{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T17:54:47Z","timestamp":1784570087540,"version":"3.55.0"},"reference-count":35,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2023,1,10]],"date-time":"2023-01-10T00:00:00Z","timestamp":1673308800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The Cohen Diabetic rat is a model of type 2 diabetes mellitus that consists of the susceptible (CDs\/y) and resistant (CDr\/y) strains. Diabetes develops in CDs\/y provided diabetogenic diet (DD) but not when fed regular diet (RD) nor in CDr\/y given either diet. We recently identified in CDs\/y a deletion in Sdf2l1, a gene that has been attributed a role in the unfolded protein response (UPR) and in the prevention of endoplasmic reticulum (ER) stress. We hypothesized that this deletion prevents expression of SDF2L1 and contributes to the pathophysiology of diabetes in CDs\/y by impairing UPR, enhancing ER stress, and preventing CDs\/y from secreting sufficient insulin upon demand. We studied SDF2L1 expression in CDs\/y and CDr\/y. We evaluated UPR by examining expression of key proteins involved in both strains fed either RD or DD. We assessed the ability of all groups of animals to secrete insulin during an oral glucose tolerance test (OGTT) over 4 weeks, and after overnight feeding (postprandial) over 4 months. We found that SDF2L1 was expressed in CDr\/y but not in CDs\/y. The pattern of expression of proteins involved in UPR, namely the PERK (EIF2\u03b1, ATF4 and CHOP) and IRE1 (XBP-1) pathways, was different in CDs\/y DD from all other groups, with consistently lower levels of expression at 4 weeks after initiation of DD and coinciding with the development of diabetes. In CDs\/y RD, insulin secretion was mildly impaired, whereas in CDs\/y DD, the ability to secrete insulin decreased over time, leading to the development of the diabetic phenotype. We conclude that in CDs\/y DD, UPR participating proteins were dysregulated and under-expressed at the time point when the diabetic phenotype became overt. In parallel, insulin secretion in CDs\/y DD became markedly impaired. Our findings suggest that under conditions of metabolic load with DD and increased demand for insulin secretion, the lack of SDF2L1 expression in CDs\/y is associated with UPR dysregulation and ER stress which, combined with oxidative stress previously attributed to the concurrent Ndufa4 mutation, are highly likely to contribute to the pathophysiology of diabetes in this model.<\/jats:p>","DOI":"10.3390\/ijms24021355","type":"journal-article","created":{"date-parts":[[2023,1,11]],"date-time":"2023-01-11T02:06:03Z","timestamp":1673402763000},"page":"1355","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Dysregulated UPR and ER Stress Related to a Mutation in the Sdf2l1 Gene Are Involved in the Pathophysiology of Diet-Induced Diabetes in the Cohen Diabetic Rat"],"prefix":"10.3390","volume":"24","author":[{"given":"Chana","family":"Yagil","sequence":"first","affiliation":[{"name":"Laboratory for Molecular Medicine and Israeli Rat Genome Center, Barzilai University Medical Center, Ashkelon 7830604, Israel"},{"name":"Faculty of Health Sciences, Ben-Gurion University of the Negev, P.O. Box 653, Beer Sheva 8410501, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ronen","family":"Varadi-Levi","sequence":"additional","affiliation":[{"name":"Laboratory for Molecular Medicine and Israeli Rat Genome Center, Barzilai University Medical Center, Ashkelon 7830604, Israel"},{"name":"Faculty of Health Sciences, Ben-Gurion University of the Negev, P.O. Box 653, Beer Sheva 8410501, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0898-1320","authenticated-orcid":false,"given":"Chen","family":"Ifrach","sequence":"additional","affiliation":[{"name":"Laboratory for Molecular Medicine and Israeli Rat Genome Center, Barzilai University Medical Center, Ashkelon 7830604, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoram","family":"Yagil","sequence":"additional","affiliation":[{"name":"Laboratory for Molecular Medicine and Israeli Rat Genome Center, Barzilai University Medical Center, Ashkelon 7830604, Israel"},{"name":"Faculty of Health Sciences, Ben-Gurion University of the Negev, P.O. Box 653, Beer Sheva 8410501, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,1,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"100477","DOI":"10.1016\/j.xcrm.2021.100477","article-title":"Four groups of type 2 diabetes contribute to the etiological and clinical heterogeneity in newly diagnosed individuals: An IMI DIRECT study","volume":"3","author":"Brorsson","year":"2022","journal-title":"Cell Rep. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"107","DOI":"10.3389\/fphys.2019.00107","article-title":"Heterogeneity of Metabolic Defects in Type 2 Diabetes and Its Relation to Reactive Oxygen Species and Alterations in Beta-Cell Mass","volume":"10","author":"Elksnis","year":"2019","journal-title":"Front. 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