Zhang Xiaonan, Liu Yan, Xia Mengxue, Yang Manwen, Wu Yingjie, Zhang Fang
National Clinical Research Center for Eye disease, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200080, China.
Liaoning Provence Key Laboratory of Genome Engineered Animal Models, National Center of Genetically Engineered Animal Models for International Research, Institute for Genome Engineered Animal Models of Human Diseases, Dalian Medical University, Dalian 116000, China.
Biochem Biophys Rep. 2025 Aug 22;43:102182. doi: 10.1016/j.bbrep.2025.102182. eCollection 2025 Sep.
Diabetic retinopathy (DR), a leading cause of blindness among working-age adults, lacks targeted therapies besides glucose management. Early retinal lesions are linked to serum metabolites, but the underlying peripheral regulatory networks is unclear.
We first established a streptozotocin (STZ)-induced mouse model of early DR exhibiting retinal inflammation characteristics. This study employed an integrative approach, combining retinal and serum transcriptomic and metabolomic profiles with genome-wide association study (GWAS) data, to identify peripheral metabolites potentially linking early retinal lesions.
STZ-induced mice exhibited retinal inflammation and metabolic dysregulation. Metabolites including glucose, sorbitol, and mannitol were altered in both serum and retina, implicating their potential involvement in retinal inflammation. Utilizing GWAS data of diabetic patients, we further explore the potential the upstream regulation of shared metabolites and their peripheral pathways potentially instigating early retinal inflammation through metabolite-related genes correlated with single nucleotide polymorphisms. Key enzyme genes including HK1, HKDC1, AKR1B1 in hyperglycemic pathway, CEL and HMGCR in cholesterol pathway, and ACSL1, PPT2 in palmitic acid pathway, may connect the metabolic network of hyperglycemia, hyperfructosemia and disrupted lipid metabolism to retinopathy.
This study elucidates the upstream regulatory network of peripheral serum metabolites associated with early retinal lesions. Specifically, the SNPs in key peripheral enzyme genes may exert remote effects on retinal inflammation in DR. This finding provides insights into the systemic metabolic management and offering peripheral precise early detection and treatment.
糖尿病视网膜病变（DR）是工作年龄成年人失明的主要原因，除血糖管理外缺乏针对性治疗。早期视网膜病变与血清代谢物有关，但其潜在的外周调节网络尚不清楚。
我们首先建立了链脲佐菌素（STZ）诱导的具有视网膜炎症特征的早期DR小鼠模型。本研究采用综合方法，将视网膜和血清转录组学及代谢组学谱与全基因组关联研究（GWAS）数据相结合，以确定可能与早期视网膜病变相关的外周代谢物。
STZ诱导的小鼠表现出视网膜炎症和代谢失调。血清和视网膜中葡萄糖、山梨醇和甘露醇等代谢物发生了变化，表明它们可能参与视网膜炎症。利用糖尿病患者的GWAS数据，我们进一步探索了共享代谢物的上游调节潜力及其通过与单核苷酸多态性相关的代谢物相关基因可能引发早期视网膜炎症的外周途径。高血糖途径中的关键酶基因HK1、HKDC1、AKR1B1，胆固醇途径中的CEL和HMGCR，以及棕榈酸途径中的ACSL1、PPT2，可能将高血糖、高果糖血症和脂质代谢紊乱的代谢网络与视网膜病变联系起来。
本研究阐明了与早期视网膜病变相关的外周血清代谢物的上游调节网络。具体而言，关键外周酶基因中的单核苷酸多态性可能对DR中的视网膜炎症产生远程影响。这一发现为全身代谢管理提供了见解，并为外周精确早期检测和治疗提供了依据。
