744.3 - The lysine demethylase KDM6A regulates pancreatic β cells function

Bo Zhang (University of Tennessee Health Science Center), Shirley Wang (University of Tennessee Health Science Center), Zhongjie Sun (University of Tennessee Health Science Center)

Background and Objective. Diabetes mellitus refers to a group of metabolic disorders characterized by impaired glucose homeostasis. Both type 1 diabetes (T1D) and type 2 diabetes (T2D) are characterized by insulin insufficiency. β cell failure in diabetes are often due to posttranslational modifications of histones and transcription factors. Lysine demethylase 6A (KDM6A) belongs to the KDM6 family of histone H3 lysine 27 (H3K27) demethylases which is important for development of various organs. The objective of this study is to investigate whether KDM6A regulates pancreatic β cell function using targeted β cell-specific deletion of KDM6A gene.

Methods and Results. Briefly, inducible insulin 1-cre and KDM6A-loxp mice were bed to generate cre-loxp mice. Injection of tamoxifen induced deletion of KDM6A gene in β cells which led to increased H3K27me3 levels. KDM6A-KO mice exhibited reduced baseline insulin levels compared with wild-type mice. Interestingly, despite low baseline insulin levels, KDM6A-KO mice demonstrated enhanced glucose tolerance. Insulin release was increased in KDM6A-KO mice vs WT mice at 15 min following glucose challenge. Furthermore, ex vivo glucose-induced insulin secretion was increased in cultured islets isolated from KDM6A-KO mice. In cultured Min6 β cells, knockdown of KDM6A using KDM6A shRNA largely enhanced glucose-induced insulin release. When challenged with high-fat diet, KDM6A-KO mice displayed similar weight gain vs wild-type mice. However, the insulin sensitivity test showed that KDM6A-KO enhanced peripheral insulin sensitivity as evidenced by the delayed recovery of glucose level in KDM6A-KO mice fed with high-fat diet.

Conclusion. Our results suggest a novel role of KDM6A in the regulation of pancreatic β cell function. KDM6A may be a potential therapeutic target for β cell dysfunction.