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Hyperuricemia causes pancreatic β-cell death and dysfunction through NF-κB signaling pathway
Accumulating clinical evidence suggests that hyperuricemia is associated with an increased risk of type 2 diabetes. However, it is still unclear whether elevated levels of uric acid can cause direct injury of pancreatic β-cells. In this study, we examined the effects of uric acid on β-cell viability...
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Published in: | PloS one 2013-10, Vol.8 (10), p.e78284 |
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description | Accumulating clinical evidence suggests that hyperuricemia is associated with an increased risk of type 2 diabetes. However, it is still unclear whether elevated levels of uric acid can cause direct injury of pancreatic β-cells. In this study, we examined the effects of uric acid on β-cell viability and function. Uric acid solution or normal saline was administered intraperitoneally to mice daily for 4 weeks. Uric acid-treated mice exhibited significantly impaired glucose tolerance and lower insulin levels in response to glucose challenge than did control mice. However, there were no significant differences in insulin sensitivity between the two groups. In comparison to the islets in control mice, the islets in the uric acid-treated mice were markedly smaller in size and contained less insulin. Treatment of β-cells in vitro with uric acid activated the NF-κB signaling pathway through IκBα phosphorylation, resulting in upregulated inducible nitric oxide synthase (iNOS) expression and excessive nitric oxide (NO) production. Uric acid treatment also increased apoptosis and downregulated Bcl-2 expression in Min6 cells. In addition, a reduction in insulin secretion under glucose challenge was observed in the uric acid-treated mouse islets. These deleterious effects of uric acid on pancreatic β-cells were attenuated by benzbromarone, an inhibitor of uric acid transporters, NOS inhibitor L-NMMA, and Bay 11-7082, an NF-κB inhibitor. Further investigation indicated that uric acid suppressed levels of MafA protein through enhancing its degradation. Collectively, our data suggested that an elevated level of uric acid causes β-cell injury via the NF-κB-iNOS-NO signaling axis. |
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However, it is still unclear whether elevated levels of uric acid can cause direct injury of pancreatic β-cells. In this study, we examined the effects of uric acid on β-cell viability and function. Uric acid solution or normal saline was administered intraperitoneally to mice daily for 4 weeks. Uric acid-treated mice exhibited significantly impaired glucose tolerance and lower insulin levels in response to glucose challenge than did control mice. However, there were no significant differences in insulin sensitivity between the two groups. In comparison to the islets in control mice, the islets in the uric acid-treated mice were markedly smaller in size and contained less insulin. Treatment of β-cells in vitro with uric acid activated the NF-κB signaling pathway through IκBα phosphorylation, resulting in upregulated inducible nitric oxide synthase (iNOS) expression and excessive nitric oxide (NO) production. Uric acid treatment also increased apoptosis and downregulated Bcl-2 expression in Min6 cells. In addition, a reduction in insulin secretion under glucose challenge was observed in the uric acid-treated mouse islets. These deleterious effects of uric acid on pancreatic β-cells were attenuated by benzbromarone, an inhibitor of uric acid transporters, NOS inhibitor L-NMMA, and Bay 11-7082, an NF-κB inhibitor. Further investigation indicated that uric acid suppressed levels of MafA protein through enhancing its degradation. Collectively, our data suggested that an elevated level of uric acid causes β-cell injury via the NF-κB-iNOS-NO signaling axis.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0078284</identifier><identifier>PMID: 24205181</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Acids ; Animals ; Apoptosis ; Apoptosis - drug effects ; Atherosclerosis ; Bcl-2 protein ; Cell culture ; Cell death ; Cell Death - drug effects ; Cell injury ; Cell Survival - drug effects ; Cells, Cultured ; Diabetes ; Diabetes mellitus ; Disease ; Endocrinology ; Gene expression ; Glucose ; Glucose - metabolism ; Glucose tolerance ; Health risks ; Hospitals ; Hypertension ; Hyperuricemia ; Hyperuricemia - metabolism ; Inhibitors ; Insulin ; Insulin - metabolism ; Insulin resistance ; Insulin secretion ; Insulin-Secreting Cells - drug effects ; Insulin-Secreting Cells - metabolism ; Islets of Langerhans - drug effects ; Islets of Langerhans - metabolism ; Kinases ; MafA protein ; Male ; Metabolic disorders ; Metabolic syndrome ; Mice ; Mice, Inbred BALB C ; NF-kappa B - metabolism ; NF-κB protein ; Nitric oxide ; Nitric Oxide - metabolism ; Nitric Oxide Synthase Type II - metabolism ; Nitric-oxide synthase ; Pancreas ; Penicillin ; Phosphorylation ; Proteins ; Proto-Oncogene Proteins c-bcl-2 - metabolism ; Rodents ; Secretion ; Signal transduction ; Signal Transduction - drug effects ; Signaling ; Transcription factors ; Uric acid ; Uric Acid - adverse effects</subject><ispartof>PloS one, 2013-10, Vol.8 (10), p.e78284</ispartof><rights>2013 Jia et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License: https://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2013 Jia et al 2013 Jia et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c526t-6c8e641904b809e35907a2aefa27a7e1067c081e9813b2bc77909fd4346316c43</citedby><cites>FETCH-LOGICAL-c526t-6c8e641904b809e35907a2aefa27a7e1067c081e9813b2bc77909fd4346316c43</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.proquest.com/docview/1445923181/fulltextPDF?pq-origsite=primo$$EPDF$$P50$$Gproquest$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.proquest.com/docview/1445923181?pq-origsite=primo$$EHTML$$P50$$Gproquest$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,25753,27924,27925,37012,44590,53791,53793,75126</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24205181$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Song, Libing</contributor><creatorcontrib>Jia, Lu</creatorcontrib><creatorcontrib>Xing, Jing</creatorcontrib><creatorcontrib>Ding, Ying</creatorcontrib><creatorcontrib>Shen, Yachen</creatorcontrib><creatorcontrib>Shi, Xuhui</creatorcontrib><creatorcontrib>Ren, Wei</creatorcontrib><creatorcontrib>Wan, Meng</creatorcontrib><creatorcontrib>Guo, Jianjin</creatorcontrib><creatorcontrib>Zheng, Shujing</creatorcontrib><creatorcontrib>Liu, Yun</creatorcontrib><creatorcontrib>Liang, Xiubin</creatorcontrib><creatorcontrib>Su, Dongming</creatorcontrib><title>Hyperuricemia causes pancreatic β-cell death and dysfunction through NF-κB signaling pathway</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>Accumulating clinical evidence suggests that hyperuricemia is associated with an increased risk of type 2 diabetes. However, it is still unclear whether elevated levels of uric acid can cause direct injury of pancreatic β-cells. In this study, we examined the effects of uric acid on β-cell viability and function. Uric acid solution or normal saline was administered intraperitoneally to mice daily for 4 weeks. Uric acid-treated mice exhibited significantly impaired glucose tolerance and lower insulin levels in response to glucose challenge than did control mice. However, there were no significant differences in insulin sensitivity between the two groups. In comparison to the islets in control mice, the islets in the uric acid-treated mice were markedly smaller in size and contained less insulin. Treatment of β-cells in vitro with uric acid activated the NF-κB signaling pathway through IκBα phosphorylation, resulting in upregulated inducible nitric oxide synthase (iNOS) expression and excessive nitric oxide (NO) production. Uric acid treatment also increased apoptosis and downregulated Bcl-2 expression in Min6 cells. In addition, a reduction in insulin secretion under glucose challenge was observed in the uric acid-treated mouse islets. These deleterious effects of uric acid on pancreatic β-cells were attenuated by benzbromarone, an inhibitor of uric acid transporters, NOS inhibitor L-NMMA, and Bay 11-7082, an NF-κB inhibitor. Further investigation indicated that uric acid suppressed levels of MafA protein through enhancing its degradation. Collectively, our data suggested that an elevated level of uric acid causes β-cell injury via the NF-κB-iNOS-NO signaling axis.</description><subject>Acids</subject><subject>Animals</subject><subject>Apoptosis</subject><subject>Apoptosis - drug effects</subject><subject>Atherosclerosis</subject><subject>Bcl-2 protein</subject><subject>Cell culture</subject><subject>Cell death</subject><subject>Cell Death - drug effects</subject><subject>Cell injury</subject><subject>Cell Survival - drug effects</subject><subject>Cells, Cultured</subject><subject>Diabetes</subject><subject>Diabetes mellitus</subject><subject>Disease</subject><subject>Endocrinology</subject><subject>Gene expression</subject><subject>Glucose</subject><subject>Glucose - metabolism</subject><subject>Glucose tolerance</subject><subject>Health risks</subject><subject>Hospitals</subject><subject>Hypertension</subject><subject>Hyperuricemia</subject><subject>Hyperuricemia - metabolism</subject><subject>Inhibitors</subject><subject>Insulin</subject><subject>Insulin - metabolism</subject><subject>Insulin resistance</subject><subject>Insulin secretion</subject><subject>Insulin-Secreting Cells - drug effects</subject><subject>Insulin-Secreting Cells - metabolism</subject><subject>Islets of Langerhans - drug effects</subject><subject>Islets of Langerhans - metabolism</subject><subject>Kinases</subject><subject>MafA protein</subject><subject>Male</subject><subject>Metabolic disorders</subject><subject>Metabolic syndrome</subject><subject>Mice</subject><subject>Mice, Inbred BALB C</subject><subject>NF-kappa B - metabolism</subject><subject>NF-κB protein</subject><subject>Nitric oxide</subject><subject>Nitric Oxide - metabolism</subject><subject>Nitric Oxide Synthase Type II - metabolism</subject><subject>Nitric-oxide synthase</subject><subject>Pancreas</subject><subject>Penicillin</subject><subject>Phosphorylation</subject><subject>Proteins</subject><subject>Proto-Oncogene Proteins c-bcl-2 - metabolism</subject><subject>Rodents</subject><subject>Secretion</subject><subject>Signal transduction</subject><subject>Signal Transduction - drug effects</subject><subject>Signaling</subject><subject>Transcription factors</subject><subject>Uric acid</subject><subject>Uric Acid - adverse effects</subject><issn>1932-6203</issn><issn>1932-6203</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>PIMPY</sourceid><sourceid>DOA</sourceid><recordid>eNp1Ustu1DAUtRCIlsIfIIjEOoNfsZ0NElSUVqpgA1ssx75JPMrYwU5A81ss-Yh-ExkmrdoFK9vX55x7rn0QeknwhjBJ3m7jnIIZNmMMsMFYKqr4I3RKakZLQTF7fG9_gp7lvMW4YkqIp-iEcoorosgp-n65HyHNyVvYeVNYM2fIxWiCTWAmb4ub36WFYSjccuwLE1zh9rmdg518DMXUpzh3ffH5orz586HIvlss-dAtClP_y-yfoyetGTK8WNcz9O3i49fzy_L6y6er8_fXpa2omEphFQhOaswbhWtgVY2loQZaQ6WRQLCQFisCtSKsoY2VssZ16zjjghFhOTtDr4-64xCzXp8ma8J5VVO2TLogro4IF81Wj8nvTNrraLz-V4ip0yYtAw-gJXHUMtniyhDumFDQSCcbzphyDWlg0Xq3dpubHTgLYUpmeCD68Cb4Xnfxp2YKK1Yd7L5ZBVL8MUOe_mOZH1E2xZwTtHcdCNaHDNyy9CEDes3AQnt1390d6fbT2V_xRrGm</recordid><startdate>20131025</startdate><enddate>20131025</enddate><creator>Jia, Lu</creator><creator>Xing, Jing</creator><creator>Ding, Ying</creator><creator>Shen, Yachen</creator><creator>Shi, Xuhui</creator><creator>Ren, Wei</creator><creator>Wan, Meng</creator><creator>Guo, Jianjin</creator><creator>Zheng, Shujing</creator><creator>Liu, Yun</creator><creator>Liang, Xiubin</creator><creator>Su, Dongming</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><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>3V.</scope><scope>7QG</scope><scope>7QL</scope><scope>7QO</scope><scope>7RV</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TG</scope><scope>7TM</scope><scope>7U9</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FG</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABJCF</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>ARAPS</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BGLVJ</scope><scope>BHPHI</scope><scope>C1K</scope><scope>CCPQU</scope><scope>D1I</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB.</scope><scope>KB0</scope><scope>KL.</scope><scope>L6V</scope><scope>LK8</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>M7P</scope><scope>M7S</scope><scope>NAPCQ</scope><scope>P5Z</scope><scope>P62</scope><scope>P64</scope><scope>PATMY</scope><scope>PDBOC</scope><scope>PIMPY</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PTHSS</scope><scope>PYCSY</scope><scope>RC3</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20131025</creationdate><title>Hyperuricemia causes pancreatic β-cell death and dysfunction through NF-κB signaling pathway</title><author>Jia, Lu ; Xing, Jing ; Ding, Ying ; Shen, Yachen ; Shi, Xuhui ; Ren, Wei ; Wan, Meng ; Guo, Jianjin ; Zheng, Shujing ; Liu, Yun ; Liang, Xiubin ; Su, Dongming</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c526t-6c8e641904b809e35907a2aefa27a7e1067c081e9813b2bc77909fd4346316c43</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Acids</topic><topic>Animals</topic><topic>Apoptosis</topic><topic>Apoptosis - drug effects</topic><topic>Atherosclerosis</topic><topic>Bcl-2 protein</topic><topic>Cell culture</topic><topic>Cell death</topic><topic>Cell Death - drug effects</topic><topic>Cell injury</topic><topic>Cell Survival - drug effects</topic><topic>Cells, Cultured</topic><topic>Diabetes</topic><topic>Diabetes mellitus</topic><topic>Disease</topic><topic>Endocrinology</topic><topic>Gene expression</topic><topic>Glucose</topic><topic>Glucose - metabolism</topic><topic>Glucose tolerance</topic><topic>Health risks</topic><topic>Hospitals</topic><topic>Hypertension</topic><topic>Hyperuricemia</topic><topic>Hyperuricemia - metabolism</topic><topic>Inhibitors</topic><topic>Insulin</topic><topic>Insulin - metabolism</topic><topic>Insulin resistance</topic><topic>Insulin secretion</topic><topic>Insulin-Secreting Cells - drug effects</topic><topic>Insulin-Secreting Cells - metabolism</topic><topic>Islets of Langerhans - drug effects</topic><topic>Islets of Langerhans - metabolism</topic><topic>Kinases</topic><topic>MafA protein</topic><topic>Male</topic><topic>Metabolic disorders</topic><topic>Metabolic syndrome</topic><topic>Mice</topic><topic>Mice, Inbred BALB C</topic><topic>NF-kappa B - 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Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Jia, Lu</au><au>Xing, Jing</au><au>Ding, Ying</au><au>Shen, Yachen</au><au>Shi, Xuhui</au><au>Ren, Wei</au><au>Wan, Meng</au><au>Guo, Jianjin</au><au>Zheng, Shujing</au><au>Liu, Yun</au><au>Liang, Xiubin</au><au>Su, Dongming</au><au>Song, Libing</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Hyperuricemia causes pancreatic β-cell death and dysfunction through NF-κB signaling pathway</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2013-10-25</date><risdate>2013</risdate><volume>8</volume><issue>10</issue><spage>e78284</spage><pages>e78284-</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>Accumulating clinical evidence suggests that hyperuricemia is associated with an increased risk of type 2 diabetes. However, it is still unclear whether elevated levels of uric acid can cause direct injury of pancreatic β-cells. In this study, we examined the effects of uric acid on β-cell viability and function. Uric acid solution or normal saline was administered intraperitoneally to mice daily for 4 weeks. Uric acid-treated mice exhibited significantly impaired glucose tolerance and lower insulin levels in response to glucose challenge than did control mice. However, there were no significant differences in insulin sensitivity between the two groups. In comparison to the islets in control mice, the islets in the uric acid-treated mice were markedly smaller in size and contained less insulin. Treatment of β-cells in vitro with uric acid activated the NF-κB signaling pathway through IκBα phosphorylation, resulting in upregulated inducible nitric oxide synthase (iNOS) expression and excessive nitric oxide (NO) production. Uric acid treatment also increased apoptosis and downregulated Bcl-2 expression in Min6 cells. In addition, a reduction in insulin secretion under glucose challenge was observed in the uric acid-treated mouse islets. These deleterious effects of uric acid on pancreatic β-cells were attenuated by benzbromarone, an inhibitor of uric acid transporters, NOS inhibitor L-NMMA, and Bay 11-7082, an NF-κB inhibitor. Further investigation indicated that uric acid suppressed levels of MafA protein through enhancing its degradation. Collectively, our data suggested that an elevated level of uric acid causes β-cell injury via the NF-κB-iNOS-NO signaling axis.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>24205181</pmid><doi>10.1371/journal.pone.0078284</doi><oa>free_for_read</oa></addata></record> |
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subjects | Acids Animals Apoptosis Apoptosis - drug effects Atherosclerosis Bcl-2 protein Cell culture Cell death Cell Death - drug effects Cell injury Cell Survival - drug effects Cells, Cultured Diabetes Diabetes mellitus Disease Endocrinology Gene expression Glucose Glucose - metabolism Glucose tolerance Health risks Hospitals Hypertension Hyperuricemia Hyperuricemia - metabolism Inhibitors Insulin Insulin - metabolism Insulin resistance Insulin secretion Insulin-Secreting Cells - drug effects Insulin-Secreting Cells - metabolism Islets of Langerhans - drug effects Islets of Langerhans - metabolism Kinases MafA protein Male Metabolic disorders Metabolic syndrome Mice Mice, Inbred BALB C NF-kappa B - metabolism NF-κB protein Nitric oxide Nitric Oxide - metabolism Nitric Oxide Synthase Type II - metabolism Nitric-oxide synthase Pancreas Penicillin Phosphorylation Proteins Proto-Oncogene Proteins c-bcl-2 - metabolism Rodents Secretion Signal transduction Signal Transduction - drug effects Signaling Transcription factors Uric acid Uric Acid - adverse effects |
title | Hyperuricemia causes pancreatic β-cell death and dysfunction through NF-κB signaling pathway |
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