The Lysine Demethylase KDM5B Regulates Islet Function and Glucose Homeostasis
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 destruct...
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| Format: | Article |
| Language: | English |
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Wiley
2019-01-01
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| Series: | Journal of Diabetes Research |
| Online Access: | http://dx.doi.org/10.1155/2019/5451038 |
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| author | Marie Balslev Backe Chunyu Jin Luz Andreone Aditya Sankar Karl Agger Kristian Helin Andreas Nygaard Madsen Steen Seier Poulsen Madhusudhan Bysani Karl Bacos Charlotte Ling Marcelo Javier Perone Birgitte Holst Thomas Mandrup-Poulsen |
| author_facet | Marie Balslev Backe Chunyu Jin Luz Andreone Aditya Sankar Karl Agger Kristian Helin Andreas Nygaard Madsen Steen Seier Poulsen Madhusudhan Bysani Karl Bacos Charlotte Ling Marcelo Javier Perone Birgitte Holst Thomas Mandrup-Poulsen |
| author_sort | Marie Balslev Backe |
| collection | DOAJ |
| 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. |
| format | Article |
| id | doaj-art-4d4f7eb342df4876a3befcb012385c76 |
| institution | OA Journals |
| issn | 2314-6745 2314-6753 |
| language | English |
| publishDate | 2019-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of Diabetes Research |
| spelling | doaj-art-4d4f7eb342df4876a3befcb012385c762025-08-20T02:38:38ZengWileyJournal of Diabetes Research2314-67452314-67532019-01-01201910.1155/2019/54510385451038The Lysine Demethylase KDM5B Regulates Islet Function and Glucose HomeostasisMarie Balslev Backe0Chunyu Jin1Luz Andreone2Aditya Sankar3Karl Agger4Kristian Helin5Andreas Nygaard Madsen6Steen Seier Poulsen7Madhusudhan Bysani8Karl Bacos9Charlotte Ling10Marcelo Javier Perone11Birgitte Holst12Thomas Mandrup-Poulsen13Immuno-endocrinology Laboratory, Department of Biomedical Sciences, University of Copenhagen, DenmarkInstitute of Pharmacology, Department of Neuroscience and Pharmacology, University of Copenhagen, DenmarkImmuno-endocrinology, Diabetes & Metabolism Laboratory, Instituto de Investigaciones en Medicina Traslacional, Facultad de Ciencias Biomédicas, CONICET–Universidad Austral, ArgentinaBiotech Research and Innovation Centre (BRIC), University of Copenhagen, DenmarkBiotech Research and Innovation Centre (BRIC), University of Copenhagen, DenmarkBiotech Research and Innovation Centre (BRIC), University of Copenhagen, DenmarkInstitute of Pharmacology, Department of Neuroscience and Pharmacology, University of Copenhagen, DenmarkDepartment of Biomedical Sciences, Faculty of Health Sciences, University of Copenhagen, DenmarkUnit for Epigenetics and Diabetes, Department of Clinical Sciences, Lund University, Scania University Hospital, Malmo, SwedenUnit for Epigenetics and Diabetes, Department of Clinical Sciences, Lund University, Scania University Hospital, Malmo, SwedenUnit for Epigenetics and Diabetes, Department of Clinical Sciences, Lund University, Scania University Hospital, Malmo, SwedenImmuno-endocrinology Laboratory, Department of Biomedical Sciences, University of Copenhagen, DenmarkInstitute of Pharmacology, Department of Neuroscience and Pharmacology, University of Copenhagen, DenmarkImmuno-endocrinology Laboratory, Department of Biomedical Sciences, University of Copenhagen, DenmarkAims. 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.http://dx.doi.org/10.1155/2019/5451038 |
| spellingShingle | Marie Balslev Backe Chunyu Jin Luz Andreone Aditya Sankar Karl Agger Kristian Helin Andreas Nygaard Madsen Steen Seier Poulsen Madhusudhan Bysani Karl Bacos Charlotte Ling Marcelo Javier Perone Birgitte Holst Thomas Mandrup-Poulsen The Lysine Demethylase KDM5B Regulates Islet Function and Glucose Homeostasis Journal of Diabetes Research |
| title | 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_short | The Lysine Demethylase KDM5B Regulates Islet Function and Glucose Homeostasis |
| title_sort | lysine demethylase kdm5b regulates islet function and glucose homeostasis |
| url | http://dx.doi.org/10.1155/2019/5451038 |
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