{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T16:10:09Z","timestamp":1787242209824,"version":"build-2736575974"},"reference-count":103,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2022,12,23]],"date-time":"2022-12-23T00:00:00Z","timestamp":1671753600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"the National Institutes of Health (NIH)\/NIDDK","award":["DK112921"],"award-info":[{"award-number":["DK112921"]}]},{"name":"the National Institutes of Health (NIH)\/NIDDK","award":["DK020579"],"award-info":[{"award-number":["DK020579"]}]},{"name":"Manpei Suzuki Diabetes Foundation","award":["DK112921"],"award-info":[{"award-number":["DK112921"]}]},{"name":"Manpei Suzuki Diabetes Foundation","award":["DK020579"],"award-info":[{"award-number":["DK020579"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The endoplasmic reticulum (ER) is a cytosolic organelle that plays an essential role in the folding and processing of new secretory proteins, including insulin. The pathogenesis of diabetes, a group of metabolic disorders caused by dysfunctional insulin secretion (Type 1 diabetes, T1DM) or insulin sensitivity (Type 2 diabetes, T2DM), is known to involve the excess accumulation of \u201cpoorly folded proteins\u201d, namely, the induction of pathogenic ER stress in pancreatic \u03b2-cells. ER stress is known to contribute to the dysfunction of the insulin-producing pancreatic \u03b2-cells. T1DM and T2DM are multifactorial diseases, especially T2DM; both environmental and genetic factors are involved in their pathogenesis, making it difficult to create experimental disease models. In recent years, however, the development of induced pluripotent stem cells (iPSCs) and other regenerative technologies has greatly expanded research capabilities, leading to the development of new candidate therapies. In this review, we will discuss the mechanism by which dysregulated ER stress responses contribute to T2DM pathogenesis. Moreover, we describe new treatment methods targeting protein folding and ER stress pathways with a particular focus on pivotal studies of Wolfram syndrome, a monogenic form of syndromic diabetes caused by pathogenic variants in the WFS1 gene, which also leads to ER dysfunction.<\/jats:p>","DOI":"10.3390\/ijms24010230","type":"journal-article","created":{"date-parts":[[2022,12,23]],"date-time":"2022-12-23T02:36:46Z","timestamp":1671763006000},"page":"230","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["The Role of ER Stress in Diabetes: Exploring Pathological Mechanisms Using Wolfram Syndrome"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5547-9491","authenticated-orcid":false,"given":"Shuntaro","family":"Morikawa","sequence":"first","affiliation":[{"name":"Department of Medicine, Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, St. Louis, MO 63110, USA"},{"name":"Department of Pediatrics, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9944-6293","authenticated-orcid":false,"given":"Fumihiko","family":"Urano","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, St. Louis, MO 63110, USA"},{"name":"Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,12,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"758","DOI":"10.1210\/en.2013-1519","article-title":"Calcium efflux from the endoplasmic reticulum leads to beta-cell death","volume":"155","author":"Hara","year":"2014","journal-title":"Endocrinology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"944","DOI":"10.1126\/science.1146361","article-title":"IRE1 signaling affects cell fate during the unfolded protein response","volume":"318","author":"Lin","year":"2007","journal-title":"Science"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"562","DOI":"10.1016\/j.cell.2009.07.017","article-title":"RE1alpha kinase activation modes control alternate endoribonuclease outputs to determine divergent cell fates","volume":"138","author":"Han","year":"2009","journal-title":"Cell"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"18773","DOI":"10.1073\/pnas.0509487102","article-title":"On the mechanism of sensing unfolded protein in the endoplasmic reticulum","volume":"102","author":"Credle","year":"2005","journal-title":"Proc. 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