The significant findings of our study are: (1) RyR2 is post-translationally modified by O-GlcNAcylation; (2) hyperglycemia induced O-GlcNAcylation can increase SOICR through a CaMKII independent pathway via a reduction in the threshold for SOICR; and (3) S2808 is required for O-GlcNAcylation mediated changes in SOICR. Here, RYR2 is linked to Hyperglycemia.