Recent studies have recognized signaling of wingless-type family member (Wnt) 5a through c-jun N-terminal kinase (JNK) as a metabolic dysfunction regulator with potential significance to vascular function [
92,
93]. Furthermore, it was observed that noncanonical Wnt5a signaling and JNK activity may contribute to vascular insulin resistance as well as endothelial dysfunction and may represent a novel therapeutic target to protect the vasculature in patients with diabetes mellitus [
94]. Furthermore, endothelium possess a limited inherent self-repair ability because of being formed from terminally differentiated cells of low proliferative potential, called as endothelial progenitor cells (EPCs). Previous studies have stated the prime role of EPCs in progression and development of vascular complications in T2DM patients [
95,
96]. Another study has demonstrated effects of chronic administration of phosphodiesterase inhibitors on endothelial markers in T2DM patients [
97]. In this study, beneficial effects of chronic use of PDE5i on endothelial function were observed. Furthermore, chronic administration of Sildenafil was found to improve serum pro-inflammatory maker (IL-6) and hemodynamic parameter (FMD) T2DM patients. Moreover, another study has reported the role of impaired autophagy in endothelial dysfunction in diabetic patients, which may be considered as a therapeutic target for diabetic vascular compilations [
98]. In endothelial cells, eNOS uses
l-arginine to produce NO, where arginase utilizes
l-arginase to produce ornithine and urea [
99,
100]. In addition, arginase up-regulation has been shown to reduce NO production by reducing bioavailability of
l-arginine to eNOS, thus playing an important role in vascular dysfunction in diabetes [
101]. Furthermore, endothelial function was reported to be improved in T2DM patients, without changes in HbA1c levels, by intervention with a fiber-rich diet with brown rice possibly through reduction of postprandial glucose excursions [
102]. Furthermore, activation of nuclear factor (erythroid‑derived 2)‑like 2 (Nrf2), a ubiquitously expressed redox sensitive transcription factor, has been shown to attenuate endothelial dysfunction, along with downregulation of inflammatory as well as pro-oxidant genes and reduction of leukocyte–endothelial interactions [
103‐
107]. This represents a novel therapeutic approach to inhibit diabetes related vascular injury. Furthermore, a study including diabetic patients has suggested that arginase inhibitors may prevent the endothelial dysfunction and maintain NO levels in these patients [
108]. Moreover, Ipragliflozin (a novel selective sodium–glucose cotransporter 2 (SGLT2) Inhibitor) has been shown to improve hyperglycemia and prevent the development of endothelial dysfunction in a streptozotocin-induced diabetic mouse [
109]. Furthermore, another SGLT2 Inhibitor, dapagliflozin have shown to reduce blood pressure and improve glycemic control in T2DM patients [
110‐
112]. In addition to this, acute administration of dapagliflozin resulted into significantly improved systemic endothelial function, renal resistive index, arterial stiffness and parameters associated with the early stages of vascular remodeling [
110,
113]. Moreover, as add-on therapy to metformin for 16 weeks, dapagliflozin improves FMD assessed endothelial function in patients with inadequately controlled early-stage T2DM [
114]. Additionally, dipeptidyl peptidase inhibitors (such as linagliptin and voglibose), one of the recently introduced classes of oral glucose-lowering drugs, has been shown to significantly improve microvascular function in the fasting state and ameliorate cardiometabolic and renal parameters in the newly diagnosed T2DM and CAD patients [
115,
116]. Furthermore, various cross-sectional studies have observed elevated levels of ADMA in T2DM Patients with macrovascular diseases [
117,
118]. Moreover, ADMA is suggested as an independent risk factor for mortality and CVD in a wide spectrum of populations [
119,
120]. As mentioned previously, accelerated atherosclerosis in T2DM is also associated with decreased activity of PON-1. Rosuvastatin, a class of statins, was shown to improve microvascular reactivity with associated beneficial changes in the postprandial levels of ADMA and PON-1 [
121]. Furthermore, a continuous intravenous infusion of glucagon-like peptide-1 (GLP-1) analogs was reported to improve the blood glucose-independent vascular endothelial dysfunction in T2DM patients with stable CAD [
122]. Moreover, exenatide (GLP-1 analog) was shown to inhibit the postprandial vascular endothelial dysfunction and was suggested to have multiphasic anti-atherogenic actions involving not only glucose but also lipid metabolism [
123]. It was also reported that GLP-1 receptors are expressed on vascular endothelial cells and directly increase the production of NO and restrict the expression of endothelial cell adhesion factors [
124,
125]. Furthermore, Biomarkers of inflammation and endothelial dysfunction such as ICAM-1 and E-selectin were observed to be positively correlated with incident T2DM, adding to the estimation of T2DM beyond a common risk score [
126]. Additionally, circulating microparticles (endothelial- and platelet derived) levels have been proposed to be one of the important procoagulant determinants in T2DM patients [
127]. Levels of endothelial- derived microparticles such as CD105
+, PECAM-1, 62E
+ and CD106
+ as well as platelet-derived microparticles including P-selectin, fibrinogen, TF have been reported to be significantly higher in T2DM patients as compared to healthy controls [
79,
128‐
130]. Furthermore, miRs (miR-320, miR-221, miR-222, miR-503, miR-126), a class of small non-coding RNAs, are suggested to play an important role in pathogenesis of vascular damage induced by hyperglycemia [
131,
132]. Various microarray studies have observed the altered expression of miRs in T2DM patients [
132‐
134]. A recent study has shown the critical involvement of miR-503 in hyperglycemia-induced endothelial dysfunction in diabetic mice and up-regulation of ischemic limb muscles in diabetic subjects. Remarkably, inhibition of miR-503 resulted in normalization of post-ischemic neovascularization and blood flow recovery in these diabetic mice [
135]. Furthermore, numerous studies have shown decreased plasma concentration of adiponectin (APN), a multifunctional adipocytokine of adipose tissue, in T2DM patients, indicting its important role in pathogenesis of T2DM [
136‐
138]. Additionally, T-cadherin (T-cad), a unique member of the cadherin family, has been identified as an important receptor of APN [
139‐
142]. A recent in vivo study has shown that T-cad deficiency may cause endothelial dysfunction in T2DM vascular segments, suggesting an important role of T-cad in pathogenesis of T2DM. Therefore, altering T-cad deficiency may represent another potential therapeutic strategy in the amelioration as well as prevention of vascular injury in the T2DM [
143].