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The Lysine Demethylase KDM5B Regulates Islet Function and Glucose Homeostasis

Backe, Marie Balslev LU ; Jin, Chunyu ; Andreone, Luz ; Sankar, Aditya ; Agger, Karl ; Helin, Kristian ; Madsen, Andreas Nygaard ; Poulsen, Steen Seier ; Bysani, Madhusudhan LU and Bacos, Karl LU , et al. (2019) In Journal of Diabetes Research 2019.
Abstract

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... (More)

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.

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publication status
published
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in
Journal of Diabetes Research
volume
2019
article number
5451038
publisher
Hindawi Publishing Corporation
external identifiers
  • pmid:31467927
  • scopus:85071763963
ISSN
2314-6753
DOI
10.1155/2019/5451038
language
English
LU publication?
yes
id
5b71acb6-6dbb-4ff4-8598-52d8dbfcc15f
date added to LUP
2019-09-18 15:14:11
date last changed
2019-10-08 03:58:18
@article{5b71acb6-6dbb-4ff4-8598-52d8dbfcc15f,
  abstract     = {<p>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.</p>},
  author       = {Backe, Marie Balslev and Jin, Chunyu and Andreone, Luz and Sankar, Aditya and Agger, Karl and Helin, Kristian and Madsen, Andreas Nygaard and Poulsen, Steen Seier and Bysani, Madhusudhan and Bacos, Karl and Ling, Charlotte and Perone, Marcelo Javier and Holst, Birgitte and Mandrup-Poulsen, Thomas},
  issn         = {2314-6753},
  language     = {eng},
  publisher    = {Hindawi Publishing Corporation},
  series       = {Journal of Diabetes Research},
  title        = {The Lysine Demethylase KDM5B Regulates Islet Function and Glucose Homeostasis},
  url          = {http://dx.doi.org/10.1155/2019/5451038},
  doi          = {10.1155/2019/5451038},
  volume       = {2019},
  year         = {2019},
}