{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T12:02:13Z","timestamp":1790164933038,"version":"4.1.0"},"reference-count":198,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T00:00:00Z","timestamp":1790121600000},"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-cell failure is central to the pathogenesis of type 2 diabetes (T2D), developing when chronic metabolic stress overwhelms the adaptive capacity of these cells. Because insulin biosynthesis and glucose-stimulated secretion depend on tightly coordinated organelle function, crosstalk between the endoplasmic reticulum (ER) and mitochondria strongly influences \u03b2-cell fate. The two organelles are physically coupled at mitochondria-associated membranes (MAMs), contact sites that synchronize ER Ca2+ release with mitochondrial Ca2+ uptake and adenosine triphosphate (ATP) production, and that help regulate redox balance, autophagy, mitophagy and the unfolded protein response. This review draws together evidence on three questions. First, which stresses converge on the \u03b2-cell: ER stress, oxidative stress and dysregulated autophagy and mitophagy. Second, how ER\u2013mitochondria crosstalk sustains \u03b2-cell health through Ca2+ handling and the proteins that maintain MAM integrity, including inositol 1,4,5-trisphosphate (IP3) receptors, voltage-dependent anion channel 1 (VDAC1), mitofusin 2 (Mfn2) and the ER stress sensors IRE1\u03b1 and PERK. Third, how glucolipotoxic and inflammatory stress remodels these contacts and pushes communication towards a maladaptive state marked by mitochondrial Ca2+ overload, ROS accumulation, defective organelle quality control, cellular senescence and apoptosis. We contrast rodent and human data, where MAM composition and glucotoxic responses diverge, and consider therapeutic strategies, such as incretin-based agents and the mitochondrial-derived peptide MOTS-c, that target this interface to preserve \u03b2-cell function in diabetes.<\/jats:p>","DOI":"10.3390\/cells15191733","type":"journal-article","created":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T11:09:08Z","timestamp":1790161748000},"page":"1733","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Mitochondria\u2013Endoplasmic Reticulum Crosstalk in Pancreatic \u03b2-Cell Stress: A Driver of Diabetes"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-1439-0682","authenticated-orcid":false,"given":"Sara Anjum","family":"Niinuma","sequence":"first","affiliation":[{"name":"School of Medicine, Royal College of Surgeons in Ireland-Medical University of Bahrain, Busaiteen 15503, Bahrain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-1916-9833","authenticated-orcid":false,"given":"Ashleigh Suzu-Nishio","family":"Takemoto","sequence":"additional","affiliation":[{"name":"School of Medicine, Royal College of Surgeons in Ireland-Medical University of Bahrain, Busaiteen 15503, Bahrain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-8141-9844","authenticated-orcid":false,"given":"William Junior","family":"Khalil","sequence":"additional","affiliation":[{"name":"School of Medicine, Royal College of Surgeons in Ireland-Medical University of Bahrain, Busaiteen 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-Medical University of Bahrain, Busaiteen 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-Medical University of Bahrain, Busaiteen 15503, Bahrain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1016\/j.ceb.2011.04.006","article-title":"Lipid transfer and signaling at organelle contact sites: The tip of the iceberg","volume":"23","author":"Toulmay","year":"2011","journal-title":"Curr. 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