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Andreia Gonçalves, Ermelindo Leal, Artur Paiva, Carlos Ribeiro, Flávio Reis, Antonio Ambrosio, Rosa Fernandes; Sitagliptin prevents blood-retinal barrier breakdown, inflammation and neuronal cell death in the retina of type 1 diabetic animals. Invest. Ophthalmol. Vis. Sci. 2013;54(15):6340. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Diabetic retinopathy, the main microvascular complication of diabetes, is a leading cause of vision loss and blindness. A novel class of oral antidiabetic agents, the dipeptidyl peptidase type 4 (DPP-IV) inhibitors, has shown to improve glycemic control by enhancing the levels of active incretin hormones, which in turn increase insulin secretion in patients with type 2 diabetes (T2D). The aim of this work was to evaluate whether sitagliptin can exert protective effects in the retina by a mechanism independent of insulin secretion, in a type 1 diabetes (T1D) animal model.
Two weeks after streptozotocin-induced diabetes, the rats were orally treated with sitagliptin (5 mg/kg/day) for two weeks. Glucose, HbA1c and insulin levels were evaluated in serum or total blood. The blood-retinal barrier (BRB) breakdown was evaluated using Evans blue. The activity of DPP-IV was assessed using a fluorogenic substrate. The content and/or distribution of tight junction (TJ) proteins (occludin, claudin-5 and ZO-1), DPP-IV/CD26, IL-1β, TNF-α and Bax was evaluated by western blotting and/or immunohistochemistry. Retinal cell apoptosis was assessed by the TUNEL assay. The number of CD34+ cells present in the circulation was assessed by flow cytometry.
Sitagliptin treatment had no effect on weight, glucose, HbA1c or insulin levels in diabetic animals. However, it prevented the increase in the activity and content of DPP-IV/CD26 induced by diabetes in serum and retina. Sitagliptin also prevented the increase in BRB permeability and inhibited the alterations in the subcellular distribution of TJ proteins induced by diabetes. Furthermore, sitagliptin was able to prevent the increase in IL-1β, TNF-α, Bax and TUNEL-positive cells in the retinas of diabetic animals. Treatment with sitagliptin prevented the decrease in the number of CD34+ cells in the peripheral circulation of diabetic animals.
In conclusion, sitagliptin inhibits the BRB breakdown in a T1D animal model, by a mechanism independent of normalization of glycemia, by preventing changes in TJ organization. Sitagliptin also exerted protective effects against inflammation and pro-apoptotic state in the retina of diabetic rats. Altogether, these results suggest that sitagliptin might be envisaged to be used in T1D and T2D patients, to prevent or delay the development of diabetic retinopathy.
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