Mechanisms of Insulin Signal Transduction
W. Timothy Garvey,
W. Timothy Garvey
University of Alabama at Birmingham, and the Birmingham Veterans Affairs Medical Center, Birmingham, AL, USA
Search for more papers by this authorW. Timothy Garvey,
W. Timothy Garvey
University of Alabama at Birmingham, and the Birmingham Veterans Affairs Medical Center, Birmingham, AL, USA
Search for more papers by this authorAbstract
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 pleiotrophic actions, insulin engages multiple signal transduction, pathways that affect the expression and posttranslational 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 (IRS) docking molecules, (ii) activation of phosphatidylinositide 3 (PI-3) kinase, and (iii) activation of Akt/protein kinase B (PKB). 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, that then interact with systems regulating trafficking of GLUT-4-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, and present an increasing number of targets for therapeutic intervention in treating human insulin resistance.
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