Decreased expression of insulin-degrading enzyme increases gluconeogenesis and glucose production in cultured hepatocytes administered with glucagon

Insulin-degrading enzyme (IDE) is a protein with proteolytic and non-proteolytic functions that regulates glucose homeostasis. In the fasted state, glucagon regulates glycemia through induction of hepatic gluconeogenesis. The rate of hepatic gluconeogenesis is elevated in subjects with type 2 diabet...

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Autores: González-Casimiro, Carlos M., Cámara-Torres, Patricia, Merino, Beatriz, Astudillo, Alma M., Fuente, Miguel A. de la, Ramírez, Cristina, Alonso, Andrés, Cózar-Castellano, Irene, Perdomo, Germán
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2025
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/399719
Acceso en línea:http://hdl.handle.net/10261/399719
Access Level:acceso abierto
Palabra clave:Glucagon
Gluconeogenesis
Hepatocytes
Insulin-degrading enzyme
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oai_identifier_str oai:digital.csic.es:10261/399719
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network_name_str España
repository_id_str
dc.title.none.fl_str_mv Decreased expression of insulin-degrading enzyme increases gluconeogenesis and glucose production in cultured hepatocytes administered with glucagon
title Decreased expression of insulin-degrading enzyme increases gluconeogenesis and glucose production in cultured hepatocytes administered with glucagon
spellingShingle Decreased expression of insulin-degrading enzyme increases gluconeogenesis and glucose production in cultured hepatocytes administered with glucagon
González-Casimiro, Carlos M.
Glucagon
Gluconeogenesis
Hepatocytes
Insulin-degrading enzyme
title_short Decreased expression of insulin-degrading enzyme increases gluconeogenesis and glucose production in cultured hepatocytes administered with glucagon
title_full Decreased expression of insulin-degrading enzyme increases gluconeogenesis and glucose production in cultured hepatocytes administered with glucagon
title_fullStr Decreased expression of insulin-degrading enzyme increases gluconeogenesis and glucose production in cultured hepatocytes administered with glucagon
title_full_unstemmed Decreased expression of insulin-degrading enzyme increases gluconeogenesis and glucose production in cultured hepatocytes administered with glucagon
title_sort Decreased expression of insulin-degrading enzyme increases gluconeogenesis and glucose production in cultured hepatocytes administered with glucagon
dc.creator.none.fl_str_mv González-Casimiro, Carlos M.
Cámara-Torres, Patricia
Merino, Beatriz
Astudillo, Alma M.
Fuente, Miguel A. de la
Ramírez, Cristina
Alonso, Andrés
Cózar-Castellano, Irene
Perdomo, Germán
author González-Casimiro, Carlos M.
author_facet González-Casimiro, Carlos M.
Cámara-Torres, Patricia
Merino, Beatriz
Astudillo, Alma M.
Fuente, Miguel A. de la
Ramírez, Cristina
Alonso, Andrés
Cózar-Castellano, Irene
Perdomo, Germán
author_role author
author2 Cámara-Torres, Patricia
Merino, Beatriz
Astudillo, Alma M.
Fuente, Miguel A. de la
Ramírez, Cristina
Alonso, Andrés
Cózar-Castellano, Irene
Perdomo, Germán
author2_role author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Ministerio de Ciencia, Innovación y Universidades (España)
Agencia Estatal de Investigación (España)
Ministerio de Ciencia e Innovación (España)
Junta de Castilla y León
European Commission
Universidad de Valladolid
Banco Santander
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv Glucagon
Gluconeogenesis
Hepatocytes
Insulin-degrading enzyme
topic Glucagon
Gluconeogenesis
Hepatocytes
Insulin-degrading enzyme
description Insulin-degrading enzyme (IDE) is a protein with proteolytic and non-proteolytic functions that regulates glucose homeostasis. In the fasted state, glucagon regulates glycemia through induction of hepatic gluconeogenesis. The rate of hepatic gluconeogenesis is elevated in subjects with type 2 diabetes (T2D) compared with healthy subjects. Interestingly, subjects with T2D show decreased expression of hepatic IDE. However, the role of IDE on the regulation of hepatic gluconeogenesis is completely unknow. We hypothesize that IDE deficiency alters glucagon signaling and thereby gluconeogenesis. To test this hypothesis, we used mouse liver tissues and cultured hepatocytes with total or partial IDE deficiency. The glucagon signaling pathway, expression of gluconeogenic genes, glucose production, and transcriptomic analysis were performed in control and IDE-KO hepatocytes. Total or partial loss of IDE in liver tissues or cultured mouse hepatocytes resulted in lower levels of the glucagon receptor (GCGR) and the cAMP-response element binding protein (CREB). However, glucagon stimulation increased the phosphorylation of CREB, despite lower levels of cAMP in IDE-deficient mouse hepatocytes. The activation of CREB was associated with an upregulation of the gluconeogenic genes Pck1 and G6pc (~ 200% and ~ 70% respectively) and higher glucose production in IDE-deficient mouse hepatocytes. Finally, genetic depletion of IDE in HepG2 hepatocytes led to upregulation of genes involved in cellular functions related to membranes, organelles and signaling receptors. These findings may be of relevance to better understand the regulation of hepatic gluconeogenesis and the use of IDE as a potential therapeutic target for the treatment of T2D.
publishDate 2025
dc.date.none.fl_str_mv 2025
2025
2025
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
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status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/399719
url http://hdl.handle.net/10261/399719
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
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info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2019-110496RB-C21
info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2021-2023/PID2022-136605OB-C21
info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2019-110496RB-C22
info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2021-2023/PID2022-136605OB-C22
The underlying dataset has been published as supplementary material of the article in the publisher platform at DOI https://doi.org/10.1038/s41598-025-03790-2
https://doi.org/10.1038/s41598-025-03790-2
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dc.publisher.none.fl_str_mv Springer Nature
publisher.none.fl_str_mv Springer Nature
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
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spelling Decreased expression of insulin-degrading enzyme increases gluconeogenesis and glucose production in cultured hepatocytes administered with glucagonGonzález-Casimiro, Carlos M.Cámara-Torres, PatriciaMerino, BeatrizAstudillo, Alma M.Fuente, Miguel A. de laRamírez, CristinaAlonso, AndrésCózar-Castellano, IrenePerdomo, GermánGlucagonGluconeogenesisHepatocytesInsulin-degrading enzymeInsulin-degrading enzyme (IDE) is a protein with proteolytic and non-proteolytic functions that regulates glucose homeostasis. In the fasted state, glucagon regulates glycemia through induction of hepatic gluconeogenesis. The rate of hepatic gluconeogenesis is elevated in subjects with type 2 diabetes (T2D) compared with healthy subjects. Interestingly, subjects with T2D show decreased expression of hepatic IDE. However, the role of IDE on the regulation of hepatic gluconeogenesis is completely unknow. We hypothesize that IDE deficiency alters glucagon signaling and thereby gluconeogenesis. To test this hypothesis, we used mouse liver tissues and cultured hepatocytes with total or partial IDE deficiency. The glucagon signaling pathway, expression of gluconeogenic genes, glucose production, and transcriptomic analysis were performed in control and IDE-KO hepatocytes. Total or partial loss of IDE in liver tissues or cultured mouse hepatocytes resulted in lower levels of the glucagon receptor (GCGR) and the cAMP-response element binding protein (CREB). However, glucagon stimulation increased the phosphorylation of CREB, despite lower levels of cAMP in IDE-deficient mouse hepatocytes. The activation of CREB was associated with an upregulation of the gluconeogenic genes Pck1 and G6pc (~ 200% and ~ 70% respectively) and higher glucose production in IDE-deficient mouse hepatocytes. Finally, genetic depletion of IDE in HepG2 hepatocytes led to upregulation of genes involved in cellular functions related to membranes, organelles and signaling receptors. These findings may be of relevance to better understand the regulation of hepatic gluconeogenesis and the use of IDE as a potential therapeutic target for the treatment of T2D.This work was supported by grants PID2019-110496RB-C21 and PID2022-136605OB-C21 to ICC; PID2019-110496RB-C22 and PID2022-136605OB-C22 to GP funded by MCIN/AEI/https://doi.org/10.13039/501100011033 “ERDF A way of making Europe”; CGC was supported by fellowship from the Junta de Castilla y León and the European Social Fund (ORDER EDU/574/2018); PCT was supported by fellowship from the Universidad de Valladolid 2020, co-funded by Banco Santander.Peer reviewedSpringer NatureMinisterio de Ciencia, Innovación y Universidades (España)Agencia Estatal de Investigación (España)Ministerio de Ciencia e Innovación (España)Junta de Castilla y LeónEuropean CommissionUniversidad de ValladolidBanco SantanderConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]202520252025info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionapplication/pdfhttp://hdl.handle.net/10261/399719reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Inglés#PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE##PLACEHOLDER_PARENT_METADATA_VALUE#info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2019-110496RB-C21info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2021-2023/PID2022-136605OB-C21info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2019-110496RB-C22info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2021-2023/PID2022-136605OB-C22The underlying dataset has been published as supplementary material of the article in the publisher platform at DOI https://doi.org/10.1038/s41598-025-03790-2https://doi.org/10.1038/s41598-025-03790-2Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/3997192026-05-22T06:33:51Z
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