IRS1 and obesity due to melanocortin 4 receptor deficiency: As the most abundant circulating leukocytes in humans, neutrophils are increased in WAT and produce the serine protease neutrophil elastase that cleaves insulin receptor substrate 1 (IRS1), preventing IRS1 from binding to PI3K and leading to insulin resistance,418 and the activation of the PI3K pathway is also important in pancreatic carcinogenesis in obesity and DM.