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Peer-reviewedCC BYFrontiers in endocrinology

Metabolic memory in diabetic complications: evidence for persistent cellular states and limits of therapeutic reversal.

  • Yulan Cai1,2
  • Shuangyu He3
  • Feng Zeng4
  • Chuyu Liu4
4 affiliations
  1. 1Department of Endocrinology, The Second Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, China.
  2. 2Department of Endocrinology and Metabolism, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, China.
  3. 3Department of General Practice, The Second Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, China.
  4. 4Thyroid and Breast Surgery, The Second Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, China.
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Abstract

Metabolic memory is defined here as an exposure-history-dependent cellular phenotype that persists beyond immediate carry-over after verified withdrawal of the initiating exposure, principally high glucose and is accompanied by a specified functional impairment or an altered response to the same defined secondary stimulus. This operational definition separates cellular memory from clinical legacy effects, continuing local stimulation and residual structural injury. We critically examine evidence from longitudinal clinical studies, human biospecimens, animal models and controlled cell experiments, distinguishing molecular persistence, measured signaling activity, causal maintenance and treatment-free durability. DCCT/EDIC and UKPDS establish lasting benefits of earlier glycemic management but do not independently identify cellular memory as the mechanism. Experimental evidence supports selected endothelial redox circuits, epigenetic regulation and hematopoietic progenitor training; human causal evidence is substantially more limited. 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.

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Cite

BibTeXRIS
BibTeX
@article{cai2026metabolic,
  title = {{Metabolic memory in diabetic complications: evidence for persistent cellular states and limits of therapeutic reversal.}},
  author = {Yulan Cai and Shuangyu He and Feng Zeng and Chuyu Liu},
  journal = {Frontiers in endocrinology},
  year = {2026},
  month = oct,
  doi = {10.3389/fendo.2026.1954392},
  url = {https://europepmc.org/article/MED/42898654},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Metabolic memory in diabetic complications: evidence for persistent cellular states and limits of therapeutic reversal.
AU  - Yulan Cai
AU  - Shuangyu He
AU  - Feng Zeng
AU  - Chuyu Liu
PY  - 2026
DA  - 2026/10/05
JO  - Frontiers in endocrinology
DO  - 10.3389/fendo.2026.1954392
UR  - https://europepmc.org/article/MED/42898654
AB  - Metabolic memory is defined here as an exposure-history-dependent cellular phenotype that persists beyond immediate carry-over after verified withdrawal of the initiating exposure, principally high glucose and is accompanied by a specified functional impairment or an altered response to the same defined secondary stimulus. This operational definition separates cellular memory from clinical legacy effects, continuing local stimulation and residual structural injury. We critically examine evidence from longitudinal clinical studies, human biospecimens, animal models and controlled cell experiments, distinguishing molecular persistence, measured signaling activity, causal maintenance and treatment-free durability. DCCT/EDIC and UKPDS establish lasting benefits of earlier glycemic management but do not independently identify cellular memory as the mechanism. Experimental evidence supports selected endothelial redox circuits, epigenetic regulation and hematopoietic progenitor training; human causal evidence is substantially more limited. 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.
SN  - 1664-2392
ER  -