{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,16]],"date-time":"2026-04-16T10:43:21Z","timestamp":1776336201163,"version":"3.51.2"},"reference-count":40,"publisher":"The Endocrine Society","issue":"4","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2016,4,1]]},"abstract":"<jats:p>The islet in type 2 diabetes is characterized by \u03b2-cell loss, increased \u03b2-cell apoptosis, and islet amyloid derived from islet amyloid polypeptide (IAPP). When protein misfolding protective mechanisms are overcome, human IAPP (h-IAPP) forms membrane permeant toxic oligomers that induce \u03b2-cell dysfunction and apoptosis. In humans with type 2 diabetes (T2D) and mice transgenic for h-IAPP, endoplasmic reticulum (ER) stress has been inferred from nuclear translocation of CCAAT\/enhancer-binding protein homologous protein (CHOP), an established mediator of ER stress. To establish whether h-IAPP toxicity is mediated by ER stress, we evaluated diabetes onset and \u03b2-cell mass in h-IAPP transgenic (h-TG) mice with and without deletion of CHOP in comparison with wild-type controls. Diabetes was delayed in h-TG CHOP\u2212\/\u2212 mice, with relatively preserved \u03b2-cell mass and decreased \u03b2-cell apoptosis. Deletion of CHOP attenuates dysfunction of the autophagy\/lysosomal pathway in \u03b2-cells of h-TG mice, uncovering a role for CHOP in mediating h-IAPP-induced dysfunction of autophagy. As deletion of CHOP delayed but did not prevent h-IAPP-induced \u03b2-cell loss and diabetes, we examined CHOP-independent stress pathways. JNK, a target of the IRE-1pTRAF2 complex, and the Bcl-2 family proapoptotic mediator BIM, a target of ATF4, were comparably activated by h-IAPP expression in the presence and absence of CHOP. Therefore, although these studies affirm that CHOP is a mediator of h-IAPP-induced ER stress, it is not the only one. Therefore, suppression of CHOP alone is unlikely to be a durable therapeutic strategy to protect against h-IAPP toxicity because multiple stress pathways are activated.<\/jats:p>","DOI":"10.1210\/me.2015-1255","type":"journal-article","created":{"date-parts":[[2016,2,22]],"date-time":"2016-02-22T18:00:17Z","timestamp":1456164017000},"page":"446-454","source":"Crossref","is-referenced-by-count":37,"title":["CHOP Contributes to, But Is Not the Only Mediator of, IAPP Induced \u03b2-Cell Apoptosis"],"prefix":"10.1210","volume":"30","author":[{"given":"T.","family":"Gurlo","sequence":"first","affiliation":[{"name":"Larry L. Hillblom Islet Research Center, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, California 90095-7073"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J. F.","family":"Rivera","sequence":"additional","affiliation":[{"name":"Larry L. 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