posted on 2020-04-21, 21:03authored byAda 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) versusdiabetic 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.
Funding
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).