver - enzymology; Liver - physiopathology; Mice; Mice, Inbred C57BL; Mice, Knockout; Proto-Oncogene Proteins c-akt - metabolism; Signal Transduction; Up-Regulation; Carcinoembryonic antigen-related cell adhesion molecule 1; Insulin receptor; Insulin-degrading enzyme; Hepatic insulin resistance
• ISSN: 0026-0495; 1532-8600
• DOI: 10.1016/j.metabol.2018.08.001

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