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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 to increase AF, they respond differently to loss of OGN-CaMKII or OGN inhibition. 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 CaMKII and RyR2. 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. ### Competing Interest Statement Dr. Wehrens is co-founder and shareholder of ELEX Biotech, a company aiming to develop RyR2 inhibitor therapeutics. Dr. Hart receives a share of royalty received by the university on sales of the CTD 110.6 antibody, which are managed by The Johns Hopkins University. Dr. Anderson has intellectual property rights on CaMKII inhibitors owned by Johns Hopkins University. The other authors report no conflicts of interest. * AF : Atrial fibrillation CaMKII : Calcium and calmodulin-dependent protein kinase II DM : Diabetes mellitus DON : Diazo-5-oxonorleucine KTR : Kinase translocation reporter 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

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