The Lysine Demethylase KDM5B Regulates Islet Function and Glucose Homeostasis.
Animals
Carbohydrate Metabolism
/ genetics
DNA-Binding Proteins
/ genetics
Diabetes Mellitus, Experimental
/ chemically induced
Glucose
/ metabolism
Growth Disorders
/ genetics
Homeostasis
/ genetics
Insulin Resistance
/ genetics
Insulin-Secreting Cells
/ metabolism
Islets of Langerhans
/ metabolism
Jumonji Domain-Containing Histone Demethylases
/ genetics
Mice
Mice, Inbred C57BL
Mice, Inbred NOD
Mice, Knockout
Mice, SCID
Streptozocin
Journal
Journal of diabetes research
ISSN: 2314-6753
Titre abrégé: J Diabetes Res
Pays: England
ID NLM: 101605237
Informations de publication
Date de publication:
2019
2019
Historique:
received:
21
02
2019
revised:
06
05
2019
accepted:
04
06
2019
entrez:
31
8
2019
pubmed:
31
8
2019
medline:
23
1
2020
Statut:
epublish
Résumé
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. 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. 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. Our results show a novel role of KDM5B in metabolism, as KDM5B-KO mice display growth retardation and improved insulin sensitivity.
Identifiants
pubmed: 31467927
doi: 10.1155/2019/5451038
pmc: PMC6701283
doi:
Substances chimiques
DNA-Binding Proteins
0
Streptozocin
5W494URQ81
Jumonji Domain-Containing Histone Demethylases
EC 1.14.11.-
Kdm5b protein, mouse
EC 1.14.11.-
Glucose
IY9XDZ35W2
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
5451038Déclaration de conflit d'intérêts
We declare no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
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