Mechanisms of insulin signal transduction

The peptide hormone insulin is secreted from pancreatic β cells, binds to cell surface receptors, and exerts a broad spectrum of anabolic effects in multiple tissues. In mediating its pleiotropic actions, insulin engages multiple signal transduction pathways that affect the expression and post-translational modification of proteins, and regulates enzymatic pathways, subcellular protein localization, and the activation state of membrane transport systems. There are three major steps that provide for divergence of insulin signal transduction leading to different functional effects: (i) the family of insulin receptor substrate docking molecules, (ii) activation of phosphatidylinositide-3 kinase, and (iii) activation of akt/protein kinase B. Stimulation of the glucose transport system involves activation of two parallel pathways, the IRS/PI-3 kinase pathway (resulting in activation of akt/PKB and PKC λ/ζ) and the CAP/Cbl/TC10 pathway which then interact with systems regulating trafficking of GLUT4-containing vesicles and the cytoskeleton. Furthermore, multiple mechanisms modulate insulin signal transduction by affecting the serine/threonine phosphorylation state of tyrosine kinase substrates and phosphoinositides, and the tyrosine phosphorylation state of insulin receptors and IRS molecules. Thus, promulgation of the insulin action is most accurately viewed as a flexible pattern of network interactions involving a web of signal molecule cascades and effector systems. Complex patterns of interactions among signal and effector systems allow for greater plasticity in adaptive responses. Human insulin resistance involves two major loci of defects contributing to human insulin resistance: impaired proximal signal transduction characterized by reduced tyrosine phosphorylation of insulin receptor and insulin receptor substrate molecules, and abnormalities in GLUT4 vesicle trafficking that impair translocation to the cell surface.