β-Cell Dysfunction Due to Increased ER Stress in a Stem Cell Model of Wolfram Syndrome
Wolfram syndrome is an autosomal recessive disorder caused by mutations in WFS1 and is characterized by insulin-dependent diabetes mellitus, optic atrophy, and deafness. To investigate the cause of β-cell failure, we used induced pluripotent stem cells to create insulin-producing cells from individu...
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Veröffentlicht in: | Diabetes (New York, N.Y.) N.Y.), 2014-03, Vol.63 (3), p.923-933 |
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creator | LINSHAN SHANG HAIQING HUA GOLAND, Robin LEIBEL, Rudolph L EGLI, Dieter FOO, Kylie MARTINEZ, Hector WATANABE, Kazuhisa ZIMMER, Matthew KAHLER, David J FREEBY, Matthew WENDY CHUNG LEDUC, Charles |
description | Wolfram syndrome is an autosomal recessive disorder caused by mutations in WFS1 and is characterized by insulin-dependent diabetes mellitus, optic atrophy, and deafness. To investigate the cause of β-cell failure, we used induced pluripotent stem cells to create insulin-producing cells from individuals with Wolfram syndrome. WFS1-deficient β-cells showed increased levels of endoplasmic reticulum (ER) stress molecules and decreased insulin content. Upon exposure to experimental ER stress, Wolfram β-cells showed impaired insulin processing and failed to increase insulin secretion in response to glucose and other secretagogues. Importantly, 4-phenyl butyric acid, a chemical protein folding and trafficking chaperone, restored normal insulin synthesis and the ability to upregulate insulin secretion. These studies show that ER stress plays a central role in β-cell failure in Wolfram syndrome and indicate that chemical chaperones might have therapeutic relevance under conditions of ER stress in Wolfram syndrome and other forms of diabetes. |
doi_str_mv | 10.2337/db13-0717 |
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To investigate the cause of β-cell failure, we used induced pluripotent stem cells to create insulin-producing cells from individuals with Wolfram syndrome. WFS1-deficient β-cells showed increased levels of endoplasmic reticulum (ER) stress molecules and decreased insulin content. Upon exposure to experimental ER stress, Wolfram β-cells showed impaired insulin processing and failed to increase insulin secretion in response to glucose and other secretagogues. Importantly, 4-phenyl butyric acid, a chemical protein folding and trafficking chaperone, restored normal insulin synthesis and the ability to upregulate insulin secretion. These studies show that ER stress plays a central role in β-cell failure in Wolfram syndrome and indicate that chemical chaperones might have therapeutic relevance under conditions of ER stress in Wolfram syndrome and other forms of diabetes.</description><identifier>ISSN: 0012-1797</identifier><identifier>EISSN: 1939-327X</identifier><identifier>DOI: 10.2337/db13-0717</identifier><identifier>PMID: 24227685</identifier><identifier>CODEN: DIAEAZ</identifier><language>eng</language><publisher>Alexandria, VA: American Diabetes Association</publisher><subject>Animals ; Biological and medical sciences ; Calcium - metabolism ; Cell Differentiation ; Cell research ; Cellular control mechanisms ; Complex syndromes ; Diabetes. Impaired glucose tolerance ; Ear diseases ; Endocrine pancreas. Apud cells (diseases) ; Endocrinopathies ; Endoplasmic Reticulum Stress ; Etiopathogenesis. Screening. Investigations. Target tissue resistance ; Humans ; Induced Pluripotent Stem Cells - cytology ; Insulin - biosynthesis ; Insulin - metabolism ; Insulin Secretion ; Insulin-Secreting Cells - physiology ; Medical genetics ; Medical sciences ; Membrane Proteins - genetics ; Metabolism ; Mice ; Pancreatic beta cells ; Phenylbutyrates - pharmacology ; Physiological aspects ; Wolfram Syndrome - genetics ; Wolfram Syndrome - pathology</subject><ispartof>Diabetes (New York, N.Y.), 2014-03, Vol.63 (3), p.923-933</ispartof><rights>2015 INIST-CNRS</rights><rights>COPYRIGHT 2014 American Diabetes Association</rights><rights>2014 by the American Diabetes Association. 2014</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c584t-b06eb766a48fb09335b87589a6b29a8bb1966a3fadf47ed1c4fd4a5ddc767b73</citedby><cites>FETCH-LOGICAL-c584t-b06eb766a48fb09335b87589a6b29a8bb1966a3fadf47ed1c4fd4a5ddc767b73</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3931392/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3931392/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,881,27903,27904,53769,53771</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=28402882$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24227685$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>LINSHAN SHANG</creatorcontrib><creatorcontrib>HAIQING HUA</creatorcontrib><creatorcontrib>GOLAND, Robin</creatorcontrib><creatorcontrib>LEIBEL, Rudolph L</creatorcontrib><creatorcontrib>EGLI, Dieter</creatorcontrib><creatorcontrib>FOO, Kylie</creatorcontrib><creatorcontrib>MARTINEZ, Hector</creatorcontrib><creatorcontrib>WATANABE, Kazuhisa</creatorcontrib><creatorcontrib>ZIMMER, Matthew</creatorcontrib><creatorcontrib>KAHLER, David J</creatorcontrib><creatorcontrib>FREEBY, Matthew</creatorcontrib><creatorcontrib>WENDY CHUNG</creatorcontrib><creatorcontrib>LEDUC, Charles</creatorcontrib><title>β-Cell Dysfunction Due to Increased ER Stress in a Stem Cell Model of Wolfram Syndrome</title><title>Diabetes (New York, N.Y.)</title><addtitle>Diabetes</addtitle><description>Wolfram syndrome is an autosomal recessive disorder caused by mutations in WFS1 and is characterized by insulin-dependent diabetes mellitus, optic atrophy, and deafness. To investigate the cause of β-cell failure, we used induced pluripotent stem cells to create insulin-producing cells from individuals with Wolfram syndrome. WFS1-deficient β-cells showed increased levels of endoplasmic reticulum (ER) stress molecules and decreased insulin content. Upon exposure to experimental ER stress, Wolfram β-cells showed impaired insulin processing and failed to increase insulin secretion in response to glucose and other secretagogues. Importantly, 4-phenyl butyric acid, a chemical protein folding and trafficking chaperone, restored normal insulin synthesis and the ability to upregulate insulin secretion. These studies show that ER stress plays a central role in β-cell failure in Wolfram syndrome and indicate that chemical chaperones might have therapeutic relevance under conditions of ER stress in Wolfram syndrome and other forms of diabetes.</description><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Calcium - metabolism</subject><subject>Cell Differentiation</subject><subject>Cell research</subject><subject>Cellular control mechanisms</subject><subject>Complex syndromes</subject><subject>Diabetes. Impaired glucose tolerance</subject><subject>Ear diseases</subject><subject>Endocrine pancreas. Apud cells (diseases)</subject><subject>Endocrinopathies</subject><subject>Endoplasmic Reticulum Stress</subject><subject>Etiopathogenesis. Screening. Investigations. Target tissue resistance</subject><subject>Humans</subject><subject>Induced Pluripotent Stem Cells - cytology</subject><subject>Insulin - biosynthesis</subject><subject>Insulin - metabolism</subject><subject>Insulin Secretion</subject><subject>Insulin-Secreting Cells - physiology</subject><subject>Medical genetics</subject><subject>Medical sciences</subject><subject>Membrane Proteins - genetics</subject><subject>Metabolism</subject><subject>Mice</subject><subject>Pancreatic beta cells</subject><subject>Phenylbutyrates - pharmacology</subject><subject>Physiological aspects</subject><subject>Wolfram Syndrome - genetics</subject><subject>Wolfram Syndrome - pathology</subject><issn>0012-1797</issn><issn>1939-327X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkt9qFDEUxgdR7LZ64QtIQIR6MTV_ZiaZG6Fsay2sCLZQ70L-nKyRmaSdzIj7Wj6Iz2TGrtWF5Vwk5PzOF_LlK4oXBJ9QxvhbqwkrMSf8UbEgLWtLRvmXx8UCY0JLwlt-UBym9A1j3OR6WhzQilLeiHpR3Pz6WS6h69DZJrkpmNHHgM4mQGNEl8EMoBJYdP4ZXY0DpIR8QCrvoUd_pj5GCx2KDt3Ezg2qR1ebYIfYw7PiiVNdgufb9ai4fn9-vfxQrj5dXC5PV6WpRTWWGjegedOoSjiNW8ZqLXgtWtVo2iqhNWlzkzllXcXBElM5W6naWsMbrjk7Kt7dy95OugdrIIyD6uTt4Hs1bGRUXu52gv8q1_G7ZC0jrKVZ4HgrMMS7CdIoe59MfpoKEKckSY0J45jxGX11j65VB9IHF7OimXF5ymZj26yXqXIPtYYA-foYwPl8vMOf7OFzWei92TvwZmcgMyP8GNdqSkmKi9Ve1gwxpQHcgzMEyzk6co6OnKOT2Zf_W_lA_s1KBl5vAZWMmr87GJ_-caLCVAjKfgPdFclL</recordid><startdate>20140301</startdate><enddate>20140301</enddate><creator>LINSHAN SHANG</creator><creator>HAIQING HUA</creator><creator>GOLAND, Robin</creator><creator>LEIBEL, Rudolph L</creator><creator>EGLI, Dieter</creator><creator>FOO, Kylie</creator><creator>MARTINEZ, Hector</creator><creator>WATANABE, Kazuhisa</creator><creator>ZIMMER, Matthew</creator><creator>KAHLER, David J</creator><creator>FREEBY, Matthew</creator><creator>WENDY CHUNG</creator><creator>LEDUC, Charles</creator><general>American Diabetes Association</general><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>8GL</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20140301</creationdate><title>β-Cell Dysfunction Due to Increased ER Stress in a Stem Cell Model of Wolfram Syndrome</title><author>LINSHAN SHANG ; HAIQING HUA ; GOLAND, Robin ; LEIBEL, Rudolph L ; EGLI, Dieter ; FOO, Kylie ; MARTINEZ, Hector ; WATANABE, Kazuhisa ; ZIMMER, Matthew ; KAHLER, David J ; FREEBY, Matthew ; WENDY CHUNG ; LEDUC, Charles</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c584t-b06eb766a48fb09335b87589a6b29a8bb1966a3fadf47ed1c4fd4a5ddc767b73</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Calcium - metabolism</topic><topic>Cell Differentiation</topic><topic>Cell research</topic><topic>Cellular control mechanisms</topic><topic>Complex syndromes</topic><topic>Diabetes. Impaired glucose tolerance</topic><topic>Ear diseases</topic><topic>Endocrine pancreas. Apud cells (diseases)</topic><topic>Endocrinopathies</topic><topic>Endoplasmic Reticulum Stress</topic><topic>Etiopathogenesis. Screening. Investigations. Target tissue resistance</topic><topic>Humans</topic><topic>Induced Pluripotent Stem Cells - cytology</topic><topic>Insulin - biosynthesis</topic><topic>Insulin - metabolism</topic><topic>Insulin Secretion</topic><topic>Insulin-Secreting Cells - physiology</topic><topic>Medical genetics</topic><topic>Medical sciences</topic><topic>Membrane Proteins - genetics</topic><topic>Metabolism</topic><topic>Mice</topic><topic>Pancreatic beta cells</topic><topic>Phenylbutyrates - pharmacology</topic><topic>Physiological aspects</topic><topic>Wolfram Syndrome - genetics</topic><topic>Wolfram Syndrome - pathology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>LINSHAN SHANG</creatorcontrib><creatorcontrib>HAIQING HUA</creatorcontrib><creatorcontrib>GOLAND, Robin</creatorcontrib><creatorcontrib>LEIBEL, Rudolph L</creatorcontrib><creatorcontrib>EGLI, Dieter</creatorcontrib><creatorcontrib>FOO, Kylie</creatorcontrib><creatorcontrib>MARTINEZ, Hector</creatorcontrib><creatorcontrib>WATANABE, Kazuhisa</creatorcontrib><creatorcontrib>ZIMMER, Matthew</creatorcontrib><creatorcontrib>KAHLER, David J</creatorcontrib><creatorcontrib>FREEBY, Matthew</creatorcontrib><creatorcontrib>WENDY CHUNG</creatorcontrib><creatorcontrib>LEDUC, Charles</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Gale In Context: High School</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Diabetes (New York, N.Y.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>LINSHAN SHANG</au><au>HAIQING HUA</au><au>GOLAND, Robin</au><au>LEIBEL, Rudolph L</au><au>EGLI, Dieter</au><au>FOO, Kylie</au><au>MARTINEZ, Hector</au><au>WATANABE, Kazuhisa</au><au>ZIMMER, Matthew</au><au>KAHLER, David J</au><au>FREEBY, Matthew</au><au>WENDY CHUNG</au><au>LEDUC, Charles</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>β-Cell Dysfunction Due to Increased ER Stress in a Stem Cell Model of Wolfram Syndrome</atitle><jtitle>Diabetes (New York, N.Y.)</jtitle><addtitle>Diabetes</addtitle><date>2014-03-01</date><risdate>2014</risdate><volume>63</volume><issue>3</issue><spage>923</spage><epage>933</epage><pages>923-933</pages><issn>0012-1797</issn><eissn>1939-327X</eissn><coden>DIAEAZ</coden><abstract>Wolfram syndrome is an autosomal recessive disorder caused by mutations in WFS1 and is characterized by insulin-dependent diabetes mellitus, optic atrophy, and deafness. To investigate the cause of β-cell failure, we used induced pluripotent stem cells to create insulin-producing cells from individuals with Wolfram syndrome. WFS1-deficient β-cells showed increased levels of endoplasmic reticulum (ER) stress molecules and decreased insulin content. Upon exposure to experimental ER stress, Wolfram β-cells showed impaired insulin processing and failed to increase insulin secretion in response to glucose and other secretagogues. Importantly, 4-phenyl butyric acid, a chemical protein folding and trafficking chaperone, restored normal insulin synthesis and the ability to upregulate insulin secretion. These studies show that ER stress plays a central role in β-cell failure in Wolfram syndrome and indicate that chemical chaperones might have therapeutic relevance under conditions of ER stress in Wolfram syndrome and other forms of diabetes.</abstract><cop>Alexandria, VA</cop><pub>American Diabetes Association</pub><pmid>24227685</pmid><doi>10.2337/db13-0717</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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source | Journals@Ovid Ovid Autoload; MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; PubMed Central |
subjects | Animals Biological and medical sciences Calcium - metabolism Cell Differentiation Cell research Cellular control mechanisms Complex syndromes Diabetes. Impaired glucose tolerance Ear diseases Endocrine pancreas. Apud cells (diseases) Endocrinopathies Endoplasmic Reticulum Stress Etiopathogenesis. Screening. Investigations. Target tissue resistance Humans Induced Pluripotent Stem Cells - cytology Insulin - biosynthesis Insulin - metabolism Insulin Secretion Insulin-Secreting Cells - physiology Medical genetics Medical sciences Membrane Proteins - genetics Metabolism Mice Pancreatic beta cells Phenylbutyrates - pharmacology Physiological aspects Wolfram Syndrome - genetics Wolfram Syndrome - pathology |
title | β-Cell Dysfunction Due to Increased ER Stress in a Stem Cell Model of Wolfram Syndrome |
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