PERONE Marcelo Javier
The lysine demethylase KDM5B regulates islet function and glucose homeostasis
BACKE, M; JIN, C; ANDREONE, L; SANKAR, A; AGGER, K; HELIN, K; MADSEN, AN; POULSEN, SS; BYSANI, M; BACOS, K; LING, C; PERONE, MJ; HOLST, B; MANDRUP-POULSEN, T
journal of diabetes research
Aims. Posttranslational modifications of histones and transcription factors regulate gene expression and are implicated inbeta-cell failure and diabetes. We have recently shown that preserving H3K27 and H3K4 methylation using the lysinedemethylase inhibitor GSK-J4 reduces cytokine-induced destruction of beta-cells and improves beta-cell function. Here, weinvestigate the therapeutic potential of GSK-J4 to prevent diabetes development and examine the importance of H3K4methylation for islet function. Materials and Methods. We used two mouse models of diabetes to investigate thetherapeutic potential of GSK-J4. To clarify the importance of H3K4 methylation, we characterized a mouse strain withknockout (KO) of the H3K4 demethylase KDM5B. Results. GSK-J4 administration failed to prevent the development ofexperimental diabetes induced by multiple low-dose streptozotocin or adoptive transfer of splenocytes from acutely diabeticNOD 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 tomaintain normoglycemia following oral glucose tolerance test, likely via improved insulin sensitivity, as suggested byinsulin tolerance testing and phosphorylation of proteins belonging to the insulin signaling pathway. When challenged withhigh-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 improvedinsulin sensitivity.