Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) is an enzyme with 
important regulatory functions in the heart and brain, and its chronic 
activation can be pathological. CaMKII activation is seen in heart failure, and 
can directly induce pathological changes in ion channels, Ca(2+) handling and 
gene transcription. Here, in human, rat and mouse, we identify a novel mechanism 
linking CaMKII and hyperglycaemic signalling in diabetes mellitus, which is a 
key risk factor for heart and neurodegenerative diseases. Acute hyperglycaemia 
causes covalent modification of CaMKII by O-linked N-acetylglucosamine 
(O-GlcNAc). O-GlcNAc modification of CaMKII at Ser 279 activates CaMKII 
autonomously, creating molecular memory even after Ca(2+) concentration 
declines. O-GlcNAc-modified CaMKII is increased in the heart and brain of 
diabetic humans and rats. In cardiomyocytes, increased glucose concentration 
significantly enhances CaMKII-dependent activation of spontaneous sarcoplasmic 
reticulum Ca(2+) release events that can contribute to cardiac mechanical 
dysfunction and arrhythmias. These effects were prevented by pharmacological 
inhibition of O-GlcNAc signalling or genetic ablation of CaMKIIδ. In intact 
perfused hearts, arrhythmias were aggravated by increased glucose concentration 
through O-GlcNAc- and CaMKII-dependent pathways. In diabetic animals, acute 
blockade of O-GlcNAc inhibited arrhythmogenesis. Thus, O-GlcNAc modification of 
CaMKII is a novel signalling event in pathways that may contribute critically to 
cardiac and neuronal pathophysiology in diabetes and other diseases.