{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T09:05:42Z","timestamp":1789117542930,"version":"build-2803163510"},"reference-count":50,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T00:00:00Z","timestamp":1789084800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T00:00:00Z","timestamp":1789084800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001700","name":"Ministry of Education, Culture, Sports, Science and Technology","doi-asserted-by":"publisher","award":["26K02809"],"award-info":[{"award-number":["26K02809"]}],"id":[{"id":"10.13039\/501100001700","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007449","name":"Takeda Science Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007449","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100008673","name":"Yasuda Memorial Medical Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100008673","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J of Diabetes Invest"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Pancreatic islet cells continuously synthesize and secrete large quantities of peptide hormones, making them uniquely dependent on robust proteostasis networks to maintain cellular function. Traditionally, the unfolded protein response (UPR) is considered a stress\u2010responsive pathway that protects cells from endoplasmic reticulum (ER) dysfunction or triggers apoptosis when ER stress is excessive. Here, we propose that proteostasis functions as an active physiological signaling network that governs islet cell adaptation, plasticity, and long\u2010term homeostasis, extending beyond its conventional role in the response to cellular damage. In pancreatic \u03b2 cells, glucose signaling suppresses the expression of the proapoptotic factor CHOP through both IRS2\u2010dependent and IRS2\u2010independent pathways, indicating that metabolic signaling directly remodels the ER stress response. In contrast, the CHOP\u2013GADD34\u2013eIF2\u03b1 dephosphorylation axis constitutes a negative feedback mechanism that fine\u2010tunes translational recovery and determines the balance between adaptation and cell death. Moreover, 4E\u2010BP1\u2010mediated inhibition of mRNA translation and modulation of mTOR signaling alleviate proteotoxic stress and promote \u03b2\u2010cell survival under conditions of increased secretory demand. In addition to translational control, IGF2 receptor\u2010mediated signaling has recently been implicated in the regulation of autophagy, further linking lysosomal quality control to \u03b2\u2010cell proteostasis. Importantly, proteostasis also affects \u03b1\u2010cell biology, where UPR signaling regulates glucagon secretion and contributes to \u03b1\u2010to\u2010\u03b2 cell transdifferentiation, highlighting a previously unrecognized role of ER homeostasis in endocrine cell identity. Finally, recent findings indicate that progressive impairment of proteostasis is a hallmark of islet aging, integrating defects in protein folding, translation, autophagy, and stress adaptation into the pathogenesis of diabetes.<\/jats:p>","DOI":"10.1111\/jdi.70438","type":"journal-article","created":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T08:06:03Z","timestamp":1789113963000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Proteostasis in the regulation of pancreatic islet cell plasticity"],"prefix":"10.1111","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0822-8750","authenticated-orcid":false,"given":"Jun","family":"Shirakawa","sequence":"first","affiliation":[{"name":"Laboratory of Diabetes and Metabolic Disorders, Institute for Molecular and Cellular Regulation (IMCR) Gunma University  Maebashi Japan"},{"name":"Department of Endocrinology and Metabolism, Graduate School of Medicine Yokohama City University  Yokohama City Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,11]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1038\/s41580-020-00317-7","article-title":"Mechanisms controlling pancreatic islet cell function in insulin secretion","volume":"22","author":"Campbell JE","year":"2021","journal-title":"Nat Rev Mol Cell Biol"},{"key":"e_1_2_10_3_1","first-page":"11","article-title":"Emerging perspectives in proteostasis: Bridging mechanisms and therapeutics for human diseases","volume":"11","author":"Borlepawar A","year":"2026","journal-title":"Signal Transduct Target Ther"},{"key":"e_1_2_10_4_1","doi-asserted-by":"crossref","first-page":"421","DOI":"10.1038\/s41580-020-0250-z","article-title":"Mechanisms, regulation and functions of the unfolded protein response","volume":"21","author":"Hetz C","year":"2020","journal-title":"Nat Rev Mol Cell 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