{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T20:38:52Z","timestamp":1790282332486,"version":"4.1.0"},"reference-count":308,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2025,12,17]],"date-time":"2025-12-17T00:00:00Z","timestamp":1765929600000},"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>Pancreatic \u03b2-cells are metabolically active endocrine cells with a high oxygen demand to sustain glucose-stimulated insulin secretion (GSIS). Hypoxia, arising from vascular disruption, islet isolation, or pathological states such as type 2 diabetes (T2D) and obstructive sleep apnoea (OSA), is a potent metabolic stressor that impairs \u03b2-cell function, survival, and differentiation. At the molecular level, hypoxia-inducible factors (HIF-1\u03b1 and HIF-2\u03b1) orchestrate transcriptional programs that shift \u03b2-cell metabolism from oxidative phosphorylation to glycolysis, modulate mitochondrial function, and regulate survival pathways such as autophagy and mitophagy. Crosstalk with nutrient-sensing mechanisms, redox regulation, growth factor signaling, and protein synthesis control further shapes adaptive or maladaptive outcomes. Hypoxia alters glucose, lipid, and amino acid metabolism, while mitochondrial dysfunction, oxidative stress, and inflammatory signaling contribute to progressive \u03b2-cell failure. Therapeutic strategies including incretin hormones, GABAergic signaling, erythropoietin, ChREBP inhibition, and activation of calcineurin\u2013NFAT or oxygen-binding globins\u2014offer potential to preserve \u03b2-cell viability under hypoxia. In islet transplantation, oxygen delivery technologies, ischemic preconditioning, mesenchymal stem cell\u2013derived exosomes, and encapsulation systems show promise in mitigating hypoxic injury and improving graft survival. This review synthesizes current knowledge on \u03b2-cell responses to hypoxic stress, with emphasis on metabolic reprogramming, molecular signaling, and translational interventions, underscoring that targeted modulation of \u03b2-cell metabolism and oxygen handling can enhance resilience to hypoxia and improve outcomes in diabetes therapy and islet transplantation.<\/jats:p>","DOI":"10.3390\/cells14242014","type":"journal-article","created":{"date-parts":[[2025,12,17]],"date-time":"2025-12-17T13:42:52Z","timestamp":1765978972000},"page":"2014","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Metabolic Stress and Adaptation in Pancreatic \u03b2-Cells to Hypoxia: Mechanisms, Modulators, and Implications for Transplantation"],"prefix":"10.3390","volume":"14","author":[{"given":"Jannat","family":"Akram","sequence":"first","affiliation":[{"name":"School of Medicine, Royal College of Surgeons in Ireland-Bahrain, Adliya 15503, Bahrain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Prianna","family":"Menezes","sequence":"additional","affiliation":[{"name":"School of Medicine, Royal College of Surgeons in Ireland-Bahrain, Adliya 15503, Bahrain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-8842-6545","authenticated-orcid":false,"given":"Noorul Ibtesam","family":"Idris","sequence":"additional","affiliation":[{"name":"School of Medicine, Royal College of Surgeons in Ireland-Bahrain, Adliya 15503, Bahrain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joanna Eliza","family":"Thomas","sequence":"additional","affiliation":[{"name":"School of Medicine, Royal College of Surgeons in Ireland-Bahrain, Adliya 15503, Bahrain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-3419-4118","authenticated-orcid":false,"given":"Radwan","family":"Darwish","sequence":"additional","affiliation":[{"name":"School of Medicine, Royal College of Surgeons in Ireland-Bahrain, Adliya 15503, Bahrain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Afrin","family":"Tania","sequence":"additional","affiliation":[{"name":"School of Medicine, Royal College of Surgeons in Ireland-Bahrain, Adliya 15503, Bahrain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5762-3917","authenticated-orcid":false,"given":"Alexandra E.","family":"Butler","sequence":"additional","affiliation":[{"name":"Research Department, Royal College of Surgeons in Ireland-Bahrain, Adliya 15503, Bahrain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5342-2501","authenticated-orcid":false,"given":"Abu Saleh Md","family":"Moin","sequence":"additional","affiliation":[{"name":"Research Department, Royal College of Surgeons in Ireland-Bahrain, Adliya 15503, Bahrain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"12524","DOI":"10.1074\/jbc.M110.194738","article-title":"Cellular Hypoxia of Pancreatic \u03b2-Cells Due to High Levels of Oxygen Consumption for Insulin Secretion In Vitro","volume":"286","author":"Sato","year":"2011","journal-title":"J. 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