{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T21:45:34Z","timestamp":1790113534073,"version":"4.0.1"},"reference-count":125,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T00:00:00Z","timestamp":1784505600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Diabetes Mellitus (DM) is a metabolic disorder characterized by chronic hyperglycemia resulting from the body\u2019s inability to produce insulin or effectively respond to it. In this review, we summarize the cellular and molecular mechanisms involved in common clinical manifestations of DM, including neuropathy, retinopathy, nephropathy, sensorineural hearing loss, cardiovascular disease, stroke, immune dysfunction, and chronic wounds. Common pathways explored in these dysfunctions include the polyol pathway, formation of advanced glycation end products (AGEs) and their interaction with the receptor for advanced glycation end products (RAGE), mitochondrial dysfunctions leading to overproduction of reactive oxygen species (ROS), and the chronic state of inflammation and inflammatory cytokines. Furthermore, we explore current and developing treatments for DM, along with more targeted therapies for the clinical manifestations of DM. In summary, this review gives a comprehensive overview of the pathways involved in the clinical manifestations of DM, and how these pathways are targets for therapeutics and treatments.<\/jats:p>","DOI":"10.3390\/cells15141296","type":"journal-article","created":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T16:19:27Z","timestamp":1784564367000},"page":"1296","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Diabetes-Related Complications: Mechanisms and Emerging Therapies"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-3070-5662","authenticated-orcid":false,"given":"Vijaya","family":"Prathigudupu","sequence":"first","affiliation":[{"name":"College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA 91766, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minhyuk","family":"Lee","sequence":"additional","affiliation":[{"name":"College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA 91766, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isaac","family":"Uriarte","sequence":"additional","affiliation":[{"name":"College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA 91766, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gadiel","family":"So","sequence":"additional","affiliation":[{"name":"College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA 91766, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rabina","family":"Kaur","sequence":"additional","affiliation":[{"name":"College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA 91766, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabrina","family":"Kaur","sequence":"additional","affiliation":[{"name":"College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA 91766, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fatima","family":"Ghacham","sequence":"additional","affiliation":[{"name":"College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA 91766, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2586-1160","authenticated-orcid":false,"given":"Vishwanath","family":"Venketaraman","sequence":"additional","affiliation":[{"name":"College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA 91766, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,20]]},"reference":[{"key":"ref_1","unstructured":"World Health Organization (2026, April 20). Diabetes. Available online: https:\/\/www.who.int\/news-room\/fact-sheets\/detail\/diabetes."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"American Diabetes Association (2010). Diagnosis and Classification of Diabetes Mellitus. Diabetes Care, 33, S62\u2013S69.","DOI":"10.2337\/dc10-S062"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1038\/s41574-020-00425-6","article-title":"The trials and tribulations of determining HbA1c targets for diabetes mellitus","volume":"16","author":"Klein","year":"2020","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1038\/414813a","article-title":"Biochemistry and molecular cell biology of diabetic complications","volume":"414","author":"Brownlee","year":"2001","journal-title":"Nature"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1186\/s12964-022-01016-w","article-title":"Common mechanisms underlying diabetic vascular complications: Focus on the interaction of metabolic disorders, immuno-inflammation, and endothelial dysfunction","volume":"21","author":"Xue","year":"2023","journal-title":"Cell Commun. Signal."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1186\/s12933-023-01965-7","article-title":"The role of oxidative stress in diabetes mellitus-induced vascular endothelial dysfunction","volume":"22","author":"An","year":"2023","journal-title":"Cardiovasc. Diabetol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"8379327","DOI":"10.1155\/2017\/8379327","article-title":"Diabetes-Induced Reactive Oxygen Species: Mechanism of Their Generation and Role in Renal Injury","volume":"2017","author":"Fakhruddin","year":"2017","journal-title":"J. Diabetes Res."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Yang, D.R., Wang, M.Y., Zhang, C.L., and Wang, Y. (2024). Endothelial dysfunction in vascular complications of diabetes: A comprehensive review of mechanisms and implications. Front. Endocrinol., 15.","DOI":"10.3389\/fendo.2024.1359255"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1177\/2047487319878373","article-title":"The link between diabetes and atherosclerosis","volume":"26","author":"Prattichizzo","year":"2019","journal-title":"Eur. J. Prev. Cardiol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"7213","DOI":"10.1021\/acs.jmedchem.7b00058","article-title":"Targeting the Receptor for Advanced Glycation Endproducts (RAGE): A Medicinal Chemistry Perspective","volume":"60","author":"Bongarzone","year":"2017","journal-title":"J. Med. Chem."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"968","DOI":"10.1089\/ars.2023.0524","article-title":"Oxidative Stress, Endothelial Dysfunction, and N-Acetylcysteine in Type 2 Diabetes Mellitus","volume":"40","author":"Li","year":"2024","journal-title":"Antioxid. Redox Signal."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Liu, Z., Lu, J., Sha, W., and Lei, T. (2025). Comprehensive treatment of diabetic endothelial dysfunction based on pathophysiological mechanism. Front. Med., 12.","DOI":"10.3389\/fmed.2025.1509884"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3634948","DOI":"10.1155\/2016\/3634948","article-title":"Insulin Resistance and Endothelial Dysfunction Constitute a Common Therapeutic Target in Cardiometabolic Disorders","volume":"2016","author":"Janus","year":"2016","journal-title":"Mediat. Inflamm."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Wang, E., Wang, H., and Chakrabarti, S. (2023). Endothelial-to-mesenchymal transition: An underappreciated mediator of diabetic complications. Front. Endocrinol., 14.","DOI":"10.3389\/fendo.2023.1050540"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1016\/j.yexmp.2017.03.007","article-title":"High glucose induced endothelial to mesenchymal transition in human umbilical vein endothelial cell","volume":"102","author":"Yu","year":"2017","journal-title":"Exp. Mol. Pathol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1016\/j.ecl.2013.06.001","article-title":"Diabetic neuropathy","volume":"42","author":"Vinik","year":"2013","journal-title":"Endocrinol. Metab. Clin. N. Am."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1007\/s11916-024-01243-5","article-title":"Diabetic neuropathy: Pathophysiology review","volume":"28","author":"Strand","year":"2024","journal-title":"Curr. Pain Headache Rep."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1038\/s41572-019-0092-1","article-title":"Diabetic neuropathy","volume":"5","author":"Feldman","year":"2019","journal-title":"Nat. Rev. Dis. Prim."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1002\/ame2.12001","article-title":"Redox imbalance stress in diabetes mellitus: Role of the polyol pathway","volume":"1","author":"Yan","year":"2018","journal-title":"Anim. Model. Exp. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1007\/s11916-022-01061-7","article-title":"Evidence-Based Treatment of Painful Diabetic Neuropathy: A Systematic Review","volume":"26","author":"Barman","year":"2022","journal-title":"Curr. Pain Headache Rep."},{"key":"ref_21","first-page":"226","article-title":"Diabetic peripheral neuropathy: Prevention and treatment","volume":"109","author":"Bragg","year":"2024","journal-title":"Am. Fam. Physician"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"100903","DOI":"10.1016\/j.preteyeres.2020.100903","article-title":"Retinal capillary basement membrane thickening: Role in the pathogenesis of diabetic retinopathy","volume":"82","author":"Roy","year":"2021","journal-title":"Prog. Retin Eye Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3218","DOI":"10.2174\/09298673113209990022","article-title":"Pericyte loss in diabetic retinopathy: Mechanisms and consequences","volume":"20","author":"Beltramo","year":"2013","journal-title":"Curr. Med. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"D\u2019Esposito, F., Cappellani, F., Visalli, F., Capobianco, M., Rapisarda, L., Avitabile, A., Cannizzaro, L., Malaguarnera, R., Gagliano, G., and Maniaci, A. (2025). Pericytes as Key Players in Retinal Diseases: A Comprehensive Narrative Review. Biology, 14.","DOI":"10.3390\/biology14070736"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"5257","DOI":"10.1167\/iovs.07-0112","article-title":"Inducible nitric oxide synthase isoform is a key mediator of leukostasis and blood-retinal barrier breakdown in diabetic retinopathy","volume":"48","author":"Leal","year":"2007","journal-title":"Invest Ophthalmol. Vis. Sci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"4457","DOI":"10.1167\/iovs.02-1063","article-title":"The role of advanced glycation end products in retinal microvascular leukostasis","volume":"44","author":"Moore","year":"2003","journal-title":"Invest Ophthalmol. Vis. Sci."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Seo, H., Park, S.J., and Song, M. (2025). Diabetic Retinopathy (DR): Mechanisms, Current Therapies, and Emerging Strategies. Cells, 14.","DOI":"10.3390\/cells14050376"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1622","DOI":"10.1097\/IAE.0000000000001022","article-title":"Optical Coherence Tomography Characteristics Of Macular Edema And Hard Exudates And Their Association With Lipid Serum Levels In Type 2 Diabetes","volume":"36","author":"Davoudi","year":"2016","journal-title":"Retina"},{"key":"ref_29","first-page":"CD013775","article-title":"Prognostic factors for the development and progression of proliferative diabetic retinopathy in people with diabetic retinopathy","volume":"2","author":"Perais","year":"2023","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1186\/s40942-016-0051-x","article-title":"Neovascular glaucoma: A review","volume":"2","author":"Rodrigues","year":"2016","journal-title":"Int. J. Retin. Vitr."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Wang, S., Hua, R., Zhao, Y., and Liu, L. (2024). Laser Treatment for Diabetic Retinopathy: History, Mechanism, and Novel Technologies. J. Clin. Med., 13.","DOI":"10.3390\/jcm13185439"},{"key":"ref_32","first-page":"1694187","article-title":"Current Advances in Pharmacotherapy and Technology for Diabetic Retinopathy: A Systematic Review","volume":"2018","author":"Lu","year":"2018","journal-title":"J. Ophthalmol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1167\/iovs.65.14.39","article-title":"Retinal docosahexaenoic acid is significantly reduced in diabetic humans and mice: Possible relationship to diabetic retinopathy","volume":"65","author":"Sugasini","year":"2024","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"112419","DOI":"10.1016\/j.mce.2024.112419","article-title":"Oridonin attenuates diabetic retinopathy progression by suppressing NLRP3 inflammasome pathway","volume":"596","author":"Zhang","year":"2025","journal-title":"Mol. Cell. Endocrinol."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Sorbinil Retinopathy Triail Research Group (1990). A randomized trial of sorbinil, an aldose reductase inhibitor, in diabetic retinopathy. Arch. Ophthalmol., 108, 1234\u20131244.","DOI":"10.1001\/archopht.1990.01070110050024"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"375","DOI":"10.4093\/dmj.2013.37.5.375","article-title":"Ruboxistaurin for the treatment of diabetic peripheral neuropathy: A systematic review of randomized clinical trials","volume":"37","author":"Bansal","year":"2013","journal-title":"Diabetes Metab. J."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"The DAMAD Study Group (1989). Effect of aspirin alone and aspirin plus dipyridamole in early diabetic retinopathy. A multicenter randomized controlled clinical trial. Diabetes, 38, 491\u2013498.","DOI":"10.2337\/diabetes.38.4.491"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"108111","DOI":"10.1016\/j.jbc.2024.108111","article-title":"PRDX4 mitigates diabetic retinopathy by inhibiting reactive gliosis, apoptosis, ER stress, oxidative stress, and mitochondrial dysfunction in M\u00fcller cells","volume":"301","author":"Huang","year":"2024","journal-title":"J. Biol. Chem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1111\/dom.14007","article-title":"An updated overview of diabetic nephropathy: Diagnosis, prognosis, treatment goals and latest guidelines","volume":"22","author":"Selby","year":"2020","journal-title":"Diabetes Obes. Metab."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1111\/joim.13690","article-title":"Clinical findings and kidney morphology in chronic kidney disease of unknown cause in India","volume":"294","author":"Annadata","year":"2023","journal-title":"J. Intern. Med."},{"key":"ref_41","first-page":"1","article-title":"AGE-RAGE Stress, Stressors, and Antistressors in Health and Disease","volume":"27","author":"Prasad","year":"2018","journal-title":"Int. J. Angiol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"4488","DOI":"10.1172\/JCI90699","article-title":"TNF regulates transcription of NLRP3 inflammasome components and inflammatory molecules in cryopyrinopathies","volume":"127","author":"McGeough","year":"2017","journal-title":"J. Clin. Investig."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1038\/s41419-017-0135-z","article-title":"Cellular death, reactive oxygen species (ROS) and diabetic complications","volume":"9","author":"Volpe","year":"2018","journal-title":"Cell Death Dis."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Pomroy, H.J., Mote, A., Mathew, S., Chanasseril, S., Lu, V., and Cheema, A.K. (2015). From Fork to Brain: The Role of AGE-RAGE Signaling and the Western Diet in Neurodegenerative Disease. NeuroSci, 6.","DOI":"10.3390\/neurosci6030089"},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Shen, S., Ji, C., and Wei, K. (2022). Cellular Senescence and Regulated Cell Death of Tubular Epithelial Cells in Diabetic Kidney Disease. Front. Endocrinol., 13.","DOI":"10.3389\/fendo.2022.924299"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Xu, J., Zhou, L., and Liu, Y. (2020). Cellular Senescence in Kidney Fibrosis: Pathologic Significance and Therapeutic Strategies. Front. Pharmacol., 11.","DOI":"10.3389\/fphar.2020.601325"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1177\/0004563217728964","article-title":"Associations between glycaemic control and activation of the renin-angiotensin-aldosterone system in participants with type 2 diabetes mellitus and hypertension","volume":"55","author":"Griffin","year":"2018","journal-title":"Ann. Clin. Biochem."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1023","DOI":"10.1681\/ASN.2016060666","article-title":"Glomerular Hyperfiltration in Diabetes: Mechanisms, Clinical Significance, and Treatment","volume":"28","author":"Tonneijck","year":"2017","journal-title":"J. Am. Soc. Nephrol. JASN"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1536\/ihj.37.153","article-title":"Tubuloglomerular feedback","volume":"37","author":"Ito","year":"1996","journal-title":"Jpn. Heart J."},{"key":"ref_50","first-page":"CD007004","article-title":"Aldosterone antagonists for preventing the progression of chronic kidney disease","volume":"4","author":"Bolignano","year":"2014","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1","DOI":"10.7326\/0003-4819-149-1-200807010-00231","article-title":"Diabetes and hearing impairment in the United States: Audiometric evidence from the National Health and Nutrition Examination Survey, 1999 to 2004","volume":"149","author":"Bainbridge","year":"2008","journal-title":"Ann. Intern Med."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1016\/j.otohns.2005.02.004","article-title":"Cochlear changes in patients with type 1 diabetes mellitus","volume":"133","author":"Fukushima","year":"2005","journal-title":"Otolaryngol. Head Neck Surg."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"934","DOI":"10.1001\/archotol.132.9.934","article-title":"Effects of Type 2 Diabetes Mellitus on Cochlear Structure in Humans","volume":"132","author":"Fukushima","year":"2006","journal-title":"Arch. Otolaryngol. Head Neck Surg."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1186\/s10020-023-00737-z","article-title":"Diabetes mellitus and hearing loss","volume":"29","author":"Deng","year":"2023","journal-title":"Mol. Med."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"109072","DOI":"10.1016\/j.heares.2024.109072","article-title":"Associations between diabetes mellitus and sensorineural hearing loss from humans and animal studies","volume":"450","author":"Williams","year":"2024","journal-title":"Hear Res."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"772","DOI":"10.25122\/jml-2021-0300","article-title":"Prevalence of hearing loss among patients with type 2 diabetes","volume":"15","author":"Shafiepour","year":"2022","journal-title":"J. Med. Life"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"101423","DOI":"10.1016\/j.arr.2021.101423","article-title":"Diabetes mellitus and hearing loss: A review","volume":"71","author":"Wu","year":"2021","journal-title":"Ageing Res. Rev."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"358","DOI":"10.1093\/ageing\/afr145","article-title":"Older individuals with diabetes have an increased risk of recurrent falls: Analysis of potential mediating factors: The Longitudinal Ageing Study Amsterdam","volume":"41","author":"Pijpers","year":"2012","journal-title":"Age Ageing"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"400","DOI":"10.2522\/ptj.20140604","article-title":"Impact of Diabetic Complications on Balance and Falls: Contribution of the Vestibular System","volume":"96","author":"Lin","year":"2016","journal-title":"Phys. Ther."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1055\/s-0039-1697033","article-title":"Diabetes and Auditory-Vestibular Pathology","volume":"40","author":"Elangovan","year":"2019","journal-title":"Semin Hear."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1097\/MAO.0000000000001018","article-title":"Vascular and Neuroepithelial Histopathology of the Saccule in Humans With Diabetes Mellitus","volume":"37","author":"Kocdor","year":"2016","journal-title":"Otol. Neurotol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1055\/s-0039-1697032","article-title":"Diabetes and the Vestibular System","volume":"40","author":"Piker","year":"2019","journal-title":"Semin Hear."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"570","DOI":"10.2337\/cd25-0002","article-title":"Hearing Care Within Diabetes Care: Strategies for Direct Inclusion","volume":"43","author":"Powell","year":"2025","journal-title":"Clin. Diabetes"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1097\/NPT.0000000000000382","article-title":"Vestibular Rehabilitation for Peripheral Vestibular Hypofunction: An Updated Clinical Practice Guideline From the Academy of Neurologic Physical Therapy of the American Physical Therapy Association","volume":"46","author":"Hall","year":"2022","journal-title":"J. Neurol. Phys. Ther."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1016\/j.ihj.2013.10.015","article-title":"The nuances of atherogenic dyslipidemia in diabetes: Focus on triglycerides and current management strategies","volume":"65","author":"Manoria","year":"2013","journal-title":"Indian Heart J."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1186\/s12933-018-0762-4","article-title":"Association between insulin resistance and the development of cardiovascular disease","volume":"17","author":"Ormazabal","year":"2018","journal-title":"Cardiovasc Diabetol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1069","DOI":"10.1161\/ATVBAHA.114.303284","article-title":"Small dense low-density lipoprotein-cholesterol concentrations predict risk for coronary heart disease: The Atherosclerosis Risk In Communities (ARIC) study","volume":"34","author":"Hoogeveen","year":"2014","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"Jiang, H., Zhou, Y., Nabavi, S.M., Sahebkar, A., Little, P.J., Xu, S., Weng, J., and Ge, J. (2022). Mechanisms of oxidized LDL-mediated endothelial dysfunction and its consequences for the development of atherosclerosis. Front Cardiovasc Med., 9.","DOI":"10.3389\/fcvm.2022.925923"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"5245308","DOI":"10.1155\/2020\/5245308","article-title":"Mechanistic insights into the oxidized low-density lipoprotein-induced atherosclerosis","volume":"2020","author":"Khatana","year":"2020","journal-title":"Oxid. Med. Cell Longev."},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Poznyak, A., Grechko, A.V., Poggio, P., Myasoedova, V.A., Alfieri, V., and Orekhov, A.N. (2020). The diabetes mellitus\u2013atherosclerosis connection: The role of lipid and glucose metabolism and chronic inflammation. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21051835"},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Jebari-Benslaiman, S., Galicia-Garc\u00eda, U., Larrea-Sebal, A., Olaetxea, J.R., Alloza, I., Vandenbroeck, K., Benito-Vicente, A., and Mart\u00edn, C. (2022). Pathophysiology of atherosclerosis. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23063346"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1429","DOI":"10.1517\/14656566.2011.563506","article-title":"Combination therapy with statin and fibrate in patients with dyslipidemia associated with insulin resistance, metabolic syndrome and type 2 diabetes mellitus","volume":"12","author":"Ginsberg","year":"2011","journal-title":"Expert Opin. Pharmacother."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1186\/1475-2840-5-20","article-title":"Atherogenic dyslipidemia in metabolic syndrome and type 2 diabetes: Therapeutic options beyond statins","volume":"5","author":"Tenenbaum","year":"2006","journal-title":"Cardiovasc Diabetol."},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Vaidya, A.R., Wolska, N., Vara, D., Mailer, R.K., Schr\u00f6der, K., and Pula, G. (2021). Diabetes and thrombosis: A central role for vascular oxidative stress. Antioxidants, 10.","DOI":"10.3390\/antiox10050706"},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Dubsk\u00fd, M., Veleba, J., Sojakov\u00e1, D., Marhefkova, N., Fejfarov\u00e1, V., and Jude, E.B. (2023). Endothelial dysfunction in diabetes mellitus: New insights. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241310705"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"742719","DOI":"10.1155\/2011\/742719","article-title":"Platelet function in patients with diabetes mellitus: From a theoretical to a practical perspective","volume":"2011","author":"Kakouros","year":"2011","journal-title":"Int. J. Endocrinol."},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Pechlivani, N., and Ajjan, R.A. (2018). Thrombosis and vascular inflammation in diabetes: Mechanisms and potential therapeutic targets. Front. Cardiovasc. Med., 5.","DOI":"10.3389\/fcvm.2018.00001"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"620","DOI":"10.1161\/CIRCRESAHA.115.306301","article-title":"Endothelial Cell Dysfunction and the Pathobiology of Atherosclerosis","volume":"118","author":"Gimbrone","year":"2016","journal-title":"Circ. Res."},{"key":"ref_79","first-page":"569654","article-title":"Hyperglycemia and endothelial dysfunction in atherosclerosis: Lessons from type 1 diabetes","volume":"2012","author":"Funk","year":"2012","journal-title":"Int. J. Vasc. Med."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"377","DOI":"10.4330\/wjc.v2.i11.377","article-title":"Coronary microvascular dysfunction in diabetes mellitus: A review","volume":"2","author":"Picchi","year":"2010","journal-title":"World J. Cardiol."},{"key":"ref_81","doi-asserted-by":"crossref","unstructured":"Salvatore, T., Galiero, R., Caturano, A., Vetrano, E., Loffredo, G., Rinaldi, L., Catalini, C., Gjeloshi, K., Albanese, G., and Di Martino, A. (2022). Coronary Microvascular Dysfunction in Diabetes Mellitus: Pathogenetic Mechanisms and Potential Therapeutic Options. Biomedicines, 10.","DOI":"10.3390\/biomedicines10092274"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"154910","DOI":"10.1016\/j.metabol.2021.154910","article-title":"Heart failure in diabetes","volume":"125","author":"Jankauskas","year":"2021","journal-title":"Metab. Clin. Exp."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1186\/s13098-025-01986-0","article-title":"Diabetic cardiomyopathy: A comprehensive review of diagnosis, management, and future directions","volume":"17","author":"Balakrishnan","year":"2025","journal-title":"Diabetol. Metab. Syndr."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"e80479","DOI":"10.7554\/eLife.80479","article-title":"Single-cell RNA-seq of heart reveals intercellular communication drivers of myocardial fibrosis in diabetic cardiomyopathy","volume":"12","author":"Li","year":"2023","journal-title":"eLife"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"158","DOI":"10.1186\/s12933-021-01354-y","article-title":"Aggravation of functional mitral regurgitation on left ventricle stiffness in type 2 diabetes mellitus patients evaluated by CMR tissue tracking","volume":"20","author":"Zhang","year":"2021","journal-title":"Cardiovasc. Diabetol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"634","DOI":"10.1002\/ejhf.2432","article-title":"Cardiac autonomic neuropathy and risk of incident heart failure among adults with type 2 diabetes","volume":"24","author":"Kaze","year":"2022","journal-title":"Eur. J. Heart Fail."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"32","DOI":"10.59556\/japi.72.0667","article-title":"A Study of Cardiac Autonomic Neuropathy in Patient with Diabetes Mellitus","volume":"72","author":"Mirg","year":"2024","journal-title":"J. Assoc. Physicians India"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1111\/dom.15062","article-title":"Heart failure and diabetes: Clinical significance and epidemiology of this two-way association","volume":"25","author":"Jerkins","year":"2023","journal-title":"Diabetes Obes. Metab."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1159\/000520909","article-title":"Heart Failure in Patients with Diabetes and Chronic Kidney Disease: Challenges and Opportunities","volume":"12","author":"Vijay","year":"2022","journal-title":"Cardiorenal Med."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1186\/s12933-018-0728-6","article-title":"Prevalence of cardiovascular disease in type 2 diabetes: A systematic literature review of scientific evidence from across the world in 2007\u20132017","volume":"17","author":"Einarson","year":"2018","journal-title":"Cardiovasc. Diabetol."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1111\/nyas.14583","article-title":"Diabetes, stroke, and neuroresilience: Looking beyond hyperglycemia","volume":"1495","author":"Krinock","year":"2021","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_92","doi-asserted-by":"crossref","unstructured":"Maida, C.D., Daidone, M., Pacinella, G., Norrito, R.L., Pinto, A., and Tuttolomondo, A. (2022). Diabetes and Ischemic Stroke: An Old and New Relationship an Overview of the Close Interaction between These Diseases. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23042397"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1016\/j.numecd.2007.02.003","article-title":"Diabetic and non-diabetic subjects with ischemic stroke: Differences, subtype distribution and outcome","volume":"18","author":"Tuttolomondo","year":"2008","journal-title":"Nutr. Metab. Cardiovasc. Dis."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1038\/s41392-023-01400-z","article-title":"Diabetic vascular diseases: Molecular mechanisms and therapeutic strategies","volume":"8","author":"Li","year":"2023","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1007\/s11154-023-09807-3","article-title":"Effects of GLP-1 receptor agonists on neurological complications of diabetes","volume":"24","author":"Ariza","year":"2023","journal-title":"Rev. Endocr. Metab. Disord."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"530","DOI":"10.1177\/23969873241234238","article-title":"Risk of major adverse cardiovascular events and stroke associated with treatment with GLP-1 or the dual GIP\/GLP-1 receptor agonist tirzepatide for type 2 diabetes: A systematic review and meta-analysis","volume":"9","author":"Stefanou","year":"2024","journal-title":"Eur. Stroke J."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"1789","DOI":"10.1161\/CIRCULATIONAHA.124.069568","article-title":"Sodium-Glucose Cotransporter-2 Inhibitors and Major Adverse Cardiovascular Outcomes: A SMART-C Collaborative Meta-Analysis","volume":"149","author":"Patel","year":"2024","journal-title":"Circulation"},{"key":"ref_98","doi-asserted-by":"crossref","unstructured":"Burgess, J.L., Wyant, W.A., Abdo Abujamra, B., Kirsner, R.S., and Jozic, I. (2021). Diabetic Wound-Healing Science. Medicina, 57.","DOI":"10.3390\/medicina57101072"},{"key":"ref_99","doi-asserted-by":"crossref","unstructured":"Aitcheson, S.M., Frentiu, F.D., Hurn, S.E., Edwards, K., and Murray, R.Z. (2021). Skin Wound Healing: Normal Macrophage Function and Macrophage Dysfunction in Diabetic Wounds. Molecules, 26.","DOI":"10.3390\/molecules26164917"},{"key":"ref_100","doi-asserted-by":"crossref","unstructured":"Holl, J., Kowalewski, C., Zimek, Z., Fiedor, P., Kaminski, A., Oldak, T., Moniuszko, M., and Eljaszewicz, A. (2021). Chronic Diabetic Wounds and Their Treatment with Skin Substitutes. Cells, 10.","DOI":"10.3390\/cells10030655"},{"key":"ref_101","first-page":"1434","article-title":"Diabetes induces stable intrinsic changes to myeloid cells that contribute to chronic inflammation during wound healing in mice","volume":"6","author":"Bannon","year":"2013","journal-title":"Dis. Model Mech."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1089\/wound.2011.0308","article-title":"Wound Healing Angiogenesis: Innovations and Challenges in Acute and Chronic Wound Healing","volume":"1","author":"Durham","year":"2012","journal-title":"Adv. Wound Care."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"1449","DOI":"10.1016\/j.jacc.2004.11.067","article-title":"Circulating Endothelial Progenitor Cells Are Reduced in Peripheral Vascular Complications of Type 2 Diabetes Mellitus","volume":"45","author":"Fadini","year":"2005","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"e3268","DOI":"10.1002\/dmrr.3268","article-title":"International Working Group on the Diabetic Foot. Definitions and criteria for diabetic foot disease","volume":"36","author":"Bus","year":"2020","journal-title":"Diabetes Metab. Res. Rev."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"1684","DOI":"10.12998\/wjcc.v11.i8.1684","article-title":"Diabetic foot ulcer: A comprehensive review of pathophysiology and management modalities","volume":"11","author":"Raja","year":"2023","journal-title":"World J. Clin. Cases"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"1719","DOI":"10.1016\/S0140-6736(05)67698-2","article-title":"The global burden of diabetic foot disease","volume":"366","author":"Boulton","year":"2005","journal-title":"Lancet"},{"key":"ref_107","doi-asserted-by":"crossref","unstructured":"Rubitschung, K., Sherwood, A., Crisologo, A.P., Bhavan, K., Haley, R.W., Wukich, D.K., Castellino, L., Hwang, H., La Fontaine, J., and Chhabra, A. (2021). Pathophysiology and Molecular Imaging of Diabetic Foot Infections. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222111552"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"e0014323","DOI":"10.1128\/cmr.00143-23","article-title":"Anaerobes in diabetic foot infections: Pathophysiology, epidemiology, virulence, and management","volume":"37","author":"Villa","year":"2024","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"853","DOI":"10.1111\/iwj.13687","article-title":"A systematic review of ozone therapy for treating chronically refractory wounds and ulcers","volume":"19","author":"Wen","year":"2022","journal-title":"Int. Wound J."},{"key":"ref_110","doi-asserted-by":"crossref","unstructured":"Krawczenko, A., and Klimczak, A. (2022). Adipose Tissue-Derived Mesenchymal Stem\/Stromal Cells and Their Contribution to Angiogenic Processes in Tissue Regeneration. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23052425"},{"key":"ref_111","doi-asserted-by":"crossref","unstructured":"Farabi, B., Roster, K., Hirani, R., Tepper, K., Atak, M.F., and Safai, B. (2024). The Efficacy of Stem Cells in Wound Healing: A Systematic Review. Int. J. Mol. Sci., 25.","DOI":"10.20944\/preprints202402.1023.v1"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.ijsu.2017.02.008","article-title":"Efficacy and safety of acellular dermal matrix in diabetic foot ulcer treatment: A systematic review and meta-analysis","volume":"40","author":"Guo","year":"2017","journal-title":"Int. J. Surg."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1016\/S1067-2516(02)80020-5","article-title":"Blood flow changes in diabetic foot ulcers treated with dermal replacement therapy","volume":"41","author":"Newton","year":"2002","journal-title":"J. Foot Ankle Surg."},{"key":"ref_114","doi-asserted-by":"crossref","unstructured":"Yue, T., Shi, Y., Luo, S., Weng, J., Wu, Y., and Zheng, X. (2022). The role of inflammation in immune system of diabetic retinopathy: Molecular mechanisms, pathogenetic role and therapeutic implications. Front Immunol., 13.","DOI":"10.3389\/fimmu.2022.1055087"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"115734","DOI":"10.1016\/j.biopha.2023.115734","article-title":"Diabetes mellitus: Classification, mediators, and complications; A gate to identify potential targets for the development of new effective treatments","volume":"168","author":"Antar","year":"2023","journal-title":"BioMed Pharmacother."},{"key":"ref_116","first-page":"442","article-title":"Type 2 Diabetes and its Impact on the Immune System","volume":"16","author":"Berbudi","year":"2020","journal-title":"Curr. Diabetes Rev."},{"key":"ref_117","doi-asserted-by":"crossref","unstructured":"Alexander, M., Cho, E., Gliozheni, E., Salem, Y., Cheung, J., and Ichii, H. (2024). Pathology of Diabetes-Induced Immune Dysfunction. Int. J. Mol. Sci., 25.","DOI":"10.3390\/ijms25137105"},{"key":"ref_118","doi-asserted-by":"crossref","unstructured":"Ferlita, S., Yegiazaryan, A., Noori, N., Lal, G., Nguyen, T., To, K., and Venketaraman, V. (2019). Type 2 Diabetes Mellitus and Altered Immune System Leading to Susceptibility to Pathogens, Especially Mycobacterium tuberculosis. J. Clin. Med., 8.","DOI":"10.3390\/jcm8122219"},{"key":"ref_119","doi-asserted-by":"crossref","unstructured":"Masson, W., Lobo, M., Nogueira, J.P., Rodriguez-Granillo, A.M., Barbagelata, L.E., and Siniawski, D. (2024). Anti-inflammatory effect of semaglutide: Updated systematic review and meta-analysis. Front Cardiovasc Med., 11.","DOI":"10.3389\/fcvm.2024.1379189"},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"1037","DOI":"10.1007\/s00125-021-05398-3","article-title":"Current and future therapies for type 1 diabetes","volume":"64","author":"Kreiner","year":"2021","journal-title":"Diabetologia"},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1038\/nrendo.2016.76","article-title":"The potential of endurance exercise-derived exosomes to treat metabolic diseases","volume":"12","author":"Safdar","year":"2016","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/j.jshs.2022.11.003","article-title":"Exercise training-induced changes in exerkine concentrations may be relevant to the metabolic control of type 2 diabetes mellitus patients: A systematic review and meta-analysis of randomized controlled trials","volume":"12","author":"Izquierdo","year":"2023","journal-title":"J. Sport Health Sci."},{"key":"ref_123","doi-asserted-by":"crossref","unstructured":"Marton, L.T., Pescinini-E-Salzedas, L.M., Camargo, M.E.C., Barbalho, S.M., Haber, J.F.D.S., Sinatora, R.V., Detregiachi, C.R.P., Girio, R.J.S., Buchaim, D.V., and Cincotto Dos Santos Bueno, P. (2021). The Effects of Curcumin on Diabetes Mellitus: A Systematic Review. Front Endocrinol., 12.","DOI":"10.3389\/fendo.2021.669448"},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"bqab058","DOI":"10.1210\/endocr\/bqab058","article-title":"Senolytics: Potential for Alleviating Diabetes and Its Complications","volume":"162","author":"Palmer","year":"2021","journal-title":"Endocrinology"},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"1250","DOI":"10.1038\/s41401-024-01448-9","article-title":"Semaglutide administration protects cardiomyocytes in db\/db mice via energetic improvement and mitochondrial quality control","volume":"46","author":"Tian","year":"2025","journal-title":"Acta Pharmacol. Sin."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/14\/1296\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T04:17:46Z","timestamp":1784780266000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/14\/1296"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,20]]},"references-count":125,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["cells15141296"],"URL":"https:\/\/doi.org\/10.3390\/cells15141296","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,20]]}}}