Schematic diagram proposing that INS and ALDO act both independently and additively through their respective receptors. Under physiological levels (left-hand side) of these hormones appropriate vascular and cardiac relaxation is favoured, via NO-dependent mechanisms. In contrast, when excessive levels of INS and ALDO/MR activation (right-hand side) result from nutrient excess/obesity (Figure 1), this relationship shifts to promote cardiovascular stiffening and dysfunction by pathways involving increased activity of the endothelial Na⁺ channel, EnNaC, and decreased NO bioavailability (see text). In excess, INS and ALDO synergize to promote mTORC2/SGK1 activation of EnNaC and consequent CV fibrosis, stiffening and impaired function. Akt, Protein kinase B; CV, cardiovascular; EC MR, endothelial cell mineralocorticoid receptor; EnNaC, endothelial cell epithelial Na⁺ channel; eNOS, endothelial nitric oxide synthase; IRS-1, insulin receptor substrate 1; mTORC2, rapamycin-insensitive mTOR protein complex; NO, nitric oxide; PI3K, phosphoinositide 3 kinase; ROS, reactive oxygen species; SGK1, serum and glucocorticoid regulated kinase.