{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T10:59:36Z","timestamp":1791197976575,"version":"4.1.0"},"reference-count":136,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T00:00:00Z","timestamp":1791158400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:p>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 \u03b2-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.<\/jats:p>","DOI":"10.3389\/fendo.2026.1954392","type":"journal-article","created":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T10:08:26Z","timestamp":1791194906000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Metabolic memory in diabetic complications: evidence for persistent cellular states and limits of therapeutic reversal"],"prefix":"10.3389","volume":"17","author":[{"given":"Yulan","family":"Cai","sequence":"first","affiliation":[{"name":"Department of Endocrinology, The Second Affiliated Hospital of Zunyi Medical University","place":["Zunyi, Guizhou, China"]},{"name":"Department of Endocrinology and Metabolism, Affiliated Hospital of Zunyi Medical University","place":["Zunyi, Guizhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuangyu","family":"He","sequence":"additional","affiliation":[{"name":"Department of General Practice, The Second Affiliated Hospital of Zunyi Medical University","place":["Zunyi, Guizhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Zeng","sequence":"additional","affiliation":[{"name":"Thyroid and Breast Surgery, The Second Affiliated Hospital of Zunyi Medical University","place":["Zunyi, Guizhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuyu","family":"Liu","sequence":"additional","affiliation":[{"name":"Thyroid and Breast Surgery, The Second Affiliated Hospital of Zunyi Medical University","place":["Zunyi, Guizhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,10,5]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199309303291401","article-title":"The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus","volume":"329","year":"1993","journal-title":"N Engl J Med"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.290.16.2159","article-title":"Sustained effect of intensive treatment of type 1 diabetes mellitus on development and progression of diabetic nephropathy: the EDIC study","volume":"290","year":"2003","journal-title":"JAMA"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1001\/archopht.126.12.1707","article-title":"Prolonged effect of intensive therapy on the risk of retinopathy complications in patients with type 1 diabetes mellitus: 10 years after the Diabetes Control and Complications Trial","volume":"126","author":"White","year":"2008","journal-title":"Arch Ophthalmol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.2337\/dc15-1990","article-title":"Intensive diabetes treatment and cardiovascular outcomes in type 1 diabetes: the DCCT\/EDIC Study 30-year follow-up","volume":"39","year":"2016","journal-title":"Diabetes Care"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0806470","article-title":"10-year follow-up of intensive glucose control in type 2 diabetes","volume":"359","author":"Holman","year":"2008","journal-title":"N Engl J Med"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(24)00537-3","article-title":"Post-trial monitoring of a randomised controlled trial of intensive glycaemic control in type 2 diabetes extended from 10 years to 24 years (UKPDS 91)","volume":"404","author":"Adler","year":"2024","journal-title":"Lancet"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.2337\/dc17-1144","article-title":"The legacy effect in type 2 diabetes: impact of early glycemic control on future complications","volume":"42","author":"Laiteerapong","year":"2019","journal-title":"Diabetes Care"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1186\/s12933-018-0677-0","article-title":"Long-term visit-to-visit glycemic variability as predictor of micro- and macrovascular complications in patients with type 2 diabetes: the Rio de Janeiro Type 2 Diabetes Cohort Study","volume":"17","author":"Cardoso","year":"2018","journal-title":"Cardiovasc Diabetol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20081188","article-title":"Transient high glucose causes persistent epigenetic changes and altered gene expression during subsequent normoglycemia","volume":"205","author":"El-Osta","year":"2008","journal-title":"J Exp Med"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.2337\/db13-1251","article-title":"Evaluating the role of epigenetic histone modifications in the metabolic memory of type 1 diabetes","volume":"63","author":"Miao","year":"2014","journal-title":"Diabetes"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1603712113","article-title":"Epigenomic profiling reveals an association between persistence of DNA methylation and metabolic memory in the DCCT\/EDIC type 1 diabetes cohort","volume":"113","author":"Chen","year":"2016","journal-title":"Proc Natl Acad Sci USA"},{"key":"B12","doi-asserted-by":"publisher","first-page":"797","DOI":"10.1089\/ars.2009.2932","article-title":"Role of mitochondrial DNA damage in the development of diabetic retinopathy, and the metabolic memory phenomenon associated with its progression","volume":"13","author":"Madsen-Bouterse","year":"2010","journal-title":"Antioxid Redox Signal"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.4161\/15592294.2014.967584","article-title":"Genome-wide DNA methylation analysis identifies a metabolic memory profile in patient-derived diabetic foot ulcer fibroblasts","volume":"9","author":"Park","year":"2014","journal-title":"Epigenetics"},{"key":"B14","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1186\/s12933-024-02195-1","article-title":"Persistent epigenetic signals propel a senescence-associated secretory phenotype and trained innate immunity in CD34-positive hematopoietic stem cells from diabetic patients","volume":"23","author":"Vinci","year":"2024","journal-title":"Cardiovasc Diabetol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1172\/JCI115216","article-title":"Decrease in skin collagen glycation with improved glycemic control in patients with insulin-dependent diabetes mellitus","volume":"87","author":"Lyons","year":"1991","journal-title":"J Clin Invest"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.16-19759","article-title":"The role of DNA methylation in the metabolic memory phenomenon associated with the continued progression of diabetic retinopathy","volume":"57","author":"Mishra","year":"2016","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1096\/fj.202502260RR","article-title":"Glucose induces DNMT1\/IMPDH2-dependent metabolic memory in endothelial cells upon reprograming nucleotide metabolism","volume":"40","author":"Vasishta","year":"2026","journal-title":"FASEB J"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.112.266171","article-title":"Distinguishing hyperglycemic changes by Set7 in vascular endothelial cells","volume":"110","author":"Okabe","year":"2012","journal-title":"Circ Res"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0143814","article-title":"Metformin and resveratrol inhibited high glucose-induced metabolic memory of endothelial senescence through the SIRT1\/p300\/p53\/p21 pathway","volume":"10","author":"Zhang","year":"2015","journal-title":"PloS One"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.120.046464","article-title":"Hyperglycemia induces trained immunity in macrophages and their precursors and promotes atherosclerosis","volume":"144","author":"Edgar","year":"2021","journal-title":"Circulation"},{"key":"B21","doi-asserted-by":"publisher","first-page":"196","DOI":"10.1093\/cvr\/cvab013","article-title":"Endothelial cell metabolic memory causes cardiovascular dysfunction in diabetes","volume":"118","author":"Yao","year":"2022","journal-title":"Cardiovasc Res"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehv599","article-title":"MicroRNA profiling unveils hyperglycaemic memory in the diabetic heart","volume":"37","author":"Costantino","year":"2016","journal-title":"Eur Heart J"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/j.omtn.2022.12.009","article-title":"Positive feedback loop of miR-320 and CD36 regulates the hyperglycemic memory-induced diabetic diastolic cardiac dysfunction","volume":"31","author":"Zhan","year":"2023","journal-title":"Mol Ther Nucleic Acids"},{"key":"B24","doi-asserted-by":"publisher","first-page":"104","DOI":"10.1038\/s42003-018-0108-5","article-title":"Activated protein C reverses epigenetically sustained p66Shc expression in plaque-associated macrophages in diabetes","volume":"1","author":"Shahzad","year":"2018","journal-title":"Commun Biol"},{"key":"B25","doi-asserted-by":"publisher","first-page":"5062","DOI":"10.1038\/s41467-022-32477-9","article-title":"Reversal of the renal hyperglycemic memory in diabetic kidney disease by targeting sustained tubular p21 expression","volume":"13","author":"Al-Dabet","year":"2022","journal-title":"Nat Commun"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1016\/j.jid.2020.10.023","article-title":"Transient high glucose causes persistent vascular dysfunction and delayed wound healing by the DNMT1-mediated Ang-1\/NF-\u03baB pathway","volume":"141","author":"Zhao","year":"2021","journal-title":"J Invest Dermatol"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.26508\/lsa.202302382","article-title":"Reversal of high-glucose-induced transcriptional and epigenetic memories through NRF2 pathway activation","volume":"7","author":"Wilson-Verdugo","year":"2024","journal-title":"Life Sci Alliance"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.12-10854","article-title":"Epigenetic modification of Sod2 in the development of diabetic retinopathy and in the metabolic memory: role of histone methylation","volume":"54","author":"Zhong","year":"2013","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1155\/2022\/3555889","article-title":"Mitochondrial dynamics in the metabolic memory of diabetic retinopathy","volume":"2022","author":"Mohammad","year":"2022","journal-title":"J Diabetes Res"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.3390\/ijms24098076","article-title":"Mitochondrial quality control and metabolic memory phenomenon associated with continued progression of diabetic retinopathy","volume":"24","author":"Kowluru","year":"2023","journal-title":"Int J Mol Sci"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1007\/s12035-023-03534-1","article-title":"Impaired removal of the damaged mitochondria in the metabolic memory phenomenon associated with continued progression of diabetic retinopathy","volume":"61","author":"Kowluru","year":"2024","journal-title":"Mol Neurobiol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1002\/dmrr.2384","article-title":"Impaired transport of mitochondrial transcription factor A and the metabolic memory phenomenon associated with the progression of diabetic retinopathy","volume":"29","author":"Santos","year":"2013","journal-title":"Diabetes Metab Res Rev"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1016\/j.exer.2014.02.010","article-title":"Posttranslational modification of mitochondrial transcription factor A in impaired mitochondria biogenesis: implications in diabetic retinopathy and metabolic memory phenomenon","volume":"121","author":"Santos","year":"2014","journal-title":"Exp Eye Res"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.112.266593","article-title":"Gene silencing of the mitochondrial adaptor p66Shc suppresses vascular hyperglycemic memory in diabetes","volume":"111","author":"Paneni","year":"2012","journal-title":"Circ Res"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1126\/science.1164097","article-title":"ATP-citrate lyase links cellular metabolism to histone acetylation","volume":"324","author":"Wellen","year":"2009","journal-title":"Science"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2015.08.024","article-title":"Histone methylation dynamics and gene regulation occur through the sensing of one-carbon metabolism","volume":"22","author":"Mentch","year":"2015","journal-title":"Cell Metab"},{"key":"B37","doi-asserted-by":"publisher","first-page":"24","DOI":"10.1016\/j.tcb.2020.09.010","article-title":"Metabolic coordination of cell fate by \u03b1-ketoglutarate-dependent dioxygenases","volume":"31","author":"Baksh","year":"2021","journal-title":"Trends Cell Biol"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1038\/srep40544","article-title":"Sustained kidney biochemical derangement in treated experimental diabetes: a clue to metabolic memory","volume":"7","author":"de Oliveira","year":"2017","journal-title":"Sci Rep"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1126\/science.1250684","article-title":"mTOR- and HIF-1\u03b1-mediated aerobic glycolysis as metabolic basis for trained immunity","volume":"345","author":"Cheng","year":"2014","journal-title":"Science"},{"key":"B40","doi-asserted-by":"publisher","first-page":"135","DOI":"10.1016\/j.cell.2017.11.025","article-title":"Metabolic induction of trained immunity through the mevalonate pathway","volume":"172","author":"Bekkering","year":"2018","journal-title":"Cell"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1007\/s00109-020-01915-w","article-title":"Rewiring of glucose metabolism defines trained immunity induced by oxidized low-density lipoprotein","volume":"98","author":"Keating","year":"2020","journal-title":"J Mol Med (Berl)"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-007-0684-2","article-title":"Reactive oxygen species mediate a cellular \u2018memory\u2019 of high glucose stress signalling","volume":"50","author":"Ihnat","year":"2007","journal-title":"Diabetologia"},{"key":"B43","doi-asserted-by":"publisher","first-page":"1344","DOI":"10.1016\/j.cmet.2025.03.006","article-title":"O-GlcNAcylation-mediated endothelial metabolic memory contributes to cardiac damage via small extracellular vesicles","volume":"37","author":"Ding","year":"2025","journal-title":"Cell Metab"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.2337\/diabetes.50.12.2792","article-title":"Diabetes-associated sustained activation of the transcription factor nuclear factor-\u03baB","volume":"50","author":"Bierhaus","year":"2001","journal-title":"Diabetes"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1016\/j.tem.2024.06.010","article-title":"Autophagy and lysosomal dysfunction in diabetes and its complications","volume":"35","author":"Arden","year":"2024","journal-title":"Trends Endocrinol Metab"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1016\/j.mce.2015.12.019","article-title":"Fatty acid induced metabolic memory involves alterations in renal histone H3K36me2 and H3K27me3","volume":"422","author":"Kumar","year":"2016","journal-title":"Mol Cell Endocrinol"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1038\/srep40220","article-title":"High fat diet-induced changes of mouse hepatic transcription and enhancer activity can be reversed by subsequent weight loss","volume":"7","author":"Siersb\u00e6k","year":"2017","journal-title":"Sci Rep"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1172\/JCI11235","article-title":"Hyperglycemia inhibits endothelial nitric oxide synthase activity by posttranslational modification at the Akt site","volume":"108","author":"Du","year":"2001","journal-title":"J Clin Invest"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1186\/1475-2840-13-112","article-title":"Disruption of endothelial adherens junctions by high glucose is mediated by protein kinase C-\u03b2-dependent vascular endothelial cadherin tyrosine phosphorylation","volume":"13","author":"Haidari","year":"2014","journal-title":"Cardiovasc Diabetol"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2013.12.014","article-title":"Endothelial PGC-1\u03b1 mediates vascular dysfunction in diabetes","volume":"19","author":"Sawada","year":"2014","journal-title":"Cell Metab"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.2337\/db24-0997","article-title":"Targeting SETD7 rescues diabetes-induced impairment of angiogenic response by transcriptional repression of semaphorin-3G","volume":"74","author":"Mohammed","year":"2025","journal-title":"Diabetes"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1111\/jcmm.18336","article-title":"Sirt7\/HIC1 complex participates in hyperglycaemia-mediated EndMT via modulation of SDC1 expression in diabetic kidney disease and metabolic memory","volume":"28","author":"Lu","year":"2024","journal-title":"J Cell Mol Med"},{"key":"B53","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1038\/s41467-017-02425-z","article-title":"Diabetes impairs wound healing by DNMT1-dependent dysregulation of hematopoietic stem-cell differentiation towards macrophages","volume":"9","author":"Yan","year":"2018","journal-title":"Nat Commun"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1901348","article-title":"Hyperglycemic memory of innate immune cells promotes in vitro proinflammatory responses of human monocytes and murine macrophages","volume":"206","author":"Thiem","year":"2021","journal-title":"J Immunol"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.120.316653","article-title":"Transient intermittent hyperglycemia accelerates atherosclerosis by promoting myelopoiesis","volume":"127","author":"Flynn","year":"2020","journal-title":"Circ Res"},{"key":"B56","doi-asserted-by":"publisher","first-page":"499","DOI":"10.1089\/ten.TEC.2014.0414","article-title":"Three-dimensional human tissue models that incorporate diabetic foot ulcer-derived fibroblasts mimic in vivo features of chronic wounds","volume":"21","author":"Maione","year":"2015","journal-title":"Tissue Eng Part C Methods"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1111\/exd.14405","article-title":"Cellular reprogramming of diabetic foot ulcer fibroblasts triggers a pro-healing miRNA-mediated epigenetic signature","volume":"30","author":"Pastar","year":"2021","journal-title":"Exp Dermatol"},{"key":"B58","doi-asserted-by":"publisher","first-page":"10277","DOI":"10.1038\/s41467-024-54385-w","article-title":"Vasculogenic skin reprogramming requires TET-mediated gene demethylation in fibroblasts for rescuing impaired perfusion in diabetes","volume":"15","author":"Mohanty","year":"2024","journal-title":"Nat Commun"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00300.2014","article-title":"Mechanosignaling through YAP and TAZ drives fibroblast activation and fibrosis","volume":"308","author":"Liu","year":"2015","journal-title":"Am J Physiol Lung Cell Mol Physiol"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.190836","article-title":"TNF-\u03b1 represses fibroblast-to-myofibroblast transition through the histone methyltransferase SETDB2","volume":"10","author":"Bauer","year":"2025","journal-title":"JCI Insight"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.1172\/JCI65390","article-title":"Inactivation of specific \u03b2 cell transcription factors in type 2 diabetes","volume":"123","author":"Guo","year":"2013","journal-title":"J Clin Invest"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2012.07.029","article-title":"Pancreatic \u03b2 cell dedifferentiation as a mechanism of diabetic \u03b2 cell failure","volume":"150","author":"Talchai","year":"2012","journal-title":"Cell"},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2013.12.002","article-title":"Pdx1 maintains \u03b2 cell identity and function by repressing an \u03b1 cell program","volume":"19","author":"Gao","year":"2014","journal-title":"Cell Metab"},{"key":"B64","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2013.08.010","article-title":"Nkx6.1 is essential for maintaining the functional state of pancreatic beta cells","volume":"4","author":"Taylor","year":"2013","journal-title":"Cell Rep"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-012-2666-2","article-title":"Beta cell nuclear musculoaponeurotic fibrosarcoma oncogene family A (MafA) is deficient in type 2 diabetes","volume":"55","author":"Butler","year":"2012","journal-title":"Diabetologia"},{"key":"B66","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2009.07.002","article-title":"PDX1 deficiency causes mitochondrial dysfunction and defective insulin secretion through TFAM suppression","volume":"10","author":"Gauthier","year":"2009","journal-title":"Cell Metab"},{"key":"B67","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2015-2860","article-title":"Evidence of \u03b2-cell dedifferentiation in human type 2 diabetes","volume":"101","author":"Cinti","year":"2016","journal-title":"J Clin Endocrinol Metab"},{"key":"B68","doi-asserted-by":"publisher","first-page":"4621","DOI":"10.1038\/s41467-022-32425-7","article-title":"Adaptation to chronic ER stress enforces pancreatic \u03b2-cell plasticity","volume":"13","author":"Chen","year":"2022","journal-title":"Nat Commun"},{"key":"B69","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2014.03.010","article-title":"Pancreatic \u03b2 cell dedifferentiation in diabetes and redifferentiation following insulin therapy","volume":"19","author":"Wang","year":"2014","journal-title":"Cell Metab"},{"key":"B70","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2022.111719","article-title":"Glycemic control releases regenerative potential of pancreatic beta cells blocked by severe hyperglycemia","volume":"41","author":"Furth-Lavi","year":"2022","journal-title":"Cell Rep"},{"key":"B71","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1016\/j.cmet.2019.05.006","article-title":"Acceleration of \u03b2 cell aging determines diabetes and senolysis improves disease outcomes","volume":"30","author":"Aguayo-Mazzucato","year":"2019","journal-title":"Cell Metab"},{"key":"B72","doi-asserted-by":"publisher","DOI":"10.1369\/jhc.2008.951194","article-title":"Keratinocyte migration, proliferation, and differentiation in chronic ulcers from patients with diabetes and normal wounds","volume":"56","author":"Usui","year":"2008","journal-title":"J Histochem Cytochem"},{"key":"B73","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2133.2008.08789.x","article-title":"Hyperglycaemic conditions decrease cultured keratinocyte mobility: implications for impaired wound healing in patients with diabetes","volume":"159","author":"Lan","year":"2008","journal-title":"Br J Dermatol"},{"key":"B74","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2019.00024","article-title":"High glucose suppresses keratinocyte migration through the inhibition of p38 MAPK\/autophagy pathway","volume":"10","author":"Li","year":"2019","journal-title":"Front Physiol"},{"key":"B75","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1083\/jcb.201409032","article-title":"FOXO1 differentially regulates both normal and diabetic wound healing","volume":"209","author":"Zhang","year":"2015","journal-title":"J Cell Biol"},{"key":"B76","doi-asserted-by":"publisher","DOI":"10.2337\/db12-1714","article-title":"High-glucose environment enhanced oxidative stress and increased interleukin-8 secretion from keratinocytes: new insights into impaired diabetic wound healing","volume":"62","author":"Lan","year":"2013","journal-title":"Diabetes"},{"key":"B77","doi-asserted-by":"publisher","DOI":"10.1016\/j.jdermsci.2019.11.004","article-title":"High glucose environment induces M1 macrophage polarization that impairs keratinocyte migration via TNF-\u03b1: an important mechanism to delay diabetic wound healing","volume":"96","author":"Huang","year":"2019","journal-title":"J Dermatol Sci"},{"key":"B78","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2022.121208","article-title":"High glucose-induced increasing reactive nitrogen species accumulation triggered mitochondrial dysfunction, inflammation, and apoptosis in keratinocytes","volume":"312","author":"Rizwan","year":"2023","journal-title":"Life Sci"},{"key":"B79","doi-asserted-by":"publisher","DOI":"10.1002\/cbin.11771","article-title":"Amniotic epithelial cells accelerate diabetic wound healing by protecting keratinocytes and fibroblasts from high-glucose-induced senescence","volume":"46","author":"Shu","year":"2022","journal-title":"Cell Biol Int"},{"key":"B80","doi-asserted-by":"publisher","DOI":"10.1093\/burnst\/tkae065","article-title":"Single-cell RNA sequencing reveals the impaired epidermal differentiation and pathological microenvironment in diabetic foot ulcer","volume":"13","author":"Liu","year":"2025","journal-title":"Burns Trauma"},{"key":"B81","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1038\/s41467-021-27801-8","article-title":"Single-cell transcriptomic landscape of diabetic foot ulcers","volume":"13","author":"Theocharidis","year":"2022","journal-title":"Nat Commun"},{"key":"B82","doi-asserted-by":"publisher","first-page":"1171","DOI":"10.1016\/j.jid.2019.01.005","article-title":"Elevated local senescence in diabetic wound healing is linked to pathological repair via CXCR2","volume":"139","author":"Wilkinson","year":"2019","journal-title":"J Invest Dermatol"},{"key":"B83","doi-asserted-by":"publisher","DOI":"10.2337\/db16-0254","article-title":"Persistent insulin resistance in podocytes caused by epigenetic changes of SHP-1 in diabetes","volume":"65","author":"Lizotte","year":"2016","journal-title":"Diabetes"},{"key":"B84","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1016\/j.trsl.2022.04.005","article-title":"Sirt7 associates with ELK1 to participate in hyperglycemia memory and diabetic nephropathy via modulation of DAPK3 expression and endothelial inflammation","volume":"247","author":"Li","year":"2022","journal-title":"Transl Res"},{"key":"B85","doi-asserted-by":"publisher","DOI":"10.1194\/jlr.P040501","article-title":"Altered renal lipid metabolism and renal lipid accumulation in human diabetic nephropathy","volume":"55","author":"Herman-Edelstein","year":"2014","journal-title":"J Lipid Res"},{"key":"B86","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-024-01802-x","article-title":"Single-cell multi-omic and spatial profiling of human kidneys implicates the fibrotic microenvironment in kidney disease progression","volume":"56","author":"Abedini","year":"2024","journal-title":"Nat Genet"},{"key":"B87","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.125.324012","article-title":"Single-cell multimodal profiling highlights persistent aortic smooth muscle cell changes in diabetic mice despite glycemic control","volume":"46","author":"Tanwar","year":"2026","journal-title":"Arterioscler Thromb Vasc Biol"},{"key":"B88","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-017-4254-y","article-title":"Hyperglycaemic memory affects the neurovascular unit of the retina in a diabetic mouse model","volume":"60","author":"Friedrichs","year":"2017","journal-title":"Diabetologia"},{"key":"B89","doi-asserted-by":"publisher","DOI":"10.2337\/diabetes.53.4.1104","article-title":"Angiopoietin-2 causes pericyte dropout in the normal retina: evidence for involvement in diabetic retinopathy","volume":"53","author":"Hammes","year":"2004","journal-title":"Diabetes"},{"key":"B90","doi-asserted-by":"publisher","DOI":"10.1016\/j.exer.2010.02.006","article-title":"Metabolic memory and diabetic retinopathy: role of inflammatory mediators in retinal pericytes","volume":"90","author":"Kowluru","year":"2010","journal-title":"Exp Eye Res"},{"key":"B91","article-title":"Glial reactivity, an early feature of diabetic retinopathy","volume":"41","author":"Rungger-Br\u00e4ndle","year":"2000","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"B92","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1016\/j.exer.2014.06.005","article-title":"Insulin treatment normalizes retinal neuroinflammation but not markers of synapse loss in diabetic rats","volume":"125","author":"Masser","year":"2014","journal-title":"Exp Eye Res"},{"key":"B93","doi-asserted-by":"publisher","DOI":"10.1016\/j.jid.2016.08.009","article-title":"Temporal stability in chronic wound microbiota is associated with poor healing","volume":"137","author":"Loesche","year":"2017","journal-title":"J Invest Dermatol"},{"key":"B94","doi-asserted-by":"publisher","first-page":"641","DOI":"10.1016\/j.chom.2019.03.006","article-title":"Strain- and species-level variation in the microbiome of diabetic wounds is associated with clinical outcomes and therapeutic efficacy","volume":"25","author":"Kalan","year":"2019","journal-title":"Cell Host Microbe"},{"key":"B95","doi-asserted-by":"publisher","DOI":"10.2337\/dc25-0300","article-title":"High transepidermal water loss at the site of wound closure is associated with increased recurrence of diabetic foot ulcers","volume":"48","author":"Sen","year":"2025","journal-title":"Diabetes Care"},{"key":"B96","doi-asserted-by":"publisher","DOI":"10.2337\/dc13-0996","article-title":"Effect of custom-made footwear on foot ulcer recurrence in diabetes: a multicenter randomized controlled trial","volume":"36","author":"Bus","year":"2013","journal-title":"Diabetes Care"},{"key":"B97","doi-asserted-by":"publisher","DOI":"10.1136\/bmjdrc-2021-002392","article-title":"Effectiveness of at-home skin temperature monitoring in reducing the incidence of foot ulcer recurrence in people with diabetes: a multicenter randomized controlled trial (DIATEMP)","volume":"9","author":"Bus","year":"2021","journal-title":"BMJ Open Diabetes Res Care"},{"key":"B98","doi-asserted-by":"publisher","DOI":"10.1111\/j.1524-475X.2009.00532.x","article-title":"3-Deoxyglucosone-collagen alters human dermal fibroblast migration and adhesion: implications for impaired wound healing in patients with diabetes","volume":"17","author":"Loughlin","year":"2009","journal-title":"Wound Repair Regener"},{"key":"B99","doi-asserted-by":"publisher","DOI":"10.1126\/science.aar3318","article-title":"Hyperglycemia drives intestinal barrier dysfunction and risk for enteric infection","volume":"359","author":"Thaiss","year":"2018","journal-title":"Science"},{"key":"B100","doi-asserted-by":"publisher","first-page":"162","DOI":"10.1016\/j.cell.2017.12.013","article-title":"Western diet triggers NLRP3-dependent innate immune reprogramming","volume":"172","author":"Christ","year":"2018","journal-title":"Cell"},{"key":"B101","doi-asserted-by":"publisher","first-page":"947","DOI":"10.1016\/j.cell.2018.09.055","article-title":"Microbially produced imidazole propionate impairs insulin signaling through mTORC1","volume":"175","author":"Koh","year":"2018","journal-title":"Cell"},{"key":"B102","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-016-4065-6","article-title":"Years of life gained by multifactorial intervention in patients with type 2 diabetes mellitus and microalbuminuria: 21 years follow-up on the Steno-2 randomised trial","volume":"59","author":"G\u00e6de","year":"2016","journal-title":"Diabetologia"},{"key":"B103","doi-asserted-by":"publisher","DOI":"10.2337\/db08-0063","article-title":"Oscillating glucose is more deleterious to endothelial function and oxidative stress than mean glucose in normal and type 2 diabetic patients","volume":"57","author":"Ceriello","year":"2008","journal-title":"Diabetes"},{"key":"B104","doi-asserted-by":"publisher","DOI":"10.1172\/JCI13776","article-title":"Acute intensive insulin therapy exacerbates diabetic blood-retinal barrier breakdown via hypoxia-inducible factor-1\u03b1 and VEGF","volume":"109","author":"Poulaki","year":"2002","journal-title":"J Clin Invest"},{"key":"B105","doi-asserted-by":"publisher","DOI":"10.3390\/ijms23094887","article-title":"NAD+ precursors repair mitochondrial function in diabetes and prevent experimental diabetic neuropathy","volume":"23","author":"Chandrasekaran","year":"2022","journal-title":"Int J Mol Sci"},{"key":"B106","doi-asserted-by":"publisher","DOI":"10.1111\/dom.14503","article-title":"Sodium\u2013glucose cotransporter-2 inhibition reduces cellular senescence in the diabetic kidney by promoting ketone body-induced NRF2 activation","volume":"23","author":"Kim","year":"2021","journal-title":"Diabetes Obes Metab"},{"key":"B107","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.cmet.2019.05.014","article-title":"Treatment with statins does not revert trained immunity in patients with familial hypercholesterolemia","volume":"30","author":"Bekkering","year":"2019","journal-title":"Cell Metab"},{"key":"B108","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-024-02802-4","article-title":"Therapeutic targeting of cellular senescence in diabetic macular edema: preclinical and phase 1 trial results","volume":"30","author":"Crespo-Garcia","year":"2024","journal-title":"Nat Med"},{"key":"B109","doi-asserted-by":"publisher","DOI":"10.1056\/EVIDoa2400009","article-title":"Safety and efficacy of senolytic UBX1325 in diabetic macular edema","volume":"4","author":"Klier","year":"2025","journal-title":"NEJM Evid"},{"key":"B110","doi-asserted-by":"publisher","DOI":"10.1016\/j.phymed.2024.155705","article-title":"Senolytic combination of dasatinib and quercetin attenuates renal damage in diabetic kidney disease","volume":"130","author":"Guo","year":"2024","journal-title":"Phytomedicine"},{"key":"B111","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2019.08.069","article-title":"Senolytics decrease senescent cells in humans: preliminary report from a clinical trial of dasatinib plus quercetin in individuals with diabetic kidney disease","volume":"47","author":"Hickson","year":"2019","journal-title":"EBioMedicine"},{"key":"B112","doi-asserted-by":"publisher","DOI":"10.7150\/thno.100991","article-title":"Clearance of senescent cells enhances skin wound healing in type 2 diabetic mice","volume":"14","author":"Samarawickrama","year":"2024","journal-title":"Theranostics"},{"key":"B113","doi-asserted-by":"publisher","first-page":"527","DOI":"10.1038\/s41467-025-67222-5","article-title":"Editing DNA methylation in vivo","volume":"17","author":"Pan","year":"2026","journal-title":"Nat Commun"},{"key":"B114","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1504720","article-title":"Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes","volume":"373","author":"Zinman","year":"2015","journal-title":"N Engl J Med"},{"key":"B115","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2024816","article-title":"Dapagliflozin in patients with chronic kidney disease","volume":"383","author":"Sylvester","year":"2020","journal-title":"N Engl J Med"},{"key":"B116","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2403347","article-title":"Effects of semaglutide on chronic kidney disease in patients with type 2 diabetes","volume":"391","author":"Perkovic","year":"2024","journal-title":"N Engl J Med"},{"key":"B117","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aee1005","article-title":"SGLT2 inhibition modulates metabolic, vascular, and inflammatory molecular markers in the kidney in youth with type 1 diabetes","volume":"18","author":"Bjornstad","year":"2026","journal-title":"Sci Transl Med"},{"key":"B118","doi-asserted-by":"publisher","DOI":"10.1096\/fj.202000860RR","article-title":"Incretin drugs effect on epigenetic machinery: new potential therapeutic implications in preventing vascular diabetic complications","volume":"34","author":"Scisciola","year":"2020","journal-title":"FASEB J"},{"key":"B119","doi-asserted-by":"publisher","DOI":"10.1155\/2011\/647017","article-title":"Downregulation of the proinflammatory state of circulating mononuclear cells by short-term treatment with pioglitazone in patients with type 2 diabetes mellitus and coronary artery disease","volume":"2011","author":"Pf\u00fctzner","year":"2011","journal-title":"PPAR Res"},{"key":"B120","doi-asserted-by":"publisher","first-page":"1103","DOI":"10.1016\/j.cell.2020.09.056","article-title":"Chromatin potential identified by shared single-cell profiling of RNA and chromatin","volume":"183","author":"Ma","year":"2020","journal-title":"Cell"},{"key":"B121","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1186\/s13059-016-0950-z","article-title":"Simultaneous profiling of transcriptome and DNA methylome from a single cell","volume":"17","author":"Hu","year":"2016","journal-title":"Genome Biol"},{"key":"B122","doi-asserted-by":"publisher","DOI":"10.1016\/j.apsb.2021.05.013","article-title":"Spatial-resolved metabolomics reveals tissue-specific metabolic reprogramming in diabetic nephropathy by using mass spectrometry imaging","volume":"11","author":"Wang","year":"2021","journal-title":"Acta Pharm Sin B"},{"key":"B123","doi-asserted-by":"publisher","first-page":"1509","DOI":"10.1016\/j.cell.2019.08.009","article-title":"Fate mapping via Ms4a3-expression history traces monocyte-derived cells","volume":"178","author":"Liu","year":"2019","journal-title":"Cell"},{"key":"B124","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-018-0744-4","article-title":"Single-cell mapping of lineage and identity in direct reprogramming","volume":"564","author":"Biddy","year":"2018","journal-title":"Nature"},{"key":"B125","doi-asserted-by":"publisher","first-page":"1410","DOI":"10.1016\/j.cell.2020.04.048","article-title":"An engineered CRISPR\u2013Cas9 mouse line for simultaneous readout of lineage histories and gene expression profiles in single cells","volume":"181","author":"Bowling","year":"2020","journal-title":"Cell"},{"key":"B126","doi-asserted-by":"publisher","first-page":"1853","DOI":"10.1016\/j.cell.2016.11.038","article-title":"Perturb-Seq: dissecting molecular circuits with scalable single-cell RNA profiling of pooled genetic screens","volume":"167","author":"Dixit","year":"2016","journal-title":"Cell"},{"key":"B127","doi-asserted-by":"publisher","first-page":"101161","DOI":"10.1016\/j.cels.2024.12.002","article-title":"Multiome Perturb-seq unlocks scalable discovery of integrated perturbation effects on the transcriptome and epigenome","volume":"16","author":"Metzner","year":"2025","journal-title":"Cell Syst"},{"key":"B128","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1007\/s44164-024-00068-1","article-title":"Modelling neurodegeneration and inflammation in early diabetic retinopathy using 3D human retinal organoids","volume":"3","author":"de Lemos","year":"2024","journal-title":"In Vitro Models"},{"key":"B129","doi-asserted-by":"publisher","DOI":"10.1039\/C7LC00134G","article-title":"A disease model of diabetic nephropathy in a glomerulus-on-a-chip microdevice","volume":"17","author":"Wang","year":"2017","journal-title":"Lab Chip"},{"key":"B130","doi-asserted-by":"publisher","DOI":"10.1016\/j.xcrm.2025.102290","article-title":"Epigenetic biomarkers predict macrovascular events in individuals with type 2 diabetes","volume":"6","author":"Garc\u00eda-Calz\u00f3n","year":"2025","journal-title":"Cell Rep Med"},{"key":"B131","doi-asserted-by":"publisher","DOI":"10.1172\/JCI170341","article-title":"Endogenous adenine mediates kidney injury in diabetic models and predicts diabetic kidney disease in patients","volume":"133","author":"Sharma","year":"2023","journal-title":"J Clin Invest"},{"key":"B132","doi-asserted-by":"publisher","DOI":"10.2337\/dc07-1755","article-title":"Skin autofluorescence: a tool to identify type 2 diabetic patients at risk for developing microvascular complications","volume":"31","author":"Gerrits","year":"2008","journal-title":"Diabetes Care"},{"key":"B133","doi-asserted-by":"publisher","DOI":"10.1016\/j.ophtha.2019.06.016","article-title":"OCT angiography metrics predict progression of diabetic retinopathy and development of diabetic macular edema: a prospective study","volume":"126","author":"Sun","year":"2019","journal-title":"Ophthalmology"},{"key":"B134","doi-asserted-by":"publisher","DOI":"10.1038\/s42255-020-0231-8","article-title":"DNA methylation mediates development of HbA1c-associated complications in type 1 diabetes","volume":"2","author":"Chen","year":"2020","journal-title":"Nat Metab"},{"key":"B135","doi-asserted-by":"publisher","DOI":"10.2337\/diabetes.54.11.3103","article-title":"Glycation and carboxymethyllysine levels in skin collagen predict the risk of future 10-year progression of diabetic retinopathy and nephropathy in the diabetes control and complications trial and epidemiology of diabetes interventions and complications participants with type 1 diabetes","volume":"54","author":"Genuth","year":"2005","journal-title":"Diabetes"},{"key":"B136","doi-asserted-by":"publisher","first-page":"6655","DOI":"10.1038\/s41598-020-63527-1","article-title":"Epigenetics and mitochondrial stability in the metabolic memory phenomenon associated with continued progression of diabetic retinopathy","volume":"10","author":"Kowluru","year":"2020","journal-title":"Sci Rep"}],"container-title":["Frontiers in Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2026.1954392\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T10:08:29Z","timestamp":1791194909000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2026.1954392\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,10,5]]},"references-count":136,"alternative-id":["10.3389\/fendo.2026.1954392"],"URL":"https:\/\/doi.org\/10.3389\/fendo.2026.1954392","relation":{},"ISSN":["1664-2392"],"issn-type":[{"value":"1664-2392","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,10,5]]},"article-number":"1954392"}}