{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T13:16:19Z","timestamp":1790946979000,"version":"4.1.0"},"reference-count":65,"publisher":"Wiley","issue":"19","license":[{"start":{"date-parts":[[2023,7,24]],"date-time":"2023-07-24T00:00:00Z","timestamp":1690156800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["R01DK114345"],"award-info":[{"award-number":["R01DK114345"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["analyticalsciencejournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Proteomics"],"published-print":{"date-parts":[[2023,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Pancreatic \u03b2\u2010cell dysfunction is an early hallmark of type 1 diabetes mellitus. Among the potentially critical factors that cause \u03b2\u2010cell dysfunction are cytokine attack, glucotoxicity, induction of endoplasmic reticulum (ER) or mitochondria stress. However, the exact molecular mechanism underlying \u03b2\u2010cell's inability to maintain glucose homeostasis under severe stresses is unknown. This study used proinflammatory cytokines, thapsigargin, and rotenone in the presence of high concentration glucose to mimicking the conditions experienced by dysfunctional \u03b2\u2010cells in human pancreatic islets, and profiled the alterations to the islet proteome with TMT\u2010based proteomics. The results were further verified with label\u2010free quantitative proteomics. The differentially expressed proteins under stress conditions reveal that immune related pathways are mostly perturbed by cytokines, while the respiratory electron transport chains and protein processing in ER pathways by rotenone. Thapsigargin together with high glucose induces dramatic increases of proteins in lipid synthesis and peroxisomal protein import pathways, with energy metabolism and vesicle secretion related pathways downregulated. High concentration glucose, on the other hand, alleviated complex I inhibition induced by rotenone. Our results contribute to a more comprehensive understanding of the molecular events involved in \u03b2\u2010cell dysfunction.<\/jats:p>","DOI":"10.1002\/pmic.202300022","type":"journal-article","created":{"date-parts":[[2023,7,25]],"date-time":"2023-07-25T02:16:29Z","timestamp":1690251389000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Effects of multiple stressors on pancreatic human islets proteome reveal new insights into the pathways involved"],"prefix":"10.1002","volume":"23","author":[{"given":"Mehari Muuz","family":"Weldemariam","sequence":"first","affiliation":[{"name":"Center for Translational Biomedical Research University of North Carolina at Greensboro, North Carolina Research Campus Kannapolis North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Putty\u2010Reddy","family":"Sudhir","sequence":"additional","affiliation":[{"name":"Center for Translational Biomedical Research University of North Carolina at Greensboro, North Carolina Research Campus Kannapolis North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jongmin","family":"Woo","sequence":"additional","affiliation":[{"name":"Center for Translational Biomedical Research University of North Carolina at Greensboro, North Carolina Research Campus Kannapolis North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6135-8706","authenticated-orcid":false,"given":"Qibin","family":"Zhang","sequence":"additional","affiliation":[{"name":"Center for Translational Biomedical Research University of North Carolina at Greensboro, North Carolina Research Campus Kannapolis North Carolina USA"},{"name":"Department of Chemistry and Biochemistry University of North Carolina at Greensboro Greensboro North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,7,24]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1097\/JIM.0000000000000229"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.2174\/157339913804143225"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-019-0524-6"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2017.05.014"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1074\/mcp.M700085-MCP200"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mce.2008.05.015"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-015-3669-6"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI92172"},{"key":"e_1_2_9_10_1","first-page":"266","article-title":"Endoplasmic reticulum stress and pancreatic \u03b2\u2010cell death","volume":"22","author":"Fonseca S. G.","year":"2011","journal-title":"Trends in Endocrinology and Metabolism"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaut.2016.04.009"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22126642"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-11056-9"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2017.7346"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M210432200"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.669492"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.chemrestox.2c00058"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-16327-0"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2019.12.005"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jproteome.1c00143"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1002\/rcm.9128"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.3901"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-09234-6"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-4-2"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.2006.04333.x"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12964-019-0499-z"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1080\/14789450.2019.1634548"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1038\/gene.2016.29"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2020.591083"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.690082"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1038\/s12276-018-0196-9"},{"key":"e_1_2_9_32_1","article-title":"Random glucose GWAS in 493,036 individuals provides insights into diabetes pathophysiology, complications and treatment stratification","author":"Lagou V.","year":"2021","journal-title":"medRxiv"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmet.2019.02.001"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2021.814047"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1210\/en.2004-1430"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms20163877"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1002\/dmrr.919"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2018.00499"},{"key":"e_1_2_9_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tem.2010.06.003"},{"key":"e_1_2_9_40_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-28826-3"},{"key":"e_1_2_9_41_1","doi-asserted-by":"publisher","DOI":"10.1002\/elps.200800152"},{"key":"e_1_2_9_42_1","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2021.625235"},{"key":"e_1_2_9_43_1","doi-asserted-by":"publisher","DOI":"10.2337\/db06-1440"},{"key":"e_1_2_9_44_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-020-76013-5"},{"key":"e_1_2_9_45_1","doi-asserted-by":"publisher","DOI":"10.3390\/cells11050793"},{"key":"e_1_2_9_46_1","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2019.00881"},{"key":"e_1_2_9_47_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2023.104516"},{"key":"e_1_2_9_48_1","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2020.00365"},{"key":"e_1_2_9_49_1","doi-asserted-by":"publisher","DOI":"10.2337\/db19-1087"},{"key":"e_1_2_9_50_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep45465"},{"key":"e_1_2_9_51_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-022-10652-8"},{"key":"e_1_2_9_52_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11606-007-0407-x"},{"key":"e_1_2_9_53_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmet.2021.101353"},{"key":"e_1_2_9_54_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-022-00707-2"},{"key":"e_1_2_9_55_1","doi-asserted-by":"publisher","DOI":"10.3390\/biom11121763"},{"key":"e_1_2_9_56_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2023.102630"},{"key":"e_1_2_9_57_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.diabres.2007.01.033"},{"key":"e_1_2_9_58_1","doi-asserted-by":"publisher","DOI":"10.2337\/db16-0671"},{"key":"e_1_2_9_59_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpregu.00544.2014"},{"key":"e_1_2_9_60_1","doi-asserted-by":"publisher","DOI":"10.1210\/jcem-71-1-152"},{"key":"e_1_2_9_61_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.4289"},{"key":"e_1_2_9_62_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrm3008"},{"key":"e_1_2_9_63_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-016-4067-4"},{"key":"e_1_2_9_64_1","doi-asserted-by":"publisher","DOI":"10.1155\/2014\/457154"},{"key":"e_1_2_9_65_1","doi-asserted-by":"publisher","DOI":"10.1111\/jcmm.13432"},{"key":"e_1_2_9_66_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1002552"}],"container-title":["PROTEOMICS"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/analyticalsciencejournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/pmic.202300022","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,21]],"date-time":"2025-10-21T15:52:51Z","timestamp":1761061971000},"score":1,"resource":{"primary":{"URL":"https:\/\/analyticalsciencejournals.onlinelibrary.wiley.com\/doi\/10.1002\/pmic.202300022"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,7,24]]},"references-count":65,"journal-issue":{"issue":"19","published-print":{"date-parts":[[2023,10]]}},"alternative-id":["10.1002\/pmic.202300022"],"URL":"https:\/\/doi.org\/10.1002\/pmic.202300022","archive":["Portico"],"relation":{},"ISSN":["1615-9853","1615-9861"],"issn-type":[{"value":"1615-9853","type":"print"},{"value":"1615-9861","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,7,24]]},"assertion":[{"value":"2023-01-18","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-07-17","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-07-24","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"2300022"}}