The lysine demethylase KDM5B regulates islet function and glucose homeostasis

ANDREONE, LUZ; HELIN, KRISTIAN; BYSANI, MADHUSUDHAN; PERONE, MARCELO JAVIER; JIN, CHUNYU; AGGER, KARL; POULSEN, STEEN S; LING, CHARLOTTE; MANDRUP-POULSEN, THOMAS; BACKE, MARIE BALSLEV; SANKAR, ADITYA; MADSEN, ANDREAS N; BACOS, KARL; HOLST, BIRGITTE

Journal of Diabetes Research

Hindawi

Año: 2019

2314-6745

Aims: Posttranslational modifications of histones and transcription factors regulate gene expression and are implicated in β-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 β-cells and improves β-cell function. Here we investigate the therapeutic potential of GSK-J4 to prevent diabetes development, and examine the specific contribution of H3K4 methylation for the previously observed improved insulin secretion. Materials and methods: We used two mouse models of diabetes to investigate the therapeutic potential of GSK-J4. To clarify the specific contribution of H3K4 methylation, we characterized a mouse strain with knock out (KO) of the H3K4 demethylase KDM5B. Results: GSK-J4 administration failed to prevent 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-I 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.