Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Ocular Fundus Diseases, Shanghai, China; Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai, China.
Department of Ophthalmology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Ocular Fundus Diseases, Shanghai, China; Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai, China.
Biomed Pharmacother. 2022 Aug;152:113222. doi: 10.1016/j.biopha.2022.113222. Epub 2022 Jun 4.
Empagliflozin (EMPA) is the first sodium-glucose co-transporter 2 inhibitor to significantly reduce cardiovascular and kidney complications in type 2 diabetes mellitus. Given this, we speculate that EMPA may have the potential to intervene in diabetic retinopathy (DR), which is another diabetes-specific microvascular complication. Db/db mice were treated with EMPA for different periods to observe the retinas and related mechanisms. EMPA effectively balanced body weight and blood glucose levels, mitigated ocular edema and microaneurysm in db/db mice. EMPA significantly inhibited oxidative stress, apoptosis and recovered tight junction in diabetic retinas. MS/MS analyses showed that EMPA suppressed aberrant branched-chain amino acid (BCAAs) accumulation in db/db retinas, which led to the inhibition of the mammalian target of rapamycin activation, downregulation of inflammation, and angiogenic factors, including TNF-ɑ, IL-6, VCAM-1, and VEGF induced by diabetes. Furthermore, branched-chain α-keto acids (BCKAs), which are catabolites of BCAAs, were increased in diabetic retinas and decreased with EMPA application. Moreover, branched-chain ketoacid dehydrogenase kinase (BCKDK) was enhanced, BCKDHA and BCKDHB were decreased in diabetic retinas. This could be reversed by EMPA treatment, thus promoting BCAAs catabolism to decrease BCAAs and BCKAs accumulation in diabetic retinas. The high levels of BCAAs in the plasma and enhanced L-type amino acid transporter 1 (LAT1) were responsible for the high levels of BCAAs in diabetic retinas, which could be inhibited by EMPA. Overall, EMPA could ameliorate DR manifestations. The normalization of BCAAs catabolism and intake may play a role in this process. This study supports EMPA as a protective drug against DR.
恩格列净（EMPA）是首个可显著降低 2 型糖尿病患者心血管和肾脏并发症的钠-葡萄糖共转运蛋白 2 抑制剂。鉴于此，我们推测 EMPA 可能具有干预糖尿病性视网膜病变（DR）的潜力，DR 是另一种糖尿病特异性微血管并发症。我们用 EMPA 对 db/db 小鼠进行了不同时间的处理，以观察其视网膜及相关机制。EMPA 有效平衡了体重和血糖水平，减轻了 db/db 小鼠的眼部水肿和微动脉瘤。EMPA 显著抑制了氧化应激、细胞凋亡，并恢复了糖尿病视网膜中的紧密连接。MS/MS 分析表明，EMPA 抑制了 db/db 视网膜中异常支链氨基酸（BCAAs）的积累，从而抑制了哺乳动物雷帕霉素靶蛋白的激活、炎症和血管生成因子（包括 TNF-ɑ、IL-6、VCAM-1 和 VEGF）的下调，这些因子是由糖尿病引起的。此外，支链α-酮酸（BCKAs），即 BCAAs 的代谢产物，在糖尿病视网膜中增加，并随 EMPA 的应用而减少。此外，支链酮酸脱氢酶激酶（BCKDK）在糖尿病视网膜中增强，BCKDHA 和 BCKDHB 减少。这可以通过 EMPA 治疗得到逆转，从而促进 BCAAs 代谢，减少糖尿病视网膜中 BCAAs 和 BCKAs 的积累。血浆中 BCAAs 水平升高和 L 型氨基酸转运蛋白 1（LAT1）增强是导致糖尿病视网膜中 BCAAs 水平升高的原因，而 EMPA 可以抑制这一过程。总之，EMPA 可以改善 DR 表现。BCAAs 代谢和摄取的正常化可能在这一过程中发挥作用。本研究支持 EMPA 作为一种防治 DR 的保护药物。
