Dapagliflozin protects neural and vascular dysfunction of the retina in diabetes

Abstract

IntroductionDapagliflozin, a sodium-glucose transporter inhibitor, effectively reduces blood glucose and is indicated for individuals with kidney diseases and cardiovascular disorders. In this study, we further expand the therapeutic benefit of dapagliflozin in the neural and vascular retina, with the potential to effectively manage diabetic retinopathy (DR), the most common complication of diabetes.Research design and methodsDb/db mice, an animal model of type 2 diabetes, were treated with dapagliflozin orally, and the electroretinogram (ERG) response and acellular capillary numbers were assessed. Messenger RNA levels of inflammatory cytokines were studied using real-time quantitative (q)PCR. We assessed endothelial cell migration in a scratch wound assay and retinal glucose uptake using human retinal endothelial cells.ResultsThe dapagliflozin treatment improved the ERG b-wave amplitude and decreased acellular capillary numbers. The scratch wound assay demonstrated a reduction in wound closure after dapagliflozin treatment. Retinal glucose uptake reduced after dapagliflozin treatment compared with the respective controls.ConclusionsOur studies suggest that dapagliflozin treatment effectively corrects neural and vascular dysfunction of the retina in diabetes. This effect is mediated by a decrease in inflammation and improved glycemic control. In addition, dapagliflozin exhibits decreased wound healing and glucose uptake, which could benefit the retina. Thus, dapagliflozin could be helpful in the management of DR, with multimodal therapeutic effects.

Determining the Role of SGLT2 Inhibition with Dapagliflozin in the Development of Diabetic Retinopathy

“…However, the nerve fiber and ganglion cell layers were disorganized in these animals [33]. Furthermore, in diabetic db/db mice, DAPA effectively reduced the formation of acellular capillaries and improved the electroretinogram response [47]. Hu et al [35] demonstrated in STZ-induced diabetic mice that DAPA treatment improved the thickness of the inner nuclear and outer nu- clear layers of the neural retina by reducing apoptosis.…”

“…As shown by many studies using SGLT2 inhibitors [33,34,[45][46][47][48][49], the DR associated protective effects of DAPA in Akimba mice is potentially mediated by the improvement in long-term glycaemic control (8 weeks). However, recent studies have shown DAPA induced reductions in oxidative stress [46] and inflammation [46,47] improved retinal vascular and neural pathology in DR. Therefore, future studies should be carried out in the Akimba model to establish the role of oxidative stress and inflammation mitigated by SGLT2 inhibition.…”

Novel Antidiabetic Drugs and the Risk of Diabetic Retinopathy: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

“…Additionally, SGLT-2i appears to exert protective effects on vascular endothelial function, potentially benefiting retinal health by enhancing glycemic control, managing hypertension and hyperlipidemia, and protecting the blood–retinal barrier and retinal capillaries [ 76 ]. Indeed, rodent studies have shown the beneficial effects of SGLT-2i on ophthalmic complications of diabetes, and human studies indicated the ability to reduce diabetic macular edema [ 77 , 78 , 79 , 80 ]. However, in our study, we did not observe a lower risk of DR complications with SGLT-2i use.…”

The Impact of SGLT2 Inhibitors in the Heart and Kidneys Regardless of Diabetes Status

“…Diabetic retinopathy is a common complication associated with diabetes, and the SGLT2i’s EMPA [ 45 ] and DAPA [ 46 ] have improved diabetic retinopathy in T2D db/db mice. Empagliflozin has also been shown to mitigate ocular edema and microaneurysms in the retina as well as inhibit the mammalian target of raptomycin activation.…”

“…Empagliflozin has also been shown to mitigate ocular edema and microaneurysms in the retina as well as inhibit the mammalian target of raptomycin activation. One of the characteristics of diabetic retinopathy in db/db mice is an increase in acellular capillary numbers [ 46 ], and DAPA has been shown to produce a substantial decrease in the acellular capillary numbers compared with placebo. Aside from this, inflammation is another main factor associated with diabetic retinopathy.…”