Kronlage M, Dewenter M, Grosso J, et al. - Given that heart failure is worsened by some glucose-lowering drugs, raising the question of how glucose mediates protective vs detrimental cardiac signaling, researchers identified a histone deacetylase 4 (HDAC4) subdomain as a molecular checkpoint of adaptive and maladaptive signaling in the diabetic heart. Particularly in cardiomyocytes (HDAC4-knockout), HDAC4 was deleted using a conditional HDAC4 allele. They subjected the mice to diabetes mellitus either by administering streptozotocin injections (type 1 diabetes mellitus model) or by crossing into mice carrying a leptin receptor mutation (db/db; type 2 diabetes mellitus model). Using biochemical and cellular assays, they determined how HDAC4, in vivo and in vitro, was influenced by glucose and the posttranslational modification by β-linked N-acetylglucosamine (O-GlcNAc). In diabetes mellitus, a cardio-protective role of O-GlcNAcylation of HDAC4 at Ser-642 was found. Also, pathological Ca²⁺/calmodulin–dependent protein kinase II signaling was counteracted by O-GlcNAcylation of HDAC4 at Ser-642. A molecular model describing how diabetic metabolism possesses significant cardio-protective characteristics besides its recognized detrimental influences was proposed in this study.