{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T13:20:54Z","timestamp":1791811254816,"version":"4.3.4"},"reference-count":43,"publisher":"American Diabetes Association","issue":"8","content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2007,8,1]]},"abstract":"<jats:p>OBJECTIVE\u2014Endoplasmic reticulum (ER) stress\u2013induced apoptosis may be a common cause of cell attrition in diseases characterized by misfolding and oligomerisation of amyloidogenic proteins. The islet in type 2 diabetes is characterized by islet amyloid derived from islet amyloid polypeptide (IAPP) and increased \u03b2-cell apoptosis. We questioned the following: 1) whether IAPP-induced \u03b2-cell apoptosis is mediated by ER stress and 2) whether \u03b2-cells in type 2 diabetes are characterized by ER stress.<\/jats:p>\n               <jats:p>RESEARCH DESIGN AND METHODS\u2014The mechanism of IAPP-induced apoptosis was investigated in INS-1 cells and human IAPP (HIP) transgenic rats. ER stress in humans was investigated by \u03b2-cell C\/EBP homologous protein (CHOP) expression in 7 lean nondiabetic, 12 obese nondiabetic, and 14 obese type 2 diabetic human pancreata obtained at autopsy. To assure specificity for type 2 diabetes, we also examined pancreata from eight cases of type 1 diabetes.<\/jats:p>\n               <jats:p>RESULTS\u2014IAPP induces \u03b2-cell apoptosis by ER stress in INS-1 cells and HIP rats. Perinuclear CHOP was rare in lean nondiabetic (2.6 \u00b1 2.0%) and more frequent in obese nondiabetic (14.6 \u00b1 3.0%) and obese diabetic (18.5 \u00b1 3.6%) pancreata. Nuclear CHOP was not detected in lean nondiabetic and rare in obese nondiabetic (0.08 \u00b1 0.04%) but six times higher (P &amp;lt; 0.01) in obese diabetic (0.49 \u00b1 0.17%) pancreata. In type 1 diabetic pancreata, perinuclear CHOP was rare (2.5 \u00b1 2.3%) and nuclear CHOP not detected.<\/jats:p>\n               <jats:p>CONCLUSIONS\u2014ER stress is a mechanism by which IAPP induces \u03b2-cell apoptosis and is characteristic of \u03b2-cells in humans with type 2 diabetes but not type 1 diabetes. These findings are consistent with a role of protein misfolding in \u03b2-cell apoptosis in type 2 diabetes.<\/jats:p>","DOI":"10.2337\/db07-0197","type":"journal-article","created":{"date-parts":[[2007,7,27]],"date-time":"2007-07-27T17:34:04Z","timestamp":1185557644000},"page":"2016-2027","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":380,"title":["High Expression Rates of Human Islet Amyloid Polypeptide Induce Endoplasmic Reticulum Stress\u2013Mediated \u03b2-Cell Apoptosis, a Characteristic of Humans With Type 2 but Not Type 1 Diabetes"],"prefix":"10.2337","volume":"56","author":[{"given":"Chang-jiang","family":"Huang","sequence":"first","affiliation":[{"name":"Larry Hillblom Islet Research Center, University of California, Los Angeles, Los Angeles, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chia-yu","family":"Lin","sequence":"additional","affiliation":[{"name":"Larry Hillblom Islet Research Center, University of California, Los Angeles, Los Angeles, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leena","family":"Haataja","sequence":"additional","affiliation":[{"name":"Larry Hillblom Islet Research Center, University of California, Los Angeles, Los Angeles, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatyana","family":"Gurlo","sequence":"additional","affiliation":[{"name":"Larry Hillblom Islet Research Center, University of California, Los Angeles, Los Angeles, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra E.","family":"Butler","sequence":"additional","affiliation":[{"name":"Larry Hillblom Islet Research Center, University of California, Los Angeles, Los Angeles, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert A.","family":"Rizza","sequence":"additional","affiliation":[{"name":"Endocrine Research Unit, Mayo Medical College, Rochester, Minnesota"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter C.","family":"Butler","sequence":"additional","affiliation":[{"name":"Larry Hillblom Islet Research Center, University of California, Los Angeles, Los Angeles, California"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1167","reference":[{"key":"2022031208485651500_R1","doi-asserted-by":"crossref","unstructured":"Meier JJ, Bhushan A, Butler AE, Rizza RA, Butler PC: Sustained beta cell apoptosis in patients with long-standing type 1 diabetes: indirect evidence for islet regeneration?Diabetologia\u200848:2221\u20132228,2005","DOI":"10.1007\/s00125-005-1949-2"},{"key":"2022031208485651500_R2","doi-asserted-by":"crossref","unstructured":"Kloppel G, Lohr M, Habich K, Oberholzer M, Heitz PU: Islet pathology and the pathogenesis of type 1 and type 2 diabetes mellitus revisited. Surv Synth Pathol Res\u20084:110\u2013125,1985","DOI":"10.1159\/000156969"},{"key":"2022031208485651500_R3","doi-asserted-by":"crossref","unstructured":"Ritzel RA, Butler PC: Replication increases \u03b2-cell vulnerability to human islet amyloid polypeptide\u2013induced apoptosis. Diabetes\u200852:1701\u20131708,2003","DOI":"10.2337\/diabetes.52.7.1701"},{"key":"2022031208485651500_R4","doi-asserted-by":"crossref","unstructured":"Marchetti P, Del Guerra S, Marselli L, Lupi R, Masini M, Pollera M, Bugliani M, Boggi U, Vistoli F, Mosca F, Del Prato S: Pancreatic islets from type 2 diabetic patients have functional defects and increased apoptosis that are ameliorated by metformin. J Clin Endocrinol Metab\u200889:5535\u20135541,2004","DOI":"10.1210\/jc.2004-0150"},{"key":"2022031208485651500_R5","doi-asserted-by":"crossref","unstructured":"Atkinson MA, Eisenbarth GS: Type 1 diabetes: new perspectives on disease pathogenesis and treatment. Lancet\u2008358:221\u2013229,2001","DOI":"10.1016\/S0140-6736(01)05415-0"},{"key":"2022031208485651500_R6","doi-asserted-by":"crossref","unstructured":"Meier JJ, Lin JC, Butler AE, Galasso R, Martinez DS, Butler PC: Direct evidence of attempted beta cell regeneration in an 89-year-old patient with recent-onset type 1 diabetes. Diabetologia\u200849:1838\u20131844,2006","DOI":"10.1007\/s00125-006-0308-2"},{"key":"2022031208485651500_R7","doi-asserted-by":"crossref","unstructured":"Robertson RP: Chronic oxidative stress as a central mechanism for glucose toxicity in pancreatic islet beta cells in diabetes. J Biol Chem\u2008279:42351\u201342354,2004","DOI":"10.1074\/jbc.R400019200"},{"key":"2022031208485651500_R8","doi-asserted-by":"crossref","unstructured":"Lupi R, Dotta F, Marselli L, Del Guerra S, Masini M, Santangelo C, Patane G, Boggi U, Piro S, Anello M, Bergamini E, Mosca F, Di Mario U, Del Prato S, Marchetti P: Prolonged exposure to free fatty acids has cytostatic and pro-apoptotic effects on human pancreatic islets: evidence that \u03b2-cell death is caspase mediated, partially dependent on ceramide pathway, and Bcl-2 regulated. Diabetes\u200851:1437\u20131442,2002","DOI":"10.2337\/diabetes.51.5.1437"},{"key":"2022031208485651500_R9","doi-asserted-by":"crossref","unstructured":"Maedler K, Sergeev P, Ris F, Oberholzer J, Joller-Jemelka HI, Spinas GA, Kaiser N, Halban PA, Donath MY: Glucose-induced beta cell production of IL-1beta contributes to glucotoxicity in human pancreatic islets. J Clin Invest\u2008110:851\u2013860,2002","DOI":"10.1172\/JCI200215318"},{"key":"2022031208485651500_R10","doi-asserted-by":"crossref","unstructured":"Janson J, Ashley RH, Harrison D, McIntyre S, Butler PC: The mechanism of islet amyloid polypeptide toxicity is membrane disruption by intermediate-sized toxic amyloid particles. Diabetes\u200848:491\u2013498,1999","DOI":"10.2337\/diabetes.48.3.491"},{"key":"2022031208485651500_R11","doi-asserted-by":"crossref","unstructured":"Butler AE, Janson J, Soeller WC, Butler PC: Increased \u03b2-cell apoptosis prevents adaptive increase in \u03b2-cell mass in mouse model of type 2 diabetes: evidence for role of islet amyloid formation rather than direct action of amyloid. Diabetes\u200852:2304\u20132314,2003","DOI":"10.2337\/diabetes.52.9.2304"},{"key":"2022031208485651500_R12","doi-asserted-by":"crossref","unstructured":"Butler AE, Jang J, Gurlo T, Carty MD, Soeller WC, Butler PC: Diabetes due to a progressive defect in \u03b2-cell mass in rats transgenic for human islet amyloid polypeptide (HIP rat): a new model for type 2 diabetes. Diabetes\u200853:1509\u20131516,2004","DOI":"10.2337\/diabetes.53.6.1509"},{"key":"2022031208485651500_R13","doi-asserted-by":"crossref","unstructured":"Boyce M, Degterev A, Yuan J: Caspases: an ancient cellular sword of Damocles. Cell Death Differ\u200811:29\u201337,2004","DOI":"10.1038\/sj.cdd.4401339"},{"key":"2022031208485651500_R14","doi-asserted-by":"crossref","unstructured":"Li F, Ambrosini G, Chu EY, Plescia J, Tognin S, Marchisio PC, Altieri DC: Control of apoptosis and mitotic spindle checkpoint by survivin. Nature\u2008396:580\u2013584,1998","DOI":"10.1038\/25141"},{"key":"2022031208485651500_R15","doi-asserted-by":"crossref","unstructured":"Schroder M, Kaufman RJ: ER stress and the unfolded protein response. Mutat Res\u2008569:29\u201363,2005","DOI":"10.1016\/j.mrfmmm.2004.06.056"},{"key":"2022031208485651500_R16","doi-asserted-by":"crossref","unstructured":"Ferri KF, Kroemer G: Organelle-specific initiation of cell death pathways. Nat Cell Biol\u20083:E255\u2013E263,2001","DOI":"10.1038\/ncb1101-e255"},{"key":"2022031208485651500_R17","doi-asserted-by":"crossref","unstructured":"Wajant H: The Fas signaling pathway: more than a paradigm. Science\u2008296:1635\u20131636,2002","DOI":"10.1126\/science.1071553"},{"key":"2022031208485651500_R18","doi-asserted-by":"crossref","unstructured":"Andersen JK: Oxidative stress in neurodegeneration: cause or consequence?Nat Med\u200810:S18\u2013S25,2004","DOI":"10.1038\/nrn1434"},{"key":"2022031208485651500_R19","doi-asserted-by":"crossref","unstructured":"Lin CY, Gurlo T, Kayed R, Butler AE, Haataja L, Glabe CG, Butler PC: Toxic human islet amyloid polypeptide (h-IAPP) oligomers are intracellular, and vaccination to induce anti-toxic oligomer antibodies does not prevent h-IAPP-induced \u03b2-cell apoptosis in h-IAPP transgenic mice. Diabetes\u200856:1324\u20131332,2007","DOI":"10.2337\/db06-1579"},{"key":"2022031208485651500_R20","doi-asserted-by":"crossref","unstructured":"Lindholm D, Wootz H, Korhonen L: ER stress and neurodegenerative diseases. Cell Death Differ\u200813:385\u2013392,2006","DOI":"10.1038\/sj.cdd.4401778"},{"key":"2022031208485651500_R21","doi-asserted-by":"crossref","unstructured":"Jayanthi S, Deng X, Noailles PA, Ladenheim B, Cadet JL: Methamphetamine induces neuronal apoptosis via cross-talks between endoplasmic reticulum and mitochondria-dependent death cascades. Faseb J\u200818:238\u2013251,2004","DOI":"10.1096\/fj.03-0295com"},{"key":"2022031208485651500_R22","doi-asserted-by":"crossref","unstructured":"Nakagawa T, Zhu H, Morishima N, Li E, Xu J, Yankner BA, Yuan J: Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-beta. Nature\u2008403:98\u2013103,2000","DOI":"10.1038\/47513"},{"key":"2022031208485651500_R23","doi-asserted-by":"crossref","unstructured":"Lamkanfi M, Kalai M, Vandenabeele P: Caspase-12: an overview. Cell Death Differ\u200811:365\u2013368,2004","DOI":"10.1038\/sj.cdd.4401364"},{"key":"2022031208485651500_R24","doi-asserted-by":"crossref","unstructured":"Fischer H, Koenig U, Eckhart L, Tschachler E: Human caspase 12 has acquired deleterious mutations. Biochem Biophys Res Commun\u2008293:722\u2013726,2002","DOI":"10.1016\/S0006-291X(02)00289-9"},{"key":"2022031208485651500_R25","doi-asserted-by":"crossref","unstructured":"Maytin EV, Ubeda M, Lin JC, Habener JF: Stress-inducible transcription factor CHOP\/gadd153 induces apoptosis in mammalian cells via p38 kinase-dependent and -independent mechanisms. Exp Cell Res\u2008267:193\u2013204,2001","DOI":"10.1006\/excr.2001.5248"},{"key":"2022031208485651500_R26","doi-asserted-by":"crossref","unstructured":"Harding HP, Ron D: Endoplasmic reticulum stress and the development of diabetes: a review. Diabetes\u200851 (Suppl. 3):S455\u2013S461,2002","DOI":"10.2337\/diabetes.51.2007.S455"},{"key":"2022031208485651500_R27","doi-asserted-by":"crossref","unstructured":"Oyadomari S, Mori M: Roles of CHOP\/GADD153 in endoplasmic reticulum stress. Cell Death Differ\u200811:381\u2013389,2004","DOI":"10.1038\/sj.cdd.4401373"},{"key":"2022031208485651500_R28","doi-asserted-by":"crossref","unstructured":"Ma Y, Hendershot LM: The role of the unfolded protein response in tumour development: friend or foe?Nat Rev Cancer\u20084:966\u2013977,2004","DOI":"10.1038\/nrc1505"},{"key":"2022031208485651500_R29","doi-asserted-by":"crossref","unstructured":"Zhang K, Kaufman RJ: Signaling the unfolded protein response from the endoplasmic reticulum. J Biol Chem\u2008279:25935\u201325938,2004","DOI":"10.1074\/jbc.R400008200"},{"key":"2022031208485651500_R30","doi-asserted-by":"crossref","unstructured":"Harding HP, Zeng H, Zhang Y, Jungries R, Chung P, Plesken H, Sabatini DD, Ron D: Diabetes mellitus and exocrine pancreatic dysfunction in perk-\/- mice reveals a role for translational control in secretory cell survival. Mol Cell\u20087:1153\u20131163,2001","DOI":"10.1016\/S1097-2765(01)00264-7"},{"key":"2022031208485651500_R31","doi-asserted-by":"crossref","unstructured":"Zuber C, Fan JY, Guhl B, Roth J: Misfolded proinsulin accumulates in expanded pre-Golgi intermediates and endoplasmic reticulum subdomains in pancreatic beta cells of Akita mice. Faseb J\u200818:917\u2013919,2004","DOI":"10.1096\/fj.03-1210fje"},{"key":"2022031208485651500_R32","doi-asserted-by":"crossref","unstructured":"Laybutt DR, Preston AM, Akerfeldt MC, Kench JG, Busch AK, Biankin AV, Biden TJ: Endoplasmic reticulum stress contributes to beta cell apoptosis in type 2 diabetes. Diabetologia\u200850:752\u2013763,2007","DOI":"10.1007\/s00125-006-0590-z"},{"key":"2022031208485651500_R33","doi-asserted-by":"crossref","unstructured":"Grill V, Bjorklund A: Overstimulation and \u03b2-cell function. Diabetes\u200850 (Suppl. 1):S122\u2013S124,2001","DOI":"10.2337\/diabetes.50.2007.S122"},{"key":"2022031208485651500_R34","doi-asserted-by":"crossref","unstructured":"Zhang K, Shen X, Wu J, Sakaki K, Saunders T, Rutkowski DT, Back SH, Kaufman RJ: Endoplasmic reticulum stress activates cleavage of CREBH to induce a systemic inflammatory response. Cell\u2008124:587\u2013599,2006","DOI":"10.1016\/j.cell.2005.11.040"},{"key":"2022031208485651500_R35","doi-asserted-by":"crossref","unstructured":"Blaber SI, Ciric B, Christophi GP, Bernett MJ, Blaber M, Rodriguez M, Scarisbrick IA: Targeting kallikrein 6 proteolysis attenuates CNS inflammatory disease. Faseb J\u200818:920\u2013922,2004","DOI":"10.1096\/fj.03-1212fje"},{"key":"2022031208485651500_R36","doi-asserted-by":"crossref","unstructured":"Khajavi M, Inoue K, Wiszniewski W, Ohyama T, Snipes GJ, Lupski JR: Curcumin treatment abrogates endoplasmic reticulum retention and aggregation-induced apoptosis associated with neuropathy-causing myelin protein zero-truncating mutants. Am J Hum Genet\u200877:841\u2013850,2005","DOI":"10.1086\/497541"},{"key":"2022031208485651500_R37","doi-asserted-by":"crossref","unstructured":"Janson J, Soeller WC, Roche PC, Nelson RT, Torchia AJ, Kreutter DK, Butler PC: Spontaneous diabetes mellitus in transgenic mice expressing human islet amyloid polypeptide. Proc Natl Acad Sci U S A\u200893:7283\u20137288,1996","DOI":"10.1073\/pnas.93.14.7283"},{"key":"2022031208485651500_R38","doi-asserted-by":"crossref","unstructured":"Sakagashira S, Hiddinga HJ, Tateishi K, Sanke T, Hanabusa T, Nanjo K, Eberhardt NL: S20G mutant amylin exhibits increased in vitro amyloidogenicity and increased intracellular cytotoxicity compared to wild-type amylin. Am J Pathol\u2008157:2101\u20132109,2000","DOI":"10.1016\/S0002-9440(10)64848-1"},{"key":"2022031208485651500_R39","doi-asserted-by":"crossref","unstructured":"Sakagashira S, Sanke T, Hanabusa T, Shimomura H, Ohagi S, Kumagaye KY, Nakajima K, Nanjo K: Missense mutation of amylin gene (S20G) in Japanese NIDDM patients. Diabetes\u200845:1279\u20131281,1996","DOI":"10.2337\/diab.45.9.1279"},{"key":"2022031208485651500_R40","doi-asserted-by":"crossref","unstructured":"Wang R, Dineley KT, Sweatt JD, Zheng H: Presenilin 1 familial Alzheimer's disease mutation leads to defective associative learning and impaired adult neurogenesis. Neuroscience\u2008126:305\u2013312,2004","DOI":"10.1016\/j.neuroscience.2004.03.048"},{"key":"2022031208485651500_R41","doi-asserted-by":"crossref","unstructured":"Nishi M, Bell GI, Steiner DF: Islet amyloid polypeptide (amylin): no evidence of an abnormal precursor sequence in 25 type 2 (non-insulin-dependent) diabetic patients. Diabetologia\u200833:628\u2013630,1990","DOI":"10.1007\/BF00400208"},{"key":"2022031208485651500_R42","doi-asserted-by":"crossref","unstructured":"Blomqvist ME, Reynolds C, Katzov H, Feuk L, Andreasen N, Bogdanovic N, Blennow K, Brookes AJ, Prince JA: Towards compendia of negative genetic association studies: an example for Alzheimer disease. Hum Genet1\u20139,2005","DOI":"10.1007\/s00439-005-0078-9"},{"key":"2022031208485651500_R43","doi-asserted-by":"crossref","unstructured":"Hitomi J, Katayama T, Eguchi Y, Kudo T, Taniguchi M, Koyama Y, Manabe T, Yamagishi S, Bando Y, Imaizumi K, Tsujimoto Y, Tohyama M: Involvement of caspase-4 in endoplasmic reticulum stress-induced apoptosis and Abeta-induced cell death. J Cell Biol\u2008165:347\u2013356,2004","DOI":"10.1083\/jcb.200310015"}],"container-title":["Diabetes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.org\/diabetes\/diabetes\/article-pdf\/56\/8\/2016\/389183\/zdb00807002016.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article-pdf\/56\/8\/2016\/389183\/zdb00807002016.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,11,2]],"date-time":"2022-11-02T16:11:18Z","timestamp":1667405478000},"score":1,"resource":{"primary":{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article\/56\/8\/2016\/14419\/High-Expression-Rates-of-Human-Islet-Amyloid"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2007,8,1]]},"references-count":43,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2007,8,1]]}},"URL":"https:\/\/doi.org\/10.2337\/db07-0197","relation":{},"ISSN":["0012-1797","1939-327X"],"issn-type":[{"value":"0012-1797","type":"print"},{"value":"1939-327X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2007,8,1]]}}}