RT info:eu-repo/semantics/article
T1 Liver-specific ablation of insulin-degrading enzyme causes hepatic insulin resistance and glucose intolerance, without affecting insulin clearance in mice
A1 Villa Pérez, Pablo .
A1 Merino, Beatriz
A1 Fernández Díaz, Cristina M. .
A1 Cidad, Pilar
A1 Lobatón, Carmen D.
A1 Moreno, Alfredo
A1 Muturi, Harrison T. .
A1 Ghadieh, Hilda E. .
A1 Najjar, Sonia M. .
A1 Leissring, Malcolm A.
A1 Cózar Castellano, Irene
A1 Perdomo Hernández, Germán M.
K1 nsulin-degrading enzyme
K1 Hepatic insulin resistance
K1 Insulin recepto
K1 Carcinoembryonic antigen-related cell adhesion molecule 1
K1 Endocrinología
K1 Endocrinology
AB 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
PB Elsevier
SN 0026-0495
YR 2018
FD 2018-11
LK http://hdl.handle.net/10259/4965
UL http://hdl.handle.net/10259/4965
LA eng
NO Ministerio de Economía, Industria y Competitividad: SAF2014-58702-C2-1-R and SAF2016-77871-C2-1-R to ICC; SAF2014-58702-C2-2-R and SAF2016-77871-C2-2-R to GP; supported by the EFSD European Research Programme on New Targets for Type 2 Diabetes supported by an educational research grant from MSD to ICC and GP; the National Institutes of Health: R01-DK054254, R01-DK083850 and RO1-HL-112248 to SMN, and R01-GM115617 to MAL; and the American Diabetes Association: Career Development Award 7-11-CD-13 to MAL.
DS Repositorio Institucional de la Universidad de Burgos
RD 21-nov-2024