Irisin通过生物钟关键基因调控胰岛β细胞功能的机制研究

Being one of the most important constituent of islet function, circadian clock is regarded as a promising therapeutical target for diabetes management. Irisin is a novel hormone secreted by myocyte that can mediate the beneficial effects of exercise on metabolism by regulating browning of the white adipose tissue and maintaining glucose homeostasis. However, its function in improving the rhythm of circadian clock in islet of Langerhans has not being demonstrated. Our prelimitary study showed that irisin improved hyperglycemia induced islet beta-cell dysfunction, and upregulate the expression of clock gene in the islet. Based on above results, we hypothesized that irisin could modulate islets circadian clock rhythm by up-regulating the AMPK pathway, which is the most important pathway regulating rhythms of the biological clock, thus contributing to the islet functional improvement. In this study, we use AMPK knockout mice and islet beta-cell specific circadian clock gene knockout mice as study models, to explore the effect of irisin on islets dysfuction and biological clock dysrhythmia, aiming to demonstrate the mechanisms involved. The outcome will provide resolvent and scientific warrant on the strategis for early prevention and therapeutical intervention for clinical diabetic islet dysfunction.

胰岛生物钟是维持胰岛功能的重要环节，也是糖尿病治疗干预的重要切入点。Irisin是一种全新的代谢调控因子，在代谢方面的作用已得到验证，可以促进白色脂肪棕色化，维持糖代谢稳态平衡。但能否参与调控胰岛生物钟节律，目前未见相关报道。我们前期研究表明，Irisin能够改善高糖所致的胰岛功能损伤，并上调胰岛生物钟基因的表达水平。我们将调节生物钟节律的重要信号通路—AMPK作为研究靶点，提出Irisin可通过AMPK信号通路调节胰岛生物钟节律，从而改善胰岛功能损伤的科学假说。本课题应用AMPK敲除及胰岛β细胞特异性生物钟基因敲除小鼠为模型，给予Irisin处理干预，从分子、细胞、组织及动物多层次观察胰岛功能变化情况，验证我们的假说，以期为临床糖尿病胰岛功能受损的早期预防与干预策略，提供新的思路和科学依据。

胰岛生物钟是维持胰岛功能的重要环节，也是糖尿病治疗干预的重要切入点。Irisin是一种全新的代谢调控因子，在代谢方面的作用已得到验证，可以促进白色脂肪棕色化，维持糖代谢稳态平衡。我们将调节生物钟节律的重要信号通路—AMPK作为研究靶点，前期研究也表明，Irisin能够改善高糖所致的胰岛功能损伤，并上调胰岛生物钟基因的表达水平。研究进展中，发现Irisin对STZ诱导的糖尿病小鼠的认知和记忆损伤具有保护作用，并就相关的分子生物机制学进行了实验探讨。同时，以GLP-1类似物作为激动剂，完成后续生物钟调控胰岛细胞功能的实验，证实其可以通过激活AMPK信号通路，部分恢复胰岛β细胞正常的生物钟节律，进而改善β细胞分泌功能。