{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T23:17:24Z","timestamp":1790983044696,"version":"4.1.0"},"reference-count":51,"publisher":"American Diabetes Association","issue":"1","license":[{"start":{"date-parts":[[2021,8,27]],"date-time":"2021-08-27T00:00:00Z","timestamp":1630022400000},"content-version":"vor","delay-in-days":3957,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/3.0\/"}],"content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2011,1,1]]},"abstract":"<jats:sec>\n                  <jats:title>OBJECTIVE<\/jats:title>\n                  <jats:p>The islet in type 2 diabetes is characterized by \u03b2-cell apoptosis, \u03b2-cell endoplasmic reticulum stress, and islet amyloid deposits derived from islet amyloid polypeptide (IAPP). Toxic oligomers of IAPP form intracellularly in \u03b2-cells in humans with type 2 diabetes, suggesting impaired clearance of misfolded proteins. In this study, we investigated whether human-IAPP (h-IAPP) disrupts the endoplasmic reticulum\u2013associated degradation\/ubiquitin\/proteasome system.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>RESEARCH DESIGN AND METHODS<\/jats:title>\n                  <jats:p>We used pancreatic tissue from humans with and without type 2 diabetes, isolated islets from h-IAPP transgenic rats, isolated human islets, and INS 832\/13 cells transduced with adenoviruses expressing either h-IAPP or a comparable expression of rodent-IAPP. Immunofluorescence and Western blotting were used to detect polyubiquitinated proteins and ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1) protein levels. Proteasome activity was measured in isolated rat and human islets. UCH-L1 was knocked down by small-interfering RNA in INS 832\/13 cells and apoptosis was evaluated.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>RESULTS<\/jats:title>\n                  <jats:p>We report accumulation of polyubiquinated proteins and UCH-L1 deficiency in \u03b2-cells of humans with type 2 diabetes. These findings were reproduced by expression of oligomeric h-IAPP but not soluble rat-IAPP. Downregulation of UCH-L1 expression and activity to reproduce that caused by h-IAPP in \u03b2-cells induced endoplasmic reticulum stress leading to apoptosis.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>CONCLUSIONS<\/jats:title>\n                  <jats:p>Our results indicate that defective protein degradation in \u03b2-cells in type 2 diabetes can, at least in part, be attributed to misfolded h-IAPP leading to UCH-L1 deficiency, which in turn further compromises \u03b2-cell viability.<\/jats:p>\n               <\/jats:sec>","DOI":"10.2337\/db10-0522","type":"journal-article","created":{"date-parts":[[2010,10,28]],"date-time":"2010-10-28T03:10:42Z","timestamp":1288235442000},"page":"227-238","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":120,"title":["\u03b2-Cell Dysfunctional ERAD\/Ubiquitin\/Proteasome System in Type 2 Diabetes Mediated by Islet Amyloid Polypeptide\u2013Induced UCH-L1 Deficiency"],"prefix":"10.2337","volume":"60","author":[{"given":"Safia","family":"Costes","sequence":"first","affiliation":[{"name":"1Larry Hillblom Islet Research Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chang-jiang","family":"Huang","sequence":"additional","affiliation":[{"name":"1Larry Hillblom Islet Research Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatyana","family":"Gurlo","sequence":"additional","affiliation":[{"name":"1Larry Hillblom Islet Research Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie","family":"Daval","sequence":"additional","affiliation":[{"name":"1Larry Hillblom Islet Research Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aleksey V.","family":"Matveyenko","sequence":"additional","affiliation":[{"name":"1Larry Hillblom Islet Research Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert A.","family":"Rizza","sequence":"additional","affiliation":[{"name":"2Endocrine Research Unit, Mayo Clinic and Medical College, Rochester, Minnesota."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra E.","family":"Butler","sequence":"additional","affiliation":[{"name":"1Larry Hillblom Islet Research Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter 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