Role of insulin and insulin resistance in androgen excess disorders

Figure 2 A brief scheme of the insulin signaling pathway in the presence of insulin resistance. Not all insulin signaling pathways are equally affected, and selective insulin resistance is observed. (Partial) resistance in the phosphatidylinositol-3-kinase/serine/threonine-specific protein kinase B pathway results in decreased glucose uptake mediated by insufficient translocation of glucose transporter 4 and decreased inhibition of lipolysis and gluconeogenesis. Additionally, deficient activation of endothelial nitric oxide synthase is also observed. Insulin-resistance-associated hyperinsulinemia promotes anabolic cell activities via the mitogen-activated protein kinase (MEK)/extracellular signal-related kinase (ERK) pathway and via mechanistic target of rapamycin complex 1. In addition to the anabolic actions of signaling via the MEK/ERK pathway, there is also enhanced expression of plasminogen 1 and endothelin 1. The inhibition of nuclear factor 2 compromises cell defense mechanisms against radical stress. Dotted lines represent inhibition, and solid lines represent stimulation/activation. IRS: Insulin receptor substrate; SHC: Src homology 2 domain-containing transforming proteins; MEK: Mitogen-activated protein kinase; ERK: Extracellular signal-related kinase; PI3K: Phosphatidylinositol-3-kinase; AKT: Serine/threonine-specific protein kinase B; mTORC: Mechanistic target of rapamycin complex 1; GLUT4: Glucose transporter 4; ET-1: Endothelin 1; eNOS: endothelial nitric oxide synthase; PAI: Plasminogen activator.