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type=\u0022text\/css\u0022 rel=\u0022stylesheet\u0022 href=\u0022\/\/d282kpwvnogo5m.cloudfront.net\/sites\/default\/files\/cdn\/css\/http\/css_Xg7z6oCTVgud_Q0huYz9x9iiD5H_2YPSJ5z2ZViSWdY.css\u0022 media=\u0022all\u0022 \/\u003E\n\u003Clink rel=\u0027stylesheet\u0027 type=\u0027text\/css\u0027 href=\u0027\/sites\/all\/modules\/contrib\/panels\/plugins\/layouts\/onecol\/onecol.css\u0027 \/\u003E\u003C\/head\u003E\u003Cbody\u003E\u003Cdiv class=\u0022panels-ajax-tab-panel panels-ajax-tab-panel-sageoa-tab-art\u0022\u003E\u003Cdiv class=\u0022panel-display panel-1col clearfix\u0022 \u003E\n  \u003Cdiv class=\u0022panel-panel panel-col\u0022\u003E\n    \u003Cdiv\u003E\u003Cdiv class=\u0022panel-pane pane-highwire-markup\u0022 \u003E\n  \n      \n  \n  \u003Cdiv class=\u0022pane-content\u0022\u003E\n    \u003Cdiv class=\u0022highwire-markup\u0022\u003E\u003Cdiv xmlns=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022 id=\u0022content-block-markup\u0022 xmlns:xhtml=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022\u003E\u003Cdiv class=\u0022article fulltext-view \u0022\u003E\u003Cspan class=\u0022highwire-journal-article-marker-start\u0022\u003E\u003C\/span\u003E\u003Cdiv class=\u0022section abstract\u0022 id=\u0022abstract-1\u0022\u003E\u003Ch2\u003ESummary\u003C\/h2\u003E\n            \u003Cp id=\u0022p-1\u0022\u003EA growing consensus links the loss of beta-cell mass with the development of type 2 diabetes mellitus. This article demonstrates that endoplasmic reticulum stress, induced by high levels of saturated free fatty acids, triggers a response that leads to eventual beta-cell apoptosis. This observation suggests one or more new targets for the therapeutic maintenance of beta-cell populations.\u003C\/p\u003E\n         \u003C\/div\u003E\u003Cul class=\u0022kwd-group\u0022\u003E\u003Cli class=\u0022kwd\u0022\u003Eendocrinology\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003Eprevention \u0026amp; screening\u003C\/li\u003E\u003Cli class=\u0022kwd\u0022\u003Ediabetes mellitus\u003C\/li\u003E\u003C\/ul\u003E\u003Cdiv class=\u0022section\u0022 id=\u0022sec-1\u0022\u003E\n         \n         \u003Cp id=\u0022p-2\u0022\u003EA growing consensus links the loss of beta-cell mass with the development of type 2 diabetes mellitus (T2DM). A lecture that was presented by D.L. Eizirik, MD, PhD, Laboratory of Experimental Medicine, Universit\u00e9 Libre de Bruxelles, Brussels, Belgium, demonstrates that endoplasmic reticulum (ER) stress, induced by high levels of saturated free fatty acids (FFAs), triggers a response that leads to eventual beta-cell apoptosis. This observation suggests one or more new targets for the therapeutic maintenance of beta-cell populations.\u003C\/p\u003E\n         \u003Cp id=\u0022p-3\u0022\u003ERecent evidence suggests that the ER stress response plays a role in the pathogenesis of diabetes through the induction of beta-cell apoptotic pathways. This stress occurs in the presence of unfolded or misfolded proteins in the lumen of the ER and triggers the unfolded protein response (UPR); the end result is an upregulation of molecular chaperones to aid in protein folding or, failing that, in the face of chronic stress, the initiation of programmed cell death, or apoptosis (Eizirik et al. \u003Cem\u003EEndocrine Reviews\u003C\/em\u003E 2008).\u003C\/p\u003E\n         \u003Cp id=\u0022p-4\u0022\u003ESaturated free fatty acids are candidate inducers of ER stress in T2DM. An investigation by Cunha et al. in Eizirik\u0027s laboratory (\u003Cem\u003EJ Cell Sci\u003C\/em\u003E 2008) exposed INS-1E (insulinoma) cells, FACS-purified rat primary beta-cells, and human islets to the unsaturated fat oleate and the saturated fat palmitate. Results showed a differential ER response based on fat saturation.\u003C\/p\u003E\n         \u003Cp id=\u0022p-5\u0022\u003EPalmitate induced the signaling of the pathways of 3 ER membrane-bound proteins, IRE1, and ATF6 \u2013 which probably are pro-cell survival in this case \u2013 but signals through the membrane-bound protein PERK as well, which can trigger apoptosis through the proapoptotic elF2alpha\/ATF4\/CHOP signaling cascade (\u003Ca id=\u0022xref-fig-1-1\u0022 class=\u0022xref-fig\u0022 href=\u0022#F1\u0022\u003EFigure 1\u003C\/a\u003E). This observation was verified through the use of the reagent salubrinal, a phosphatase inhibitor that is known to render the gatekeeper elF2alpha constitutively active. In the presence of oleate, salubrinal elicited the same UPR expression profile and cell death in INS-1E cells and FACS-purified rat primary beta-cells as those seen with exposure to the saturated fatty acid palmitate (Cnop et al. \u003Cem\u003EJournal of Biological Chem\u003C\/em\u003E 2007). These results were replicated in human islet cell preparations (Ladriere, Eizirik, and Cnop. Unpublished data).\u003C\/p\u003E\n         \u003Cdiv id=\u0022F1\u0022 class=\u0022fig pos-float  odd\u0022\u003E\u003Cdiv class=\u0022highwire-figure\u0022\u003E\u003Cdiv class=\u0022fig-inline-img-wrapper\u0022\u003E\u003Cdiv class=\u0022fig-inline-img\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/8\/7\/29\/F1.large.jpg?width=800\u0026amp;height=600\u0026amp;carousel=1\u0022 title=\u0022ER Stress Signaling Cascade.\u0022 class=\u0022fragment-images colorbox-load\u0022 rel=\u0022gallery-fragment-images-1729426096\u0022 data-figure-caption=\u0022ER Stress Signaling Cascade.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003E\u003Cimg class=\u0022fragment-image\u0022 alt=\u0022Figure 1.\u0022 src=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/8\/7\/29\/F1.medium.gif\u0022\/\u003E\u003C\/a\u003E\u003C\/div\u003E\u003C\/div\u003E\u003Cul class=\u0022highwire-figure-links inline\u0022\u003E\u003Cli class=\u00220 first\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/8\/7\/29\/F1.large.jpg?download=true\u0022 class=\u0022highwire-figure-link highwire-figure-link-download\u0022 title=\u0022Download Figure 1.\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload figure\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00221\u0022\u003E\u003Ca href=\u0022http:\/\/d282kpwvnogo5m.cloudfront.net\/content\/spmdc\/8\/7\/29\/F1.large.jpg\u0022 class=\u0022highwire-figure-link highwire-figure-link-newtab\u0022 target=\u0022_blank\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EOpen in new tab\u003C\/a\u003E\u003C\/li\u003E\u003Cli class=\u00222 last\u0022\u003E\u003Ca href=\u0022\/highwire\/powerpoint\/11284\u0022 class=\u0022highwire-figure-link highwire-figure-link-ppt\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EDownload powerpoint\u003C\/a\u003E\u003C\/li\u003E\u003C\/ul\u003E\u003C\/div\u003E\u003Cdiv class=\u0022fig-caption\u0022 xmlns:xhtml=\u0022http:\/\/www.w3.org\/1999\/xhtml\u0022\u003E\u003Cspan class=\u0022fig-label\u0022\u003EFigure 1.\u003C\/span\u003E \n               \u003Cp id=\u0022p-6\u0022 class=\u0022first-child\u0022\u003EER Stress Signaling Cascade.\u003C\/p\u003E\n            \u003Cdiv class=\u0022sb-div caption-clear\u0022\u003E\u003C\/div\u003E\u003C\/div\u003E\u003C\/div\u003E\n         \u003Cp id=\u0022p-7\u0022\u003EPalmitate also induces IRE1 signaling, promoting cell survival through downstream chaperone activation or, alternately, tipping the scales toward apoptosis through activation of Jun kinase (JNK). This association was shown using JNK inhibitors. In vitro work also was able to verify the palmitate\/UPR\/CHOP association by knocking down palmitate-induced expression with the use of CHOP siRNA and thus partially protecting beta-cells against palmitate-induced apoptosis (Cunha et al. \u003Cem\u003EJ Cell Sci\u003C\/em\u003E 2008).\u003C\/p\u003E\n         \u003Cp id=\u0022p-8\u0022\u003EConversely, IRE1 signaling that promotes cell survival through the production of chaperones (eg, BiP) was validated through the use of BiP overexpression to rescue an insulin-secreting cell line from lipid-induced apoptosis (Laybutt et al. \u003Cem\u003EDiabetologia\u003C\/em\u003E 2007).\u003C\/p\u003E\n         \u003Cp id=\u0022p-9\u0022\u003EA final association is to be made between ER stress and the dysfunction and loss of beta-cells, as seen in diabetes. Studies have shown that in the islets of db\/db (diabetic) mice, numerous ER stress factors were unregulated \u2013 this also is true of human islet preparations (Laybutt et al. \u003Cem\u003EDiabetologia\u003C\/em\u003E 2007). More to the point, both the proapoptotic CHOP expression and the ER area were increased in islets from patients with T2DM (Huang et al. \u003Cem\u003EDiabetes\u003C\/em\u003E 2007; Marchetti et al \u003Cem\u003EDiabetologia\u003C\/em\u003E 2007). Interestingly, islets from obese patients also show some increase in cytosolic CHOP expression. This, and additional evidence, suggests that ER stress may be a common mediator of both beta-cell death and insulin resistance in T2DM (Eizirik et al. \u003Cem\u003EEndocrine Reviews\u003C\/em\u003E 2008).\u003C\/p\u003E\n      \u003C\/div\u003E\u003Cul class=\u0022copyright-statement\u0022\u003E\u003Cli class=\u0022fn\u0022 id=\u0022copyright-statement-1\u0022\u003E\u00a9 2008 MD Conference Express\u003C\/li\u003E\u003C\/ul\u003E\u003Cspan class=\u0022highwire-journal-article-marker-end\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Cspan id=\u0022related-urls\u0022\u003E\u003C\/span\u003E\u003C\/div\u003E\u003Ca href=\u0022http:\/\/mdc.sagepub.com\/content\/8\/7\/29.abstract\u0022 class=\u0022hw-link hw-link-article-abstract\u0022 data-icon-position=\u0022\u0022 data-hide-link-title=\u00220\u0022\u003EView Summary\u003C\/a\u003E\u003C\/div\u003E  \u003C\/div\u003E\n\n  \n  \u003C\/div\u003E\n\u003C\/div\u003E\n  \u003C\/div\u003E\n\u003C\/div\u003E\n\u003C\/div\u003E\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_figures.js?nzmci1\u0022\u003E\u003C\/script\u003E\n\u003Cscript type=\u0022text\/javascript\u0022 src=\u0022http:\/\/mdc.sagepub.com\/sites\/all\/modules\/highwire\/highwire\/plugins\/highwire_markup_process\/js\/highwire_openurl.js?nzmci1\u0022\u003E\u003C\/script\u003E\n\u003C\/body\u003E\u003C\/html\u003E"}