INS and obesity due to melanocortin 4 receptor deficiency: In fact, insulin-resistant endothelium and the resultant impairment in PI3K-AKT-eNOS signaling have been proposed to underlie much of the endothelial dysfunction observed in the setting of obesity and T2D, predisposing to hypertension, atherosclerosis, and vascular disease (Janus et al., 2016; Kearney et al., 2008; Muniyappa and Sowers, 2013).