Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) protect against diabetic cardiovascular diseases and nephropathy. However, their activity in diabetic retinopathy (DR) remains unclear. Our retrospective cohort study involving 1626 T2DM patients revealed superior efficacy of GLP-1 RAs in controlling DR compared to other glucose-lowering medications, suggesting their advantage in DR treatment. By single-cell RNA-sequencing analysis and immunostaining, we observed a high expression of GLP-1R in retinal endothelial cells, which was down-regulated under diabetic conditions. Treatment of GLP-1 RAs significantly restored the receptor expression, resulting in an improvement in retinal degeneration, vascular tortuosity, avascular vessels, and vascular integrity in diabetic mice. GO and GSEA analyses further implicated enhanced mitochondrial gene translation and mitochondrial functions by GLP-1 RAs. Additionally, the treatment attenuated STING signaling activation in retinal endothelial cells, which is typically activated by leaked mitochondrial DNA. Expression of mRNA was positively correlated to the levels of angiogenic and inflammatory factors in the endothelial cells of human fibrovascular membranes. Further investigation revealed that the cAMP-responsive element binding protein played a role in the GLP-1R signaling pathway on suppression of STING signaling. This study demonstrates a novel role of GLP-1 RAs in the protection of diabetic retinal vasculature by inhibiting STING-elicited inflammatory signals.

中文翻译：

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胰高血糖素样肽 1 受体激动剂通过抑制异常 STING 信号传导来挽救糖尿病血管内皮损伤

胰高血糖素样肽 1 受体激动剂 (GLP-1 RA) 可预防糖尿病心血管疾病和肾病。然而，它们在糖尿病视网膜病变（DR）中的活性仍不清楚。我们对 1626 名 T2DM 患者进行的回顾性队列研究显示，与其他降糖药物相比，GLP-1 RA 在控制 DR 方面的功效更佳，表明它们在 DR 治疗中的优势。通过单细胞RNA测序分析和免疫染色，我们观察到GLP-1R在视网膜内皮细胞中高表达，在糖尿病条件下表达下调。 GLP-1 RA 治疗显着恢复了受体表达，从而改善了糖尿病小鼠的视网膜变性、血管迂曲、无血管和血管完整性。 GO 和 GSEA 分析进一步表明 GLP-1 RA 增强了线粒体基因翻译和线粒体功能。此外，该治疗减弱了视网膜内皮细胞中 STING 信号的激活，而该信号通常是由泄漏的线粒体 DNA 激活的。 mRNA的表达与人纤维血管膜内皮细胞中血管生成和炎症因子的水平呈正相关。进一步研究表明，cAMP 反应元件结合蛋白在 GLP-1R 信号通路中发挥作用，抑制 STING 信号传导。这项研究证明了 GLP-1 RA 通过抑制 STING 引发的炎症信号来保护糖尿病视网膜血管系统的新作用。