Hyperuricemia Predisposes to the Onset of Diabetes via Promoting Pancreatic β-Cell Death in Uricase-Deficient Male Mice.
Jie LuYuwei HeLingling CuiXiaoming XingZhen LiuXinde LiHui ZhangHailong LiWenyan SunAichang JiYao WangHuiyong YinChanggui LiPublished in: Diabetes (2020)
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 in which the uricase (Uox) gene is absent. 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 a high-fat diet (HFD) and/or injections of multiple low-dose streptozotocin (MLD-STZ) to provoke the potential role of urate. Notably, while Uox-KO mice developed glucose intolerance in the basal condition, no mice spontaneously developed 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 led to diabetes, as evidenced by the increased random glucose. Reduced β-cell masses and increased terminal deoxynucleotidyl TUNEL-positive β-cells suggested that HU-mediated diabetes was cell death dependent. However, urate-lowering therapy (ULT) cannot ameliorate the diabetes incidence or reverse β-cell apoptosis with significance. ULT displayed a significant therapeutic effect of HU-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 does not cause diabetes by inhibiting islet β-cell survival.
Keyphrases
- type diabetes
- high fat diet
- diabetic rats
- cell death
- cardiovascular disease
- glycemic control
- wild type
- low dose
- high fat diet induced
- insulin resistance
- single cell
- oxidative stress
- adipose tissue
- mouse model
- blood glucose
- cell cycle arrest
- stem cells
- blood pressure
- induced apoptosis
- cell therapy
- dna methylation
- metabolic syndrome
- bone marrow
- cell proliferation
- mesenchymal stem cells
- signaling pathway
- gene expression
- molecular dynamics
- high glucose
- genome wide identification
- skeletal muscle
- transcription factor
- density functional theory
- bioinformatics analysis
- endoplasmic reticulum stress