1. Liver-specific ablation of insulin-degrading enzyme causes hepatic insulin resistance and glucose intolerance, without affecting insulin clearance in mice
- Author
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Beatriz Merino, Malcolm A. Leissring, Carmen D. Lobatón, Harrison T. Muturi, Sonia M. Najjar, Cristina M. Fernández-Díaz, Pablo Villa-Pérez, Alfredo Moreno, Hilda E. Ghadieh, Germán Perdomo, Pilar Cidad, Irene Cózar-Castellano, Ministerio de Economía, Industria y Competitividad (España), Ministerio de Economía y Competitividad (España), European Commission, National Institutes of Health (US), and American Diabetes Association
- 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 - 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., 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., 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.
- Published
- 2018