Diabetes mellitus (DM) is a chronic metabolic disorder affecting millions of people worldwide, characterized by dysregulated glucose homeostasis and hyperglycemia. Diabetic retinopathy (DR) is one of the serious multisystemic complications. Aging is an important risk factor for DR. Endothelial sirtuin 1 (SIRT1) plays an important role in regulating the pathophysiology of glucose metabolism, cellular senescence, and aging. Liraglutide, an analog of Glucagon-like peptide 1 (GLP-1), has been widely used in the treatment of DM. However, the effects of Liraglutide on DR are less reported. Here, we investigated whether treatment with Liraglutide has beneficial effects on high glucose (HG)-induced injury in human retinal microvascular endothelial cells (HRECs). First, we found that exposure to HG reduced the expression of glucagon-like peptide 1 receptor 1 (GLP-1R). Additionally, Liraglutide ameliorated HG-induced increase in the expression of vascular endothelial growth factor-A (VEGF-A) and interleukin 6 (IL-6). Importantly, Liraglutide ameliorated cellular senescence and increased telomerase activity in HG-challenged HRECs. Liraglutide also reduced the levels of p53 and p21. Mechanistically, Liraglutide restored the expression of SIRT1 against HG. In contrast, the knockdown of SIRT1 abolished the protective effects of Liraglutide in cellular senescence of HRECs. Our findings suggest that Liraglutide might possess a benefit on DR mediated by SIRT1.

糖尿病 (DM) 是一种影响全球数百万人的慢性代谢性疾病，其特征是葡萄糖稳态失调和高血糖。糖尿病视网膜病变（DR）是严重的多系统并发症之一。衰老是 DR 的一个重要危险因素。内皮去乙酰化酶 1 (SIRT1) 在调节葡萄糖代谢、细胞衰老和衰老的病理生理学中发挥着重要作用。利拉鲁肽是胰高血糖素样肽1 (GLP-1) 的类似物，已广泛用于治疗糖尿病。然而，利拉鲁肽对 DR 的作用报道较少。在这里，我们研究了利拉鲁肽治疗是否对高糖（HG）诱导的人视网膜微血管内皮细胞（HREC）损伤具有有益作用。首先，我们发现接触 HG 会降低胰高血糖素样肽 1 受体 1 (GLP-1R) 的表达。此外，利拉鲁肽还可改善 HG 诱导的血管内皮生长因子 A (VEGF-A) 和白细胞介素 6 (IL-6) 表达的增加。重要的是，利拉鲁肽可改善 HG 挑战的 HREC 中的细胞衰老并增加端粒酶活性。利拉鲁肽还降低了 p53 和 p21 的水平。从机制上讲，利拉鲁肽恢复了针对 HG 的 SIRT1 表达。相比之下，SIRT1 的敲除消除了利拉鲁肽对 HREC 细胞衰老的保护作用。我们的研究结果表明，利拉鲁肽可能对 SIRT1 介导的 DR 有益。