Abstract
Background: An unexpected increase in the rate of severe diabetic retinopathy was observed in the Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN)-6 clinical trial. Although this effect was attributed to a rapid decrease in blood glucose levels, a direct deleterious effect of semaglutide on the retina could not be ruled out. In order to shed light on this issue, we have performed a study aimed at testing the direct effect of semaglutide administered by eye drops on retinal neuroinflammation and microvascular abnormalities using the db/db mouse model. Methods: Eye drops containing semaglutide (0.33 mg/mL; 5 μL once/daily) or vehicle (PBS; 5 μL once daily) were administered for 15 days. Results: We found that semaglutide significantly reduced glial activation, as well as the retinal expression of Nuclear factor kB (NF-κB), proinflammatory cytokines (IL-1β, IL-6, IL-18) and Intercellular Adhesion Molecule (ICAM)-1. In addition, semaglutide prevented the apoptosis of cells from the retinal ganglion layer and activated the protein kinase B (AKT) pathway. Finally, a dramatic decrease in vascular leakage was observed in db/db mice treated with semaglutide. All these findings were observed without any change in blood glucose levels and, therefore, can be directly attributed to semaglutide. Conclusions: These experimental findings point to a beneficial rather than a deleterious effect of semaglutide on the retina of subjects with diabetes.
Highlights
Neurodegeneration has emerged in recent years as a key element involved in the pathogenesis of early stages of diabetic retinopathy (DR) [1,2]
We did not find any difference in blood glucose concentrations and body weight during study betweenindb/db mice treated with semaglutide and db/db
We found a significant increase incyclase ratio pAkt/Akt in the retinas of diabetic mice treated with semaglutide, suggesting that in theratio activation of GLP-1R
Summary
Neurodegeneration has emerged in recent years as a key element involved in the pathogenesis of early stages of diabetic retinopathy (DR) [1,2]. The Consortium for the Early Treatment of Diabetic Retinopathy (EUROCONDOR) study has shown that a significant proportion of patients present retinal microangiopathic abnormalities without any sign of neurodegeneration [4,5]. This finding suggests that neurodegeneration does not always play a role in the development of DR, and points to drugs that protect both neurons and microvessels as the best candidates for treating early stages of DR. Effects of the Topical apoptosis of cells from the retinal ganglion layer and activated the protein kinase B (AKT) pathway
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