{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,3]],"date-time":"2026-08-03T10:53:14Z","timestamp":1785754394828,"version":"3.56.0"},"reference-count":60,"publisher":"Public Library of Science (PLoS)","issue":"2","license":[{"start":{"date-parts":[[2022,2,18]],"date-time":"2022-02-18T00:00:00Z","timestamp":1645142400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["NIHR01DK098584; NIHR56DK098584; NIHR01DK123163"],"award-info":[{"award-number":["NIHR01DK098584; NIHR56DK098584; NIHR01DK123163"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["T32 DK108742"],"award-info":[{"award-number":["T32 DK108742"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000062","name":"National Institute of Diabetes and Digestive and Kidney Diseases","doi-asserted-by":"publisher","award":["NIH-P30 DK020579"],"award-info":[{"award-number":["NIH-P30 DK020579"]}],"id":[{"id":"10.13039\/100000062","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Progressive loss of pancreatic \u03b2-cell functional mass and anti-diabetic drug responsivity are classic findings in diabetes, frequently attributed to compensatory insulin hypersecretion and \u03b2-cell exhaustion. However, loss of \u03b2-cell mass and identity still occurs in mouse models of human K<jats:sub>ATP<\/jats:sub>-gain-of-function induced Neonatal Diabetes Mellitus (NDM), in the absence of insulin secretion. Here we studied the temporal progression and mechanisms underlying glucotoxicity-induced loss of functional \u03b2-cell mass in NDM mice, and the effects of sodium-glucose transporter 2 inhibitors (SGLT2i) therapy. Upon tamoxifen induction of transgene expression, NDM mice rapidly developed severe diabetes followed by an unexpected loss of insulin content, decreased proinsulin processing and increased proinsulin at 2-weeks of diabetes. These early events were accompanied by a marked increase in \u03b2-cell oxidative and ER stress, without changes in islet cell identity. Strikingly, treatment with the SGLT2 inhibitor dapagliflozin restored insulin content, decreased proinsulin:insulin ratio and reduced oxidative and ER stress. However, despite reduction of blood glucose, dapagliflozin therapy was ineffective in restoring \u03b2-cell function in NDM mice when it was initiated at &gt;40 days of diabetes, when loss of \u03b2-cell mass and identity had already occurred. Our data from mouse models demonstrate that: <jats:italic>i)<\/jats:italic> hyperglycemia <jats:italic>per se<\/jats:italic>, and not insulin hypersecretion, drives \u03b2-cell failure in diabetes, <jats:italic>ii)<\/jats:italic> recovery of \u03b2-cell function by SGLT2 inhibitors is potentially through reduction of oxidative and ER stress, <jats:italic>iii)<\/jats:italic> SGLT2 inhibitors revert\/prevent \u03b2-cell failure when used in early stages of diabetes, but not when loss of \u03b2-cell mass\/identity already occurred, <jats:italic>iv)<\/jats:italic> common execution pathways may underlie loss and recovery of \u03b2-cell function in different forms of diabetes. These results may have important clinical implications for optimal therapeutic interventions in individuals with diabetes, particularly for those with long-standing diabetes.<\/jats:p>","DOI":"10.1371\/journal.pone.0258054","type":"journal-article","created":{"date-parts":[[2022,2,18]],"date-time":"2022-02-18T18:29:29Z","timestamp":1645208969000},"page":"e0258054","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":28,"title":["SGLT2 inhibitors therapy protects glucotoxicity-induced \u03b2-cell failure in a mouse model of human KATP-induced diabetes through mitigation of oxidative and ER stress"],"prefix":"10.1371","volume":"17","author":[{"given":"Zeenat A.","family":"Shyr","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zihan","family":"Yan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro","family":"Ustione","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erin M.","family":"Egan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2048-472X","authenticated-orcid":true,"given":"Maria S.","family":"Remedi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2022,2,18]]},"reference":[{"issue":"Suppl 2","key":"pone.0258054.ref001","doi-asserted-by":"crossref","first-page":"S97","DOI":"10.2337\/diabetes.54.suppl_2.S97","article-title":"Mechanisms of pancreatic beta-cell death in type 1 and type 2 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