{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T02:19:55Z","timestamp":1790734795629,"version":"4.1.0"},"reference-count":0,"publisher":"Maad Rayan Publishing Company","content-domain":{"domain":["apb.tbzmed.ac.ir"],"crossmark-restriction":false},"short-container-title":["Adv Pharm Bull"],"abstract":"<jats:p>Lymphedema, traditionally viewed as a mechanical consequence of lymphatic obstruction, is increasingly recognized as a complex disorder rooted in metabolic dysfunction, particularly insulin resistance and chronic hyperinsulinemia. This paradigm-shifting hypothesis redefines lymphedema as a vascular complication driven by systemic metabolic stress, where prolonged hyperinsulinemia impairs lymphatic endothelial cell (LEC) function, triggering inflammation, oxidative stress, and structural damage. Insulin resistance disrupts the phosphoinositide 3-kinase (PI3K)\/AKT signaling pathway, critical for lymphangiogenesis and endothelial integrity, leading to compromised lymphatic drainage. Pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-\u03b1) and interleukin-6 (IL-6), exacerbate this dysfunction by activating nuclear factor kappa-light-chain-enhancer of activated B cells (NF-\u03baB) and promoting reactive oxygen species (ROS) production, while advanced glycation end products (AGEs) engaging RAGE amplify fibrosis and endothelial apoptosis. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), such as liraglutide and semaglutide, offer a revolutionary therapeutic approach by addressing both metabolic and vascular components of lymphedema. By enhancing PI3K\/AKT signaling, GLP-1RAs restore insulin sensitivity, mitigate hyperinsulinemia, and suppress inflammatory pathways (NF-\u03baB, TLR4). Their activation of VEGF-C\/VEGFR-3 and endothelial nitric oxide synthase (eNOS)\/NO pathways promotes lymphangiogenesis and reduces ROS-induced damage, enhancing lymphatic vessel repair. Clinical evidence, including a 2024 case report, demonstrates significant reductions in limb volume (from 10.3% to 3.4%) and restored lymphatic function in breast cancer-related lymphedema following GLP-1RA therapy. Localized administration optimizes therapeutic outcomes by targeting lymphatic endothelial cells, minimizing systemic side effects. This narrative review synthesizes lymphedema\u2019s metabolic pathophysiology, proposes localized semaglutide as a novel therapy, and suggests experimental protocols to advance lymphedema management.<\/jats:p>","DOI":"10.34172\/apb.025.43911","type":"journal-article","created":{"date-parts":[[2025,9,9]],"date-time":"2025-09-09T11:14:49Z","timestamp":1757416489000},"update-policy":"https:\/\/doi.org\/10.34172\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Localized Semaglutide Injection for Hyperinsulinemia-Induced Lymphatic Dysfunction: A Narrative Review Proposing a Promising Metabolic Perspective for Lymphedema Therapy"],"prefix":"10.34172","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5480-1688","authenticated-orcid":true,"given":"Maher Monir","family":"Akl","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3477-236X","authenticated-orcid":true,"given":"Amr","family":"Ahmed","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"20123","published-online":{"date-parts":[[2025,9,4]]},"container-title":["Advanced Pharmaceutical Bulletin"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/apb.tbzmed.ac.ir\/Inpress\/apb-43911.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/apb.tbzmed.ac.ir\/Inpress\/apb-43911.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,9]],"date-time":"2025-09-09T11:14:49Z","timestamp":1757416489000},"score":1,"resource":{"primary":{"URL":"https:\/\/apb.tbzmed.ac.ir\/Inpress\/apb-43911"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,4]]},"references-count":0,"URL":"https:\/\/doi.org\/10.34172\/apb.025.43911","relation":{},"ISSN":["2228-5881","2251-7308"],"issn-type":[{"value":"2228-5881","type":"print"},{"value":"2251-7308","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,4]]},"assertion":[{"value":"Tabriz University of Medical Sciences","name":"journal_owner","label":"Journal Owner"},{"value":"Tabriz University of Medical Sciences","name":"journal_publisher","label":"Journal Publisher"},{"value":"2024-10-26","order":1,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-08-27","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-09-04","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}