IRS1 and obesity due to melanocortin 4 receptor deficiency: First of all, the defects downstream of insulin receptor phosphorylation, such as activation of phosphorylated IRS-1 through PKC or GLUT-4 translocation through PI3K/Akt signaling pathway, are the causes of IR in some PCOS women.41,339 Second, certain proinflammatory mediators including TNF, C-reactive protein (CRP), monocyte chemoattractant protein-1 (MCP-1) and IL-18 levels are elevated in PCOS women independently of obesity.340–342 Furthermore, hyperglycemia may contribute to inflammation in PCOS, possibly by inducing oxidative stress via increased ROS production.