O-GlcNAc modification acts as a candidate intracellular mediator of coronary dysfunction in diabetic modelsO-GlcNAc Modification Linked to Heart Issues in Diabetes Models

Diabetic cardiac remodeling involves microvascular dysfunction, inflammatory myeloid responses and fibroblast activation. O-linked beta-N-acetylglucosamine (O-GlcNAc) modification connects nutrient metabolism to protein function within each compartment, but its role in coordinating communication between them remains a hypothesis. This Mini Review evaluates that hypothesis against the available evidence. Diabetic models support causal effects of endothelial O-GlcNAc perturbation on coronary dysfunction, and an arterial endothelial CaMKIIalpha–small-extracellular-vesicle circuit provides evidence for persistent communication with cardiomyocytes after glucose normalization. Macrophage substrate mechanisms and fibroblast contractile responses are drawn partly from other organs or non-diabetic disease. Their relevance is therefore assessed separately from experimental design and human association. We compare O-GlcNAc with parallel AGE–RAGE, oxidative-stress and nutrient-sensing mechanisms, identify limitations of antibody-based and site-level measurements, and address sex as a biological variable. The synthesis supports O-GlcNAc as a candidate intracellular mediator of persistent multicellular remodeling, rather than an established intercellular coordinating signal. A consolidated experimental strategy tests whether endothelial O-GlcNAc is necessary for myeloid recruitment and subsequent fibrosis under matched glycemic conditions, and whether defined endothelial cargo rescues those effects. Cell-, substrate- and time-resolved interventions will be needed to separate pathogenic persistence from adaptive O-GlcNAc responses.