Diabetes mellitus and atrial fibrillation (AF) are major unsolved public health problems, and diabetes is an independent risk factor for AF in patients. However, the mechanism(s) underlying this clinical association is unknown. Elevated protein O -GlcNAcylation (OGN) and reactive oxygen species (ROS) are increased in diabetic hearts, and calmodulin kinase II (CaMKII) is a proarrhythmic signal that may be activated by OGN (OGN-CaMKII) and ROS (ox-CaMKII). We induced type 1 (T1D) and type 2 diabetes (T2D) in a portfolio of genetic mouse models capable of dissecting the role of OGN and ROS at CaMKII and the type 2 ryanodine receptor (RyR2), an intracellular Ca2+ channel implicated as an important downstream mechanism of CaMKII-mediated arrhythmias. Here we show that T1D and T2D significantly increased AF, similar to observations in patients, and this increase required CaMKII. While T1D and T2D both require ox-CaMKII, they respond differently to loss of OGN-CaMKII. Collectively, our data affirm CaMKII as a critical proarrhythmic signal in diabetic AF, and suggest ROS primarily promotes AF by ox-CaMKII, while OGN promotes AF by diverse mechanisms and targets, including RyR2. However, the proarrhythmic consequences of OGN- and ox-CaMKII differ between T1D and T2D. These results provide new and unanticipated insights into the mechanisms for increased AF in diabetes mellitus, and suggest successful future therapies will need to be different for AF in T1D and T2D.*   AF    :   Atrial fibrillation    CaMKII    :   Calcium and calmodulin-dependent protein kinase II    DM    :   Diabetes mellitus    DON    :   Diazo-5-oxonorleucine    MsrA    :   Methionine sulfoxide reductase A    OGA    :   O -GlcNAcase    OGN    :   O -GlcNAcylation    (OGT)    :   O -GlcNAc transferase    OGN-CaMKII    :   O -GlcNAcylated CaMKII    ox-CaMKII    :   Oxidized CaMKII    STZ    :   Streptozocin    T1D    :   Type 1 diabetes mellitus    T2D    :   Type 2 diabetes mellitus    RyR2    :   Type 2 ryanodine receptors

O-GlcNAcylation and oxidation contribute to atrial fibrillation in diabetes by activating CaMKII