title: Hyperuricemia causes pancreatic β-cell death and dysfunction through NF-κB signaling pathway.
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.
authors.affiliation: Center of Metabolic Disease Research, Nanjing Medical University, Nanjing, Jiangsu Province, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Jia
authors.forename: Jing
authors.initials: J
authors.lastname: Xing
authors.forename: Ying
authors.initials: Y
authors.lastname: Ding
authors.forename: Yachen
authors.initials: Y
authors.lastname: Shen
authors.forename: Xuhui
authors.initials: X
authors.lastname: Shi
authors.forename: Wei
authors.initials: W
authors.lastname: Ren
authors.forename: Meng
authors.initials: M
authors.lastname: Wan
authors.forename: Jianjin
authors.initials: J
authors.lastname: Guo
authors.forename: Shujing
authors.initials: S
authors.lastname: Zheng
authors.forename: Yun
authors.initials: Y
authors.lastname: Liu
authors.forename: Xiubin
authors.initials: X
authors.lastname: Liang
authors.forename: Dongming
authors.initials: D
authors.lastname: Su
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D005947:Glucose / Q000378:metabolism; D033461:Hyperuricemia / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism*; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016328:NF-kappa B / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014527:Uric Acid / Q000009:adverse effects*
chemical_list: D007328:Insulin; D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2; D014527:Uric Acid; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D005947:Glucose