{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T11:28:10Z","timestamp":1787138890813,"version":"build-2736575974"},"reference-count":106,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T00:00:00Z","timestamp":1787097600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:p>Diabetes mellitus is a global metabolic disorder characterized by progressive pancreatic \u03b2-cell failure, which leads to inadequate insulin secretion, often in combination with insulin resistance, and ultimately disrupts glucose homeostasis. The Integrated Stress Response (ISR), a crucial signaling network that enables cells to maintain homeostasis under endogenous and exogenous pressures, has garnered increasing attention for its role in regulating islet \u03b2-cell function and contributing to their failure. In recent years, a growing body of evidence has revealed that the ISR acts as a dual-edged sword in the onset and progression of diabetes. On the one hand, ISR activation can transiently relieve biosynthetic stress and help preserve cellular homeostasis. On the other hand, persistent or dysregulated ISR signaling is increasingly associated with impaired insulin production, loss of \u03b2-cell identity, and cell death in diabetes. In this Review, we summarize the molecular architecture of the ISR, focus on its regulatory role in pancreatic \u03b2-cell stress biology, and examine how ISR-related pathways are engaged in monogenic diabetes, type 1 diabetes, and type 2 diabetes. We further evaluate current therapeutic strategies targeting ISR-associated pathways and highlight the central translational challenge in this field, aiming to provide a theoretical basis and novel insights for a deeper understanding of the molecular mechanisms driving diabetic \u03b2-cell failure and for the development of novel precision therapeutic approaches.<\/jats:p>","DOI":"10.3389\/fendo.2026.1855305","type":"journal-article","created":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T11:10:01Z","timestamp":1787137801000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["The integrated stress response in pancreatic \u03b2-cell failure in diabetes: from molecular mechanisms to precision therapeutics"],"prefix":"10.3389","volume":"17","author":[{"given":"Yijun","family":"Huang","sequence":"first","affiliation":[{"name":"The First Clinical College of Zunyi Medical University","place":["Zunyi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Zeng","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, School of Preclinical Medicine, Zunyi Medical University","place":["Zunyi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinying","family":"Zhong","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, School of Preclinical Medicine, Zunyi Medical University","place":["Zunyi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, School of Preclinical Medicine, Zunyi Medical University","place":["Zunyi, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,19]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/s2213-8587(25)00299-2","article-title":"11th edition of the IDF Diabetes Atlas: global, regional, and national diabetes prevalence estimates for 2024 and projections for 2050","volume":"14","author":"Genitsaridi","year":"2026","journal-title":"Lancet Diabetes Endocrinol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.2337\/dc24-S002","article-title":"2. Diagnosis and Classification of Diabetes: Standards of Care in Diabetes-2024","volume":"47","year":"2024","journal-title":"Diabetes Care"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1111\/jdi.13576","article-title":"\u03b2-Cell failure in diabetes: Common susceptibility and mechanisms shared between type 1 and type 2 diabetes","volume":"12","author":"Ikegami","year":"2021","journal-title":"J Diabetes Investig"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1038\/s44318-024-00338-4","article-title":"The integrated stress response drives MET oncogene overexpression in cancers","volume":"44","author":"Cerqua","year":"2025","journal-title":"EMBO J"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmet.2017.06.001","article-title":"Endoplasmic reticulum stress and eIF2\u03b1 phosphorylation: the Achilles heel of pancreatic \u03b2 cells","volume":"6","author":"Cnop","year":"2017","journal-title":"Mol Metab"},{"key":"B6","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1016\/j.cmet.2009.06.002","article-title":"Translation Attenuation through eIF2\u03b1 Phosphorylation Prevents Oxidative Stress and Maintains the Differentiated State in \u03b2 Cells","volume":"10","author":"Back","year":"2009","journal-title":"Cell Metab"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1126\/science.aat5314","article-title":"The integrated stress response: from mechanism to disease","volume":"368","author":"Costa-Mattioli","year":"2020","journal-title":"Science"},{"key":"B8","doi-asserted-by":"publisher","first-page":"3160","DOI":"10.3390\/molecules28073160","article-title":"Endoplasmic reticulum stress and mitochondrial stress in drug-induced liver injury","volume":"28","author":"Pu","year":"2023","journal-title":"Molecules"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.15252\/embr.201642195","article-title":"The integrated stress response","volume":"17","author":"Pakos-Zebrucka","year":"2016","journal-title":"EMBO Rep"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.conb.2024.102886","article-title":"The integrated stress response in brain diseases: a double-edged sword for proteostasis and synapses","volume":"87","author":"Lockshin","year":"2024","journal-title":"Curr Opin Neurobiol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.92173","article-title":"DNL343 is an investigational CNS penetrant eukaryotic initiation factor 2B activator that prevents and reverses the effects of neurodegeneration caused by the integrated stress response","volume":"12","author":"Yulyaningsih","year":"2024","journal-title":"Elife"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2021.747837","article-title":"Targeting the integrated stress response in cancer therapy","volume":"12","author":"Tian","year":"2021","journal-title":"Front Pharmacol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2023.1271141","article-title":"Signaling plasticity in the integrated stress response","volume":"11","author":"Boone","year":"2023","journal-title":"Front Cell Dev Biol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-012-1252-6","article-title":"The eIF2\u03b1 kinases: their structures and functions","volume":"70","author":"Donnelly","year":"2013","journal-title":"Cell Mol Life Sci"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2025.110958","article-title":"From the integrated stress response to oxidative stress: a historical perspective","volume":"302","author":"Amiri","year":"2026","journal-title":"J Biol Chem"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1016\/j.tibs.2014.08.004","article-title":"Dimerization-induced allostery in protein kinase regulation","volume":"39","author":"Lavoie","year":"2014","journal-title":"Trends Biochem Sci"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.RA117.001294","article-title":"The luminal domain of the ER stress sensor protein Perk binds misfolded proteins and thereby triggers Perk oligomerization","volume":"293","author":"Wang","year":"2018","journal-title":"J Biol Chem"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a004424","article-title":"ER stress and its functional link to mitochondria: role in cell survival and death","volume":"3","author":"Malhotra","year":"2011","journal-title":"Cold Spring Harb Perspect Biol"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1042\/bst20190331","article-title":"Towards a model of GCN2 activation","volume":"47","author":"Masson","year":"2019","journal-title":"Biochem Soc Trans"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1042\/bst20253034","article-title":"Insights into the role of collided ribosomes during the activation of the integrated stress response","volume":"53","author":"Nanjaraj Urs","year":"2025","journal-title":"Biochem Soc Trans"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1111\/febs.15553","article-title":"The eIF2\u03b1 kinase HRI in innate immunity, proteostasis, and mitochondrial stress","volume":"288","author":"Girardin","year":"2021","journal-title":"FEBS J"},{"key":"B22","doi-asserted-by":"publisher","first-page":"636","DOI":"10.1016\/j.molcel.2018.01.019","article-title":"N(6)-methyladenosine guides mRNA alternative translation during integrated stress response","volume":"69","author":"Zhou","year":"2018","journal-title":"Mol Cell"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2022.0123","article-title":"Surviving and adapting to stress: translational control and the integrated stress response","volume":"39","author":"Wek","year":"2023","journal-title":"Antioxid Redox Signal"},{"key":"B24","doi-asserted-by":"publisher","first-page":"358","DOI":"10.1038\/s41392-025-02439-w","article-title":"Navigating the landscape of protein folding and proteostasis: from molecular chaperones to therapeutic innovations","volume":"10","author":"Kuzu","year":"2025","journal-title":"Signal Transduct Target Ther"},{"key":"B25","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1186\/s13046-024-02990-4","article-title":"Biological mechanisms and clinical significance of endoplasmic reticulum oxidoreductase 1 alpha (Ero1\u03b1) in human cancer","volume":"43","author":"Chen","year":"2024","journal-title":"J Exp Clin Cancer Res"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110.167213","article-title":"Both transcriptional regulation and translational control of Atf4 are central to the integrated stress response","volume":"285","author":"Dey","year":"2010","journal-title":"J Biol Chem"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1038\/s41401-023-01225-0","article-title":"Mammalian integrated stress responses in stressed organelles and their functions","volume":"45","author":"Lu","year":"2024","journal-title":"Acta Pharmacol Sin"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1128\/mcb.00190-16","article-title":"Complementary roles of Gadd34-and Crep-containing eukaryotic initiation factor 2\u03b1 phosphatases during the unfolded protein response","volume":"36","author":"Reid","year":"2016","journal-title":"Mol Cell Biol"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2025.1502469","article-title":"Molecular puzzle of insulin: structural assembly pathways and their role in diabetes","volume":"13","author":"Urbaniak","year":"2025","journal-title":"Front Cell Dev Biol"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2024.1386471","article-title":"Endoplasmic reticulum stress in pancreatic \u03b2-cell dysfunctionality and diabetes mellitus: a promising target for generation of functional hPSC-derived \u03b2-cells in vitro","volume":"15","author":"Diane","year":"2024","journal-title":"Front Endocrinol (Lausanne)"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1210\/er.2007-0039","article-title":"The unfolded protein response: a pathway that links insulin demand with beta-cell failure and diabetes","volume":"29","author":"Scheuner","year":"2008","journal-title":"Endocr Rev"},{"key":"B32","doi-asserted-by":"publisher","first-page":"4843","DOI":"10.3390\/ijms23094843","article-title":"Endoplasmic reticulum (ER) stress and its role in pancreatic \u03b2-cell dysfunction and senescence in type 2 diabetes","volume":"23","author":"Lee","year":"2022","journal-title":"Int J Mol Sci"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1038\/s41574-021-00510-4","article-title":"Therapeutic opportunities for pancreatic \u03b2-cell ER stress in diabetes mellitus","volume":"17","author":"Yong","year":"2021","journal-title":"Nat Rev Endocrinol"},{"key":"B34","doi-asserted-by":"publisher","first-page":"706","DOI":"10.1038\/s41419-022-05153-5","article-title":"ER stress and UPR in Alzheimer's disease: mechanisms, pathogenesis, treatments","volume":"13","author":"Ajoolabady","year":"2022","journal-title":"Cell Death Dis"},{"key":"B35","doi-asserted-by":"publisher","first-page":"1304","DOI":"10.1038\/s41467-020-15067-5","article-title":"Pharmacological induction of selective endoplasmic reticulum retention as a strategy for cancer therapy","volume":"11","author":"Mahameed","year":"2020","journal-title":"Nat Commun"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2012.08.003","article-title":"Failure of amino acid homeostasis causes cell death following proteasome inhibition","volume":"48","author":"Suraweera","year":"2012","journal-title":"Mol Cell"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1038\/s41417-024-00818-z","article-title":"Arsenic trioxide and p97 inhibitor synergize against acute myeloid leukemia by targeting nascent polypeptides and activating the ZAK\u03b1-JNK pathway","volume":"31","author":"Xie","year":"2024","journal-title":"Cancer Gene Ther"},{"key":"B38","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1111\/j.1463-1326.2010.01271.x","article-title":"The endoplasmic reticulum stress response in the pancreatic \u03b2-cell","volume":"12","author":"Volchuk","year":"2010","journal-title":"Diabetes Obes Metab"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a033092","article-title":"Protein synthesis initiation in eukaryotic cells","volume":"10","author":"Merrick","year":"2018","journal-title":"Cold Spring Harb Perspect Biol"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1016\/s1097-2765(01)00264-7","article-title":"Diabetes mellitus and exocrine pancreatic dysfunction in Perk-\/- mice reveals a role for translational control in secretory cell survival","volume":"7","author":"Harding","year":"2001","journal-title":"Mol Cell"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1210\/en.2006-1012","article-title":"Glucose activates a protein phosphatase-1-mediated signaling pathway to enhance overall translation in pancreatic beta-cells","volume":"148","author":"Vander Mierde","year":"2007","journal-title":"Endocrinology"},{"key":"B42","doi-asserted-by":"publisher","first-page":"1385","DOI":"10.3390\/jcm8091385","article-title":"Relationship between oxidative stress, ER stress, and inflammation in type 2 diabetes: the battle continues","volume":"8","author":"Burgos-Mor\u00f3n","year":"2019","journal-title":"J Clin Med"},{"key":"B43","doi-asserted-by":"publisher","first-page":"266","DOI":"10.3892\/etm.2020.9396","article-title":"Mitochondrial dysfunction and pancreatic islet \u03b2-cell failure (review)","volume":"20","author":"Sha","year":"2020","journal-title":"Exp Ther Med"},{"key":"B44","doi-asserted-by":"publisher","first-page":"981","DOI":"10.3390\/antiox12050981","article-title":"Unfolding the interactions between endoplasmic reticulum stress and oxidative stress","volume":"12","author":"Ong","year":"2023","journal-title":"Antioxidants (Basel)"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2118793119","article-title":"The endoplasmic reticulum chaperone Bip is a closure-accelerating cochaperone of Grp94","volume":"119","author":"Huang","year":"2022","journal-title":"Proc Natl Acad Sci USA"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1016\/j.biocel.2024.106598","article-title":"Endoplasmic reticulum: monitoring and maintaining protein and membrane homeostasis in the endoplasmic reticulum by the unfolded protein response","volume":"172","author":"Kettel","year":"2024","journal-title":"Int J Biochem Cell Biol"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2020.571554","article-title":"Mitochondria-associated endoplasmic reticulum membranes in the pathogenesis of type 2 diabetes mellitus","volume":"8","author":"Yang","year":"2020","journal-title":"Front Cell Dev Biol"},{"key":"B48","doi-asserted-by":"publisher","first-page":"169","DOI":"10.1016\/bs.ircmb.2021.06.001","article-title":"Role of mitochondria-associated endoplasmic reticulum membrane (Mams) interactions and calcium exchange in the development of type 2 diabetes","volume":"363","author":"Madec","year":"2021","journal-title":"Int Rev Cell Mol Biol"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.3390\/ijms17030327","article-title":"Endoplasmic reticulum stress and associated ROS","volume":"17","author":"Zeeshan","year":"2016","journal-title":"Int J Mol Sci"},{"key":"B50","doi-asserted-by":"publisher","first-page":"173","DOI":"10.3390\/biom11020173","article-title":"ER stress-sensor proteins and ER-mitochondrial crosstalk-signaling beyond (ER) stress response","volume":"11","author":"Kumar","year":"2021","journal-title":"Biomolecules"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1038\/nrm2199","article-title":"Signal integration in the endoplasmic reticulum unfolded protein response","volume":"8","author":"Ron","year":"2007","journal-title":"Nat Rev Mol Cell Biol"},{"key":"B52","doi-asserted-by":"publisher","first-page":"4362","DOI":"10.3390\/molecules26144362","article-title":"Current status of endoplasmic reticulum stress in type II diabetes","volume":"26","author":"Mustapha","year":"2021","journal-title":"Molecules"},{"key":"B53","doi-asserted-by":"publisher","first-page":"13586","DOI":"10.3390\/ijms232113586","article-title":"Gsk-3-mediated proteasomal degradation of atf4 is a proapoptotic mechanism in mouse pancreatic \u03b2-cells","volume":"23","author":"Nagao","year":"2022","journal-title":"Int J Mol Sci"},{"key":"B54","doi-asserted-by":"publisher","first-page":"4621","DOI":"10.1038\/s41467-022-32425-7","article-title":"Adaptation to chronic er stress enforces pancreatic \u03b2-cell plasticity","volume":"13","author":"Chen","year":"2022","journal-title":"Nat Commun"},{"key":"B55","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1111\/j.1463-1326.2010.01279.x","article-title":"Causes and cures for endoplasmic reticulum stress in lipotoxic \u03b2-cell dysfunction","volume":"12","author":"Cnop","year":"2010","journal-title":"Diabetes Obes Metab"},{"key":"B56","doi-asserted-by":"publisher","first-page":"1160","DOI":"10.3390\/cells9051160","article-title":"Role of endoplasmic reticulum stress sensor ire1\u03b1 in cellular physiology, calcium, ros signaling, and metaflammation","volume":"9","author":"Riaz","year":"2020","journal-title":"Cells"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2020.614123","article-title":"What is the sweetest upr flavor for the \u03b2-cell? That is the question","volume":"11","author":"Lenghel","year":"2021","journal-title":"Front Endocrinol (Lausanne)"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmet.2019.06.012","article-title":"Endoplasmic reticulum stress, degeneration of pancreatic islet \u03b2-cells, and therapeutic modulation of the unfolded protein response in diabetes","author":"Ghosh","year":"2019","journal-title":"Mol Metab"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1038\/nrd2755","article-title":"Cell death and endoplasmic reticulum stress: Disease relevance and therapeutic opportunities","volume":"7","author":"Kim","year":"2008","journal-title":"Nat Rev Drug Discov"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2017.01612","article-title":"Transcription factor C\/EBP homologous protein in health and diseases","volume":"8","author":"Yang","year":"2017","journal-title":"Front Immunol"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.03083","article-title":"The c\/ebp homologous protein (chop) transcription factor functions in endoplasmic reticulum stress-induced apoptosis and microbial infection","volume":"9","author":"Hu","year":"2019","journal-title":"Front Immunol"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.1172\/jci34587","article-title":"Chop deletion reduces oxidative stress, improves \u03b2 cell function, and promotes cell survival in multiple mouse models of diabetes","volume":"118","author":"Song","year":"2008","journal-title":"J Clin Invest"},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.1530\/ec-21-0260","article-title":"Targeting \u03b2-cell dedifferentiation and transdifferentiation: opportunities and challenges","volume":"10","author":"Wang","year":"2021","journal-title":"Endocrine Connections"},{"key":"B64","doi-asserted-by":"publisher","DOI":"10.1038\/s12276-023-01019-8","article-title":"Txnip: A key protein in the cellular stress response pathway and a potential therapeutic target","volume":"55","author":"Choi","year":"2023","journal-title":"Exp Mol Med"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2012.07.005","article-title":"Thioredoxin-interacting protein mediates er stress-induced \u03b2 cell death through initiation of the inflammasome","volume":"16","author":"Oslowski","year":"2012","journal-title":"Cell Metab"},{"key":"B66","doi-asserted-by":"publisher","DOI":"10.1186\/1750-1172-5-29","article-title":"Wolcott-Rallison syndrome","volume":"5","author":"Julier","year":"2010","journal-title":"Orphanet J Rare Dis"},{"key":"B67","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1111\/j.1463-1326.2010.01277.x","article-title":"A switch from life to death in endoplasmic reticulum stressed \u03b2\u2010cells","volume":"12","author":"Oslowski","year":"2010","journal-title":"Diabetes Obes Metab"},{"key":"B68","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2121-10-61","article-title":"Acute ablation of perk results in er dysfunctions followed by reduced insulin secretion and cell proliferation","volume":"10","author":"Feng","year":"2009","journal-title":"BMC Cell Biol"},{"key":"B69","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.m117.813790","article-title":"The protein kinase perk\/eif2ak3 regulates proinsulin processing not via protein synthesis but by controlling endoplasmic reticulum chaperones","volume":"293","author":"Sowers","year":"2018","journal-title":"J Biol Chem"},{"key":"B70","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-27344-y","article-title":"WFS1 functions in ER export of vesicular cargo proteins in pancreatic \u03b2-cells","volume":"12","author":"Wang","year":"2021","journal-title":"Nat Commun"},{"key":"B71","doi-asserted-by":"publisher","DOI":"10.3390\/ijms24010230","article-title":"The Role of ER Stress in Diabetes: Exploring Pathological Mechanisms Using Wolfram Syndrome","volume":"24","author":"Morikawa","year":"2023","journal-title":"Int J Mol Sci"},{"key":"B72","doi-asserted-by":"publisher","DOI":"10.1038\/s41374-020-0408-5","article-title":"Wolfram syndrome 1 gene regulates pathways maintaining beta-cell health and survival","volume":"100","author":"Abreu","year":"2020","journal-title":"Lab Invest"},{"key":"B73","doi-asserted-by":"publisher","DOI":"10.1038\/s41418-024-01258-w","article-title":"Isr inhibition reverses pancreatic \u03b2-cell failure in wolfram syndrome models","volume":"31","author":"Hu","year":"2024","journal-title":"Cell Death Differ"},{"key":"B74","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.abd6527","article-title":"Islet expression of type I interferon response sensors is associated with immune infiltration and viral infection in type 1 diabetes","volume":"7","author":"Apaolaza","year":"2021","journal-title":"Sci Adv"},{"key":"B75","doi-asserted-by":"publisher","DOI":"10.1016\/j.ddmec.2006.09.010","article-title":"Type 1 diabetes: Islet inflammation\u2013the contribution of cytokines and beta cells","volume":"3","author":"Gusdon","year":"2006","journal-title":"Drug Discov Today: Dis Mech"},{"key":"B76","doi-asserted-by":"publisher","first-page":"441","DOI":"10.3390\/biom15030441","article-title":"Tissue resident and infiltrating immune cells: Their influence on the demise of beta cells in type 1 diabetes","volume":"15","author":"Walker","year":"2025","journal-title":"Biomolecules"},{"key":"B77","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2017.7243","article-title":"Redox-sensitive innate immune pathways during macrophage activation in type 1 diabetes","volume":"29","author":"Burg","year":"2018","journal-title":"Antioxid Redox Signal"},{"key":"B78","doi-asserted-by":"publisher","first-page":"374","DOI":"10.1186\/s12964-025-02372-z","article-title":"The integrated stress response promotes macrophage inflammation and migration in autoimmune diabetes","volume":"23","author":"Wang","year":"2025","journal-title":"Cell Commun Signal"},{"key":"B79","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2024.06.029","article-title":"Diabetes mellitus-progress and opportunities in the evolving epidemic","volume":"187","author":"Abel","year":"2024","journal-title":"Cell"},{"key":"B80","doi-asserted-by":"publisher","DOI":"10.1016\/s0168-8227(11)70012-2","article-title":"Glucolipotoxicity and beta cells in type 2 diabetes mellitus: Target for durable therapy","volume":"93","author":"van Raalte","year":"2011","journal-title":"Diabetes Res Clin Pract"},{"key":"B81","doi-asserted-by":"publisher","DOI":"10.4093\/dmj.2022.0366","article-title":"Glucolipotoxicity Suppressed Autophagy and Insulin Contents in Human Islets, and Attenuation of PERK Activity Enhanced Them in an ATG7-Dependent Manner","volume":"48","author":"Moon","year":"2024","journal-title":"Diabetes Metab J"},{"key":"B82","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.128820","article-title":"Gcn2 regulates pancreatic \u03b2 cell mass by sensing intracellular amino acid levels","volume":"5","author":"Kanno","year":"2020","journal-title":"JCI Insight"},{"key":"B83","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2006.11.002","article-title":"Perk eif2ak3 control of pancreatic beta cell differentiation and proliferation is required for postnatal glucose homeostasis","volume":"4","author":"Zhang","year":"2006","journal-title":"Cell Metab"},{"key":"B84","doi-asserted-by":"publisher","DOI":"10.2337\/diabetes.51.7.2301","article-title":"Loss of kinase activity in a patient with wolcott-rallison syndrome caused by a novel mutation in the eif2ak3 gene","volume":"51","author":"Biason-Lauber","year":"2002","journal-title":"Diabetes"},{"key":"B85","doi-asserted-by":"publisher","first-page":"206ra138","DOI":"10.1126\/scitranslmed.3006767","article-title":"Oral treatment targeting the unfolded protein response prevents neurodegeneration and clinical disease in prion-infected mice","volume":"5","author":"Moreno","year":"2013","journal-title":"Sci Transl Med"},{"key":"B86","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1016\/j.metabol.2018.12.007","article-title":"Specific perk inhibitors enhanced glucose-stimulated insulin secretion in a mouse model of type 2 diabetes","volume":"97","author":"Kim","year":"2019","journal-title":"Metabolism"},{"key":"B87","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1516362112","article-title":"Type i interferons mediate pancreatic toxicities of perk inhibition","volume":"112","author":"Yu","year":"2015","journal-title":"Proc Natl Acad Sci"},{"key":"B88","doi-asserted-by":"publisher","DOI":"10.1038\/cddis.2015.49","article-title":"Partial restoration of protein synthesis rates by the small molecule isrib prevents neurodegeneration without pancreatic toxicity","volume":"6","author":"Halliday","year":"2015","journal-title":"Cell Death Dis"},{"key":"B89","doi-asserted-by":"publisher","first-page":"300","DOI":"10.1038\/s41419-019-1523-3","article-title":"The unfolded protein response modulators GSK2606414 and KIRA6 are potent KIT inhibitors","volume":"10","author":"Mahameed","year":"2019","journal-title":"Cell Death Dis"},{"key":"B90","doi-asserted-by":"publisher","DOI":"10.1038\/cdd.2017.58","article-title":"When perk inhibitors turn out to be new potent ripk1 inhibitors: Critical issues on the specificity and use of gsk2606414 and gsk2656157","volume":"24","author":"Rojas-Rivera","year":"2017","journal-title":"Cell Death Differ"},{"key":"B91","doi-asserted-by":"publisher","DOI":"10.7554\/elife.05033","article-title":"The small molecule isrib reverses the effects of eif2\u03b1 phosphorylation on translation and stress granule assembly","volume":"4","author":"Sidrauski","year":"2015","journal-title":"elife"},{"key":"B92","doi-asserted-by":"publisher","DOI":"10.7554\/elife.07314","article-title":"Pharmacological dimerization and activation of the exchange factor eif2b antagonizes the integrated stress response","volume":"4","author":"Sidrauski","year":"2015","journal-title":"elife"},{"key":"B93","doi-asserted-by":"publisher","DOI":"10.1126\/science.adf2034","article-title":"Retrograde mitochondrial signaling governs the identity and maturity of metabolic tissues","volume":"388","author":"Walker","year":"2025","journal-title":"Science"},{"key":"B94","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.m702672200","article-title":"Chemical chaperones reduce endoplasmic reticulum stress and prevent mutant hfe aggregate formation","volume":"282","author":"De Almeida","year":"2007","journal-title":"J Biol Chem"},{"key":"B95","doi-asserted-by":"publisher","DOI":"10.1038\/srep27486","article-title":"Chemical chaperones reduce er stress and adipose tissue inflammation in high fat diet-induced mouse model of obesity","volume":"6","author":"Chen","year":"2016","journal-title":"Sci Rep"},{"key":"B96","doi-asserted-by":"publisher","first-page":"211ra156","DOI":"10.1126\/scitranslmed.3006534","article-title":"Restoration of the unfolded protein response in pancreatic \u03b2 cells protects mice against type 1 diabetes","volume":"5","author":"Engin","year":"2013","journal-title":"Sci Transl Med"},{"key":"B97","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2013.08.023","article-title":"Glucotoxic conditions induce endoplasmic reticulum stress to cause caspase 3 mediated lamin b degradation in pancreatic \u03b2-cells: Protection by nifedipine","volume":"86","author":"Syeda","year":"2013","journal-title":"Biochem Pharmacol"},{"key":"B98","doi-asserted-by":"publisher","first-page":"11878","DOI":"10.1038\/s41598-021-91311-2","article-title":"4-phenylbutyrate (pba) treatment reduces hyperglycemia and islet amyloid in a mouse model of type 2 diabetes and obesity","volume":"11","author":"de Pablo","year":"2021","journal-title":"Sci Rep"},{"key":"B99","doi-asserted-by":"publisher","first-page":"391","DOI":"10.1016\/j.cmet.2006.10.001","article-title":"Glp-1 receptor activation improves \u03b2 cell function and survival following induction of endoplasmic reticulum stress","volume":"4","author":"Yusta","year":"2006","journal-title":"Cell Metab"},{"key":"B100","doi-asserted-by":"publisher","DOI":"10.1210\/clinem\/dgae032","article-title":"Acute exercise increases Gdf15 and unfolded protein response\/integrated stress response in muscle in type 2 diabetes","volume":"109","author":"Sabaratnam","year":"2024","journal-title":"J Clin Endocrinol Metab"},{"key":"B101","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2019.08.019","article-title":"Fibroblast growth factor 21 drives dynamics of local and systemic stress responses in mitochondrial myopathy with Mtdna deletions","volume":"30","author":"Forsstr\u00f6m","year":"2019","journal-title":"Cell Metab"},{"key":"B102","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2023.1277866","article-title":"Temporal dynamics of muscle mitochondrial uncoupling-induced integrated stress response and ferroptosis defense","volume":"14","author":"Igual Gil","year":"2023","journal-title":"Front Endocrinol"},{"key":"B103","doi-asserted-by":"publisher","DOI":"10.1172\/jci143683","article-title":"A little help from residual \u03b2 cells has long-lasting clinical benefits","volume":"131","author":"Lam","year":"2021","journal-title":"J Clin Invest"},{"key":"B104","doi-asserted-by":"publisher","DOI":"10.2337\/dc15-2849","article-title":"Elevations in the fasting serum proinsulin\u2013to\u2013C-peptide ratio precede the onset of type 1 diabetes","volume":"39","author":"Sims","year":"2016","journal-title":"Diabetes Care"},{"key":"B105","doi-asserted-by":"publisher","DOI":"10.1210\/clinem\/dgaa008","article-title":"Circulating unmethylated insulin DNA as a biomarker of human beta cell death: a multi-laboratory assay comparison","volume":"105","author":"Speake","year":"2020","journal-title":"J Clin Endocrinol Metab"},{"key":"B106","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22042151","article-title":"Cell-free DNA fragments as biomarkers of islet \u03b2-cell death in obesity and type 2 diabetes","volume":"22","author":"Arosemena","year":"2021","journal-title":"Int J Mol Sci"}],"container-title":["Frontiers in Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2026.1855305\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T11:10:02Z","timestamp":1787137802000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2026.1855305\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,19]]},"references-count":106,"alternative-id":["10.3389\/fendo.2026.1855305"],"URL":"https:\/\/doi.org\/10.3389\/fendo.2026.1855305","relation":{},"ISSN":["1664-2392"],"issn-type":[{"value":"1664-2392","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,19]]},"article-number":"1855305"}}