STING-IRF3信号通路介导2型糖尿病胰岛β细胞损伤及干预的机制研究

Type 2 diabetes mellitus (T2DM) patients have showed impaired islet beta cell function. Several studies have reported that mitochondrial dysfunction and endoplasmic reticulum (ER) stress are involved in β-cell dysfunction, but how β-cell injury is induced by mitochondrial damage and ER stress remains to be studied. Stimulator of Interferon genes (STING) is a key factor located in the ER and is involved in ER stress. Meanwhile, mitochondrial DNA leakage caused by damage can also activate the STING signaling pathway. For the first time, our group found that the STING signaling pathway was activated by FFAs in INS-1 cells. However, the relationship between STING and β-cell function has not been reported domestically and abroad. In previous studies, we found that STING-knockout mice fed with high-fat-diet showed improved insulin resistance. Therefore, we speculated that FFAs can activate STING leading to β-cell damage, and drugs can improve β-cell function via inhibiting STING signaling, such as Artemisinin. To prove this hypothesis, we will establish pancreatic islet β cell specific STING knockout T2DM mice model and FFAs mediated INS-1 cell model, using molecular biology, cell transfection and other technologies, to investigate the effect of STING signaling pathway on β-cell function and the intervention mechanism of Artemisinin from the whole - tissue - cell three levels.

2型糖尿病（T2DM）患者存在胰岛β细胞功能受损，线粒体损伤及内质网应激是参与β细胞功能受损的重要机制，但是线粒体损伤及内质网应激如何调控β细胞损伤仍有待研究。干扰素基因刺激因子（STING）是一种位于内质网膜并参与内质网应激的关键因子，同时线粒体损伤所致线粒体DNA泄漏可以激活STING信号。本课题组首次发现高脂刺激INS-1细胞，STING信号被激活。但是，STING与β细胞功能的关系，迄今国内外尚无报道。前期研究中，我们发现STING敲除小鼠胰岛素抵抗减轻。故我们推测高脂可激活STING导致β细胞受损，使用抑制STING信号的药物，如青蒿素能够改善β细胞功能。为证明该假说，我们将建立T2DM和胰岛β细胞特异性敲除STING小鼠模型及细胞模型，采用分子生物学、动物基因敲除、细胞转染等技术，从整体－组织－细胞三个层次，观察STING信号通路激活对β细胞功能的影响机制及青蒿素干预机制。

2型糖尿病(T2DM)是一种与年龄相关的疾病，其特征是胰腺β细胞功能受损和胰岛素抵抗。近期研究表明，代谢应激条件下衰老β细胞的积累导致了T2DM的进展，而针对衰老胰岛β细胞的消融可以改善预后。但是，介导β细胞衰老的具体机制目前尚不清晰。在这项研究中，我们发现高脂饮食诱导肥胖小鼠和老年小鼠衰老胰腺β细胞负荷的增加伴随着cGAS-STING通路的激活。使用cGAS或STING小干扰RNA或STING抑制剂C176下调该通路，可降低棕榈酸或过氧化氢处理的Min6细胞的SASP和衰老。C176对DIO小鼠的干预也显著减轻了胰岛的炎症和衰老，从而保护了胰腺β细胞和葡萄糖代谢的功能。我们的研究进一步揭示了代谢应激条件下线粒体DNA (mtDNA)泄漏对cGAS-STING通路的激活至关重要，这可以被mtDNA消耗剂溴化乙锭逆转。一致地，mtDNA泄漏在老年小鼠中更为严重，并因长期高脂肪饮食而加速。总之，我们证明了在代谢应激诱导的胰腺β细胞加速衰老过程中，细胞质mtDNA激活cGAS-STING途径介导SASP，这一过程可被STING抑制剂C176下调。