高尿酸血症引起胰岛β细胞损伤的分子机制研究

Although hyperuricemia (HUA) has been identified as an independent risk factor for diabetes, and islet β cell impairments paly a key in this process, the mechanisms underlying islet β cell impairments caused by HUA remain evasive. In a spontaneous HUA mouse model, the applicants have observed hyperglycemia after glucose challenge, decreased insulin secretion upon glucose stimulation, enhanced autophagy and apoptosis of islet β cells, elevated production of ROS, and increased activition of AMPK, an autophagy promoter. We propose that high uric acid may induce autophagy of β cells via triggering oxidative stress, activating the AMPK-ULK1 and AMPK-TSC1/2-mTOR pathways, promoting autophagy of islet β cells, and thus inducing ilset β cell dysfunction. In the present study, we plan to (1) examine the effects of high uric acid on autophagy, apoptosis and insulin secretion in an islet β cell line (NIT-1), after inhibiting different components of the above pathways by ROS scavengers, specific antagonists, and RNA interference; and (2) examine changes in blood glucose, insulin secretion, autophagy and apoptosis of islet β cells in the spontaneous HUA mice, after knocking out AMPK and mTOR, the key genes involved in the induction of β cell autopahgy by HUA, and CypD, a mitochondrial oxidative stress-related gene. By unraveling the molecular mechanisms of HUA-induced islet β cell impairments, this study will provide scientific basis for early treatment and prevention of HUA-induced diabetes.

高尿酸血症（HUA）是糖尿病的独立危险因素，胰岛β细胞损伤在其中发挥关键作用，但机制不清。课题组前期发现，自发HUA小鼠糖负荷后血糖明显升高、胰岛素分泌明显减少；胰岛β细胞自噬、凋亡显著增加；细胞内ROS明显增多，自噬正调控因子AMPK活性显著升高。推测高尿酸可能通过诱发氧化应激，激活AMPK-ULK1和AMPK-TSC1/2-mTOR通路，促进胰岛β细胞自噬，导致胰岛β细胞功能受损。本课题拟（1）在胰岛β细胞系中应用ROS清除剂、特异性抑制剂和RNAi分别抑制上述通路的不同环节，观察高尿酸对胰岛β细胞自噬、凋亡和胰岛素分泌的影响；（2）条件敲除高尿酸引起胰岛β细胞自噬的关键基因AMPK和mTOR，敲除线粒体氧化应激相关基因CypD，观察自发HUA小鼠血糖、胰岛素及胰岛β细胞自噬、凋亡的变化。该研究将揭示高尿酸引起胰岛β细胞损伤的分子机制，为高尿酸相关糖尿病的早期防治提供理论依据。

高尿酸血症（HUA）是糖尿病的独立危险因素，胰岛β细胞损伤在其中发挥关键作用，但机制不清。课题组前期发现，自发HUA小鼠糖负荷后血糖明显升高、胰岛素分泌明显减少；胰岛β细胞自噬、凋亡显著增加；细胞内ROS明显增多，自噬正调控因子AMPK活性显著升高。推测高尿酸可能通过诱发氧化应激，激活AMPK-ULK1和AMPK-TSC1/2-mTOR通路，促进胰岛β细胞自噬，导致胰岛β细胞功能受损。本课题拟（1）在胰岛β细胞系中应用ROS清除剂、特异性抑制剂和RNAi分别抑制上述通路的不同环节，观察高尿酸对胰岛β细胞自噬、凋亡和胰岛素分泌的影响；（2）条件敲除尿酸氧化酶基因，观察自发HUA小鼠血糖、胰岛素及胰岛β细胞自噬、凋亡的变化。该研究将揭示高尿酸引起胰岛β细胞损伤的分子机制，为高尿酸相关糖尿病的早期防治提供理论依据。

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