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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
Main Authors: Jia, Lu, Xing, Jing, Ding, Ying, Shen, Yachen, Shi, Xuhui, Ren, Wei, Wan, Meng, Guo, Jianjin, Zheng, Shujing, Liu, Yun, Liang, Xiubin, Su, Dongming
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creator Jia, Lu
Xing, Jing
Ding, Ying
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Ren, Wei
Wan, Meng
Guo, Jianjin
Zheng, Shujing
Liu, Yun
Liang, Xiubin
Su, Dongming
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.
doi_str_mv 10.1371/journal.pone.0078284
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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. 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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.</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
url http://sfxeu10.hosted.exlibrisgroup.com/loughborough?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-01-02T01%3A11%3A12IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_plos_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Hyperuricemia%20causes%20pancreatic%20%CE%B2-cell%20death%20and%20dysfunction%20through%20NF-%CE%BAB%20signaling%20pathway&rft.jtitle=PloS%20one&rft.au=Jia,%20Lu&rft.date=2013-10-25&rft.volume=8&rft.issue=10&rft.spage=e78284&rft.pages=e78284-&rft.issn=1932-6203&rft.eissn=1932-6203&rft_id=info:doi/10.1371/journal.pone.0078284&rft_dat=%3Cproquest_plos_%3E3110575551%3C/proquest_plos_%3E%3Cgrp_id%3Ecdi_FETCH-LOGICAL-c526t-6c8e641904b809e35907a2aefa27a7e1067c081e9813b2bc77909fd4346316c43%3C/grp_id%3E%3Coa%3E%3C/oa%3E%3Curl%3E%3C/url%3E&rft_id=info:oai/&rft_pqid=1445923181&rft_id=info:pmid/24205181&rfr_iscdi=true