American Diabetes Association
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Hyperuricemia Predisposes to the Onset of Diabetes via Promoting Pancreatic β-Cell Death in Uricase Deficiency Male Mice

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posted on 2020-04-21, 21:03 authored by Ada AdminAda Admin, Jie Lu, Yuwei He, Lingling Cui, Xiaoming Xing, Zhen Liu, Xinde Li, Hui Zhang, Hailong Li, Wenyan Sun, Aichang Ji, Yao Wang, Huiyong Yin, Changgui Li
Clinical studies have shown a link between hyperuricemia (HU) and diabetes, while the exact effect of soluble serum urate on glucose metabolism remains elusive. This study aims to characterize the glucose metabolic phenotypes and investigate the underlying molecular mechanisms using a novel spontaneous HU mouse model which is in absence of Uricase (Uox) gene. In an attempt to study the role of HU in glycometabolism, we implemented external stimulation on Uox-knockout (KO) and wild-type (WT) males with high-fat diet (HFD) and (/or) multiple-low-dose streptozotocin (MLD-STZ) to provoke the potential role of urate. Notably, while Uox-KO mice developed glucose intolerance in basal condition, none had spontaneously developed into diabetes even with aging. HFD-fed Uox-KO mice manifested similar insulin sensitivity compared with WT controls. HU augmented the existing glycometabolism abnormality induced by MLD-STZ, and eventually lead to diabetes evidenced by the increased random glucose. Reduced β cell masses and increased the terminal deoxynucleotidyl transferase mediated dUTP nick end labeling (TUNEL) positive β cells suggested HU-mediated diabetes was cell death dependent. However, urate-lowering treatment (ULT) cannot ameliorate the diabetes incidence nor reverse β-cell apoptosis with significance. While, ULT displayed a significant therapeutic effect of hyperuricemic-crystal associated kidney injury and tubulointerstitial damage in diabetes. Moreover, we present transcriptomic analysis of isolated islets, using Uox-KO versus WT mice and streptozotocin-induced diabetic WT (STZ-WT) versus diabetic Uox-KO (STZ-KO) mice. Shared differentially expressed genes of HU primacy revealed Stk17β is a possible target gene in HU related β-cell death. Together, this study suggests that HU accelerates but not causes diabetes by inhibiting islet β-cell survival.


This study was supported by the research project grants from National Key Research and Development Program (#2016YFC0903400), National Science Foundation of China (#31900413, #81520108007, #81770869), Shandong Province Key Research and Development Program (#2018CXGC1207) and Shandong Province Natural Science Foundation (#ZR2018ZC1053).


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