The Lysine Demethylase KDM5B Regulates Islet Function and Glucose Homeostasis

Autores
Backe, Marie Balslev; Jin, Chunyu; Andreone, Luz; Sankar, Aditya; Agger, Karl; Helin, Kristian; Madsen, Andreas N.; Poulsen, Steen S.; Bysani, Madhusudhan; Bacos, Karl; Ling, Charlotte; Perone, Marcelo Javier; Holst, Birgitte; Mandrup Poulsen, Thomas
Año de publicación
2019
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Aims. Posttranslational modifications of histones and transcription factors regulate gene expression and are implicated in beta-cell failure and diabetes. We have recently shown that preserving H3K27 and H3K4 methylation using the lysine demethylase inhibitor GSK-J4 reduces cytokine-induced destruction of beta-cells and improves beta-cell function. Here, we investigate the therapeutic potential of GSK-J4 to prevent diabetes development and examine the importance of H3K4 methylation for islet function. Materials and Methods. We used two mouse models of diabetes to investigate the therapeutic potential of GSK-J4. To clarify the importance of H3K4 methylation, we characterized a mouse strain with knockout (KO) of the H3K4 demethylase KDM5B. Results. GSK-J4 administration failed to prevent the development of experimental diabetes induced by multiple low-dose streptozotocin or adoptive transfer of splenocytes from acutely diabetic NOD to NODscid mice. KDM5B-KO mice were growth retarded with altered body composition, had low IGF-1 levels, and exhibited reduced insulin secretion. Interestingly, despite secreting less insulin, KDM5B-KO mice were able to maintain normoglycemia following oral glucose tolerance test, likely via improved insulin sensitivity, as suggested by insulin tolerance testing and phosphorylation of proteins belonging to the insulin signaling pathway. When challenged with high-fat diet, KDM5B-deficient mice displayed similar weight gain and insulin sensitivity as wild-type mice. Conclusion. Our results show a novel role of KDM5B in metabolism, as KDM5B-KO mice display growth retardation and improved insulin sensitivity.
Fil: Backe, Marie Balslev. Universidad de Copenhagen; Dinamarca
Fil: Jin, Chunyu. Universidad de Copenhagen; Dinamarca
Fil: Andreone, Luz. Universidad Austral. Facultad de Ciencias Biomédicas. Instituto de Investigaciones en Medicina Traslacional. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones en Medicina Traslacional; Argentina
Fil: Sankar, Aditya. Universidad de Copenhagen; Dinamarca. The Novo Nordisk Foundation Center for Stem Cell Biology; Dinamarca
Fil: Agger, Karl. Universidad de Copenhagen; Dinamarca. The Novo Nordisk Foundation Center for Stem Cell Biology; Dinamarca
Fil: Helin, Kristian. Universidad de Copenhagen; Dinamarca. The Novo Nordisk Foundation Center for Stem Cell Biology; Dinamarca
Fil: Madsen, Andreas N.. Universidad de Copenhagen; Dinamarca
Fil: Poulsen, Steen S.. Universidad de Copenhagen; Dinamarca
Fil: Bysani, Madhusudhan. Lund University; Suecia
Fil: Bacos, Karl. Lund University; Suecia
Fil: Ling, Charlotte. Lund University; Suecia
Fil: Perone, Marcelo Javier. Universidad de Copenhagen; Dinamarca. Universidad Austral. Facultad de Ciencias Biomédicas. Instituto de Investigaciones en Medicina Traslacional. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones en Medicina Traslacional; Argentina
Fil: Holst, Birgitte. Universidad de Copenhagen; Dinamarca
Fil: Mandrup Poulsen, Thomas. Universidad de Copenhagen; Dinamarca
Materia
Glucose metabolism
Diabetes
Beta-cells
Lysine demethylase
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/162535
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/162535
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling The Lysine Demethylase KDM5B Regulates Islet Function and Glucose HomeostasisBacke, Marie BalslevJin, ChunyuAndreone, LuzSankar, AdityaAgger, KarlHelin, KristianMadsen, Andreas N.Poulsen, Steen S.Bysani, MadhusudhanBacos, KarlLing, CharlottePerone, Marcelo JavierHolst, BirgitteMandrup Poulsen, ThomasGlucose metabolismDiabetesBeta-cellsLysine demethylasehttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Aims. Posttranslational modifications of histones and transcription factors regulate gene expression and are implicated in beta-cell failure and diabetes. We have recently shown that preserving H3K27 and H3K4 methylation using the lysine demethylase inhibitor GSK-J4 reduces cytokine-induced destruction of beta-cells and improves beta-cell function. Here, we investigate the therapeutic potential of GSK-J4 to prevent diabetes development and examine the importance of H3K4 methylation for islet function. Materials and Methods. We used two mouse models of diabetes to investigate the therapeutic potential of GSK-J4. To clarify the importance of H3K4 methylation, we characterized a mouse strain with knockout (KO) of the H3K4 demethylase KDM5B. Results. GSK-J4 administration failed to prevent the development of experimental diabetes induced by multiple low-dose streptozotocin or adoptive transfer of splenocytes from acutely diabetic NOD to NODscid mice. KDM5B-KO mice were growth retarded with altered body composition, had low IGF-1 levels, and exhibited reduced insulin secretion. Interestingly, despite secreting less insulin, KDM5B-KO mice were able to maintain normoglycemia following oral glucose tolerance test, likely via improved insulin sensitivity, as suggested by insulin tolerance testing and phosphorylation of proteins belonging to the insulin signaling pathway. When challenged with high-fat diet, KDM5B-deficient mice displayed similar weight gain and insulin sensitivity as wild-type mice. Conclusion. Our results show a novel role of KDM5B in metabolism, as KDM5B-KO mice display growth retardation and improved insulin sensitivity.Fil: Backe, Marie Balslev. Universidad de Copenhagen; DinamarcaFil: Jin, Chunyu. Universidad de Copenhagen; DinamarcaFil: Andreone, Luz. Universidad Austral. Facultad de Ciencias Biomédicas. Instituto de Investigaciones en Medicina Traslacional. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones en Medicina Traslacional; ArgentinaFil: Sankar, Aditya. Universidad de Copenhagen; Dinamarca. The Novo Nordisk Foundation Center for Stem Cell Biology; DinamarcaFil: Agger, Karl. Universidad de Copenhagen; Dinamarca. The Novo Nordisk Foundation Center for Stem Cell Biology; DinamarcaFil: Helin, Kristian. Universidad de Copenhagen; Dinamarca. The Novo Nordisk Foundation Center for Stem Cell Biology; DinamarcaFil: Madsen, Andreas N.. Universidad de Copenhagen; DinamarcaFil: Poulsen, Steen S.. Universidad de Copenhagen; DinamarcaFil: Bysani, Madhusudhan. Lund University; SueciaFil: Bacos, Karl. Lund University; SueciaFil: Ling, Charlotte. Lund University; SueciaFil: Perone, Marcelo Javier. Universidad de Copenhagen; Dinamarca. Universidad Austral. Facultad de Ciencias Biomédicas. Instituto de Investigaciones en Medicina Traslacional. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones en Medicina Traslacional; ArgentinaFil: Holst, Birgitte. Universidad de Copenhagen; DinamarcaFil: Mandrup Poulsen, Thomas. Universidad de Copenhagen; DinamarcaHindawi Publishing Corporation2019-07info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/162535Backe, Marie Balslev; Jin, Chunyu; Andreone, Luz; Sankar, Aditya; Agger, Karl; et al.; The Lysine Demethylase KDM5B Regulates Islet Function and Glucose Homeostasis; Hindawi Publishing Corporation; Journal of Diabetes Research; 2019; 5451038; 7-2019; 1-162314-67452314-6753CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1155/2019/5451038info:eu-repo/semantics/altIdentifier/url/https://www.hindawi.com/journals/jdr/2019/5451038/info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-22T11:00:19Zoai:ri.conicet.gov.ar:11336/162535instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-10-22 11:00:19.831CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv The Lysine Demethylase KDM5B Regulates Islet Function and Glucose Homeostasis
title The Lysine Demethylase KDM5B Regulates Islet Function and Glucose Homeostasis
spellingShingle The Lysine Demethylase KDM5B Regulates Islet Function and Glucose Homeostasis
Backe, Marie Balslev
Glucose metabolism
Diabetes
Beta-cells
Lysine demethylase
title_short The Lysine Demethylase KDM5B Regulates Islet Function and Glucose Homeostasis
title_full The Lysine Demethylase KDM5B Regulates Islet Function and Glucose Homeostasis
title_fullStr The Lysine Demethylase KDM5B Regulates Islet Function and Glucose Homeostasis
title_full_unstemmed The Lysine Demethylase KDM5B Regulates Islet Function and Glucose Homeostasis
title_sort The Lysine Demethylase KDM5B Regulates Islet Function and Glucose Homeostasis
dc.creator.none.fl_str_mv Backe, Marie Balslev
Jin, Chunyu
Andreone, Luz
Sankar, Aditya
Agger, Karl
Helin, Kristian
Madsen, Andreas N.
Poulsen, Steen S.
Bysani, Madhusudhan
Bacos, Karl
Ling, Charlotte
Perone, Marcelo Javier
Holst, Birgitte
Mandrup Poulsen, Thomas
author Backe, Marie Balslev
author_facet Backe, Marie Balslev
Jin, Chunyu
Andreone, Luz
Sankar, Aditya
Agger, Karl
Helin, Kristian
Madsen, Andreas N.
Poulsen, Steen S.
Bysani, Madhusudhan
Bacos, Karl
Ling, Charlotte
Perone, Marcelo Javier
Holst, Birgitte
Mandrup Poulsen, Thomas
author_role author
author2 Jin, Chunyu
Andreone, Luz
Sankar, Aditya
Agger, Karl
Helin, Kristian
Madsen, Andreas N.
Poulsen, Steen S.
Bysani, Madhusudhan
Bacos, Karl
Ling, Charlotte
Perone, Marcelo Javier
Holst, Birgitte
Mandrup Poulsen, Thomas
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Glucose metabolism
Diabetes
Beta-cells
Lysine demethylase
topic Glucose metabolism
Diabetes
Beta-cells
Lysine demethylase
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Aims. Posttranslational modifications of histones and transcription factors regulate gene expression and are implicated in beta-cell failure and diabetes. We have recently shown that preserving H3K27 and H3K4 methylation using the lysine demethylase inhibitor GSK-J4 reduces cytokine-induced destruction of beta-cells and improves beta-cell function. Here, we investigate the therapeutic potential of GSK-J4 to prevent diabetes development and examine the importance of H3K4 methylation for islet function. Materials and Methods. We used two mouse models of diabetes to investigate the therapeutic potential of GSK-J4. To clarify the importance of H3K4 methylation, we characterized a mouse strain with knockout (KO) of the H3K4 demethylase KDM5B. Results. GSK-J4 administration failed to prevent the development of experimental diabetes induced by multiple low-dose streptozotocin or adoptive transfer of splenocytes from acutely diabetic NOD to NODscid mice. KDM5B-KO mice were growth retarded with altered body composition, had low IGF-1 levels, and exhibited reduced insulin secretion. Interestingly, despite secreting less insulin, KDM5B-KO mice were able to maintain normoglycemia following oral glucose tolerance test, likely via improved insulin sensitivity, as suggested by insulin tolerance testing and phosphorylation of proteins belonging to the insulin signaling pathway. When challenged with high-fat diet, KDM5B-deficient mice displayed similar weight gain and insulin sensitivity as wild-type mice. Conclusion. Our results show a novel role of KDM5B in metabolism, as KDM5B-KO mice display growth retardation and improved insulin sensitivity.
Fil: Backe, Marie Balslev. Universidad de Copenhagen; Dinamarca
Fil: Jin, Chunyu. Universidad de Copenhagen; Dinamarca
Fil: Andreone, Luz. Universidad Austral. Facultad de Ciencias Biomédicas. Instituto de Investigaciones en Medicina Traslacional. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones en Medicina Traslacional; Argentina
Fil: Sankar, Aditya. Universidad de Copenhagen; Dinamarca. The Novo Nordisk Foundation Center for Stem Cell Biology; Dinamarca
Fil: Agger, Karl. Universidad de Copenhagen; Dinamarca. The Novo Nordisk Foundation Center for Stem Cell Biology; Dinamarca
Fil: Helin, Kristian. Universidad de Copenhagen; Dinamarca. The Novo Nordisk Foundation Center for Stem Cell Biology; Dinamarca
Fil: Madsen, Andreas N.. Universidad de Copenhagen; Dinamarca
Fil: Poulsen, Steen S.. Universidad de Copenhagen; Dinamarca
Fil: Bysani, Madhusudhan. Lund University; Suecia
Fil: Bacos, Karl. Lund University; Suecia
Fil: Ling, Charlotte. Lund University; Suecia
Fil: Perone, Marcelo Javier. Universidad de Copenhagen; Dinamarca. Universidad Austral. Facultad de Ciencias Biomédicas. Instituto de Investigaciones en Medicina Traslacional. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones en Medicina Traslacional; Argentina
Fil: Holst, Birgitte. Universidad de Copenhagen; Dinamarca
Fil: Mandrup Poulsen, Thomas. Universidad de Copenhagen; Dinamarca
description Aims. Posttranslational modifications of histones and transcription factors regulate gene expression and are implicated in beta-cell failure and diabetes. We have recently shown that preserving H3K27 and H3K4 methylation using the lysine demethylase inhibitor GSK-J4 reduces cytokine-induced destruction of beta-cells and improves beta-cell function. Here, we investigate the therapeutic potential of GSK-J4 to prevent diabetes development and examine the importance of H3K4 methylation for islet function. Materials and Methods. We used two mouse models of diabetes to investigate the therapeutic potential of GSK-J4. To clarify the importance of H3K4 methylation, we characterized a mouse strain with knockout (KO) of the H3K4 demethylase KDM5B. Results. GSK-J4 administration failed to prevent the development of experimental diabetes induced by multiple low-dose streptozotocin or adoptive transfer of splenocytes from acutely diabetic NOD to NODscid mice. KDM5B-KO mice were growth retarded with altered body composition, had low IGF-1 levels, and exhibited reduced insulin secretion. Interestingly, despite secreting less insulin, KDM5B-KO mice were able to maintain normoglycemia following oral glucose tolerance test, likely via improved insulin sensitivity, as suggested by insulin tolerance testing and phosphorylation of proteins belonging to the insulin signaling pathway. When challenged with high-fat diet, KDM5B-deficient mice displayed similar weight gain and insulin sensitivity as wild-type mice. Conclusion. Our results show a novel role of KDM5B in metabolism, as KDM5B-KO mice display growth retardation and improved insulin sensitivity.
publishDate 2019
dc.date.none.fl_str_mv 2019-07
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/162535
Backe, Marie Balslev; Jin, Chunyu; Andreone, Luz; Sankar, Aditya; Agger, Karl; et al.; The Lysine Demethylase KDM5B Regulates Islet Function and Glucose Homeostasis; Hindawi Publishing Corporation; Journal of Diabetes Research; 2019; 5451038; 7-2019; 1-16
2314-6745
2314-6753
CONICET Digital
CONICET
url http://hdl.handle.net/11336/162535
identifier_str_mv Backe, Marie Balslev; Jin, Chunyu; Andreone, Luz; Sankar, Aditya; Agger, Karl; et al.; The Lysine Demethylase KDM5B Regulates Islet Function and Glucose Homeostasis; Hindawi Publishing Corporation; Journal of Diabetes Research; 2019; 5451038; 7-2019; 1-16
2314-6745
2314-6753
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1155/2019/5451038
info:eu-repo/semantics/altIdentifier/url/https://www.hindawi.com/journals/jdr/2019/5451038/
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Hindawi Publishing Corporation
publisher.none.fl_str_mv Hindawi Publishing Corporation
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 12.982451

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