Supplementary file 1_Metabolic memory in diabetic complications: evidence for persistent cellular states and limits of therapeutic reversal.docx

Persistent chromatin marks do not necessarily imply continuously active signaling, and latent priming may become apparent only after rechallenge. In kidney, cardiovascular, retinal and wound disease, candidate cellular memory coexists with hypoxic or inflammatory niches and structural loss. Pancreatic β-cell plasticity is considered a comparative endocrine model rather than an established complication-memory circuit.

The proposed interactions among epigenetic, mitochondrial, metabolic and inflammatory mechanisms remain a framework supported by selected local feedback loops, not a universally demonstrated network. Therapeutic evidence is organized into prevention, modification or suppression of established abnormalities, and sustained molecular and functional recovery after treatment cessation after intervention withdrawal. The latter remains unestablished in patients for the mechanisms reviewed.

Early glycemic and multifactorial management remains essential, while mechanistic translation requires explicit recovery, perturbation and post-treatment follow-up designs.</p>