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  • Gliptins have become a part of


    Gliptins have become a part of various therapeutic regimens to treat type 2 diabetics in recent decades. Gliptins were developed to lower the blood glucose in type 2 diabetes patients and have been shown to be effective [4,5]. More than a dozen gliptins have been developed for the treatment of T2DM, including the most commonly used alogliptin, linagliptin, saxagliptin, sitagliptin, and vildagliptin [6]. In this study, we report that linagliptin, a commercially available DPP-4 inhibitor, actually exerts a protective effect in cultured retinal vascular endothelial cells.
    Materials and methods
    Discussion Like other gliptin compounds, linagliptin acts by inhibiting the enzymatic activity of DPP-4, stabilizing incretins such as GLP-1, and ultimately lowering blood glucose. Linagliptin is unique among the gliptins. Its administration has a mild influence on hepatic function, and it is excreted largely by non-renal routes. Therefore, dose adjustment is not required in patients with renal and hepatic impairment [5]. Aside from its ability to lower blood glucose, linagliptin has been shown to be effective for cardiovascular outcomes [8]. In vascular endothelial cells, recent studies have shown that linagliptin has vascular benefits and these properties are independent of its glucose-lowering property. Multiple separate studies have shown that linagliptin treatment could prevent diabetes condition and generation of ROS and inflammatory genes including RAGE, ICAM-1, SOD2, and PAI-1 expression in endothelial DZNep induced by its byproducts [[9], [10], [11]]. Vellecco V et al. showed that linagliptin exerts a direct vasodilation activity on vessels from both normal and hyperglycemic mice, suggesting that the vascular effect of linagliptin is independent from its ability to control glucose. Additionally, cell experiments have concluded that linagliptin increases eNOS availability and enhances NO production [12]. Romacho T et al. found that linagliptin helps to preserve microvascular endothelial function by suppressing PAR2 activation and thromboxane A2 release [13]. Endothelial progenitor cells (EPCs) play key roles in the process of endothelial repair and replacement for vascular homeostasis and neoangiogenesis [14]. In type 2 diabetes patients, EPCs are known to be reduced. A recent study reported that linagliptin acutely increases the number of endothelial progenitor cells [15]. Endothelial-to-mesenchymal transition (EndMT) is the cellular process in which endothelial cells lose their identity as a result of environmental changes, and EndMT has been implicated in vascular remodeling and various disease conditions. Studies have shown that linagliptin possesses unique specific effects and can suppress transforming growth factor-β2-induced endothelial-mesenchymal transition [16,17]. Additionally, the versatility of linagliptin is reflected in its ability to inhibit angiogenesis signaling and reduce neovascularization in both HUVECs and brain vascular endothelial cells [18,19]. In preclinical animal model studies, linagliptin administration has been shown to possess vascular protective effects. Michurina et al. report that linagliptin administration could protect the hepatic microvasculature in a diabetic fatty liver mouse model [20]. Manrique et al. demonstrate that linagliptin administration could prevent high fat diet-induced aortic stiffening, vascular oxidative stress, endothelial dysfunction, and vascular remodeling [21]. Hardigan et al. report that linagliptin administration in diabetic rats reduces plama ET-1 levels and cerebrovascular hyperreactivity. This effect is potentially the result of linagliptin causing a decrease in endothelial TLR2 expression and a subsequent increase in NO bioavailability [22]. A study using an LPS-induced rat sepsis model showed that administration of linagliptin has pleiotropic vasodilatory, antioxidant, and anti-inflammatory properties [8]. In atherosclerosic mice, linagliptin ameliorates hyperlipidemia-induced endothelial dysfunction [18]. In humans, a randomized placebo-controlled study demonstrated that Linagliptin tends to improve endothelial and microvascular function in patients with type 2 diabetes [23].