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Liver-specific ablation of insulin-degrading enzyme causes hepatic insulin resistance and glucose intolerance, without affecting insulin clearance in mice
- Source :
- UVaDOC: Repositorio Documental de la Universidad de Valladolid, Universidad de Valladolid, Repositorio Institucional de la Universidad de Burgos (RIUBU), instname, UVaDOC. Repositorio Documental de la Universidad de Valladolid, Digital.CSIC. Repositorio Institucional del CSIC
- Publication Year :
- 2018
- Publisher :
- Elsevier BV, 2018.
-
Abstract
- The study was partially presented as a poster in the 53rd Annual Meeting of the European Association for the Study of Diabetes, Lisbon 2017.<br />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.<br />[Methods] We generated mice with liver-specific deletion of Ide (L-IDE-KO) and assessed insulin clearance and action.<br />[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.<br />[Conclusion] IDE is not a rate-limiting regulator of plasma insulin levels in vivo.<br />This work was supported by grants from the 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.
- Subjects :
- 0301 basic medicine
G6PC
nsulin-degrading enzyme
Receptores de insulina
Endocrinology, Diabetes and Metabolism
medicine.medical_treatment
AKT2
FOXO1
Insulysin
Mice
Endocrinology
PCK1
Insulin-Secreting Cells
Endocrinología
Insulin-degrading enzyme
Insulin
health care economics and organizations
Mice, Knockout
biology
Chemistry
Up-Regulation
Liver
Signal Transduction
medicine.medical_specialty
Insulin-degrading enzymes
education
Hepatic insulin resistance
Article
03 medical and health sciences
Insulin resistance
Carcinoembryonic antigen-related cell adhesion molecule 1
Internal medicine
medicine
Animals
Insulin receptors
Gluconeogenesis
Encimas degradadoras de insulina
Glucose Tolerance Test
medicine.disease
Mice, Inbred C57BL
Insulin receptor
Insulin recepto
030104 developmental biology
biology.protein
Insulin Resistance
human activities
Proto-Oncogene Proteins c-akt
Subjects
Details
- ISSN :
- 00260495
- Volume :
- 88
- Database :
- OpenAIRE
- Journal :
- Metabolism
- Accession number :
- edsair.doi.dedup.....80464241c3bc55b83bd01749f4ccf403