Physiology lecture on endocrine system physiology details mechanism of action of insulin.

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There are 2 fundamental signal transducing pathways by which insulin acts:
1. Phosphotidylinositol3 kinase or PI3Kinase pathway
2. RasMAP kinase pathway.

Insulin acts by binding to its receptors which are present on the cell membrane of its target cell. Insulin receptors are enzyme linked receptors which have inherent tyrosine kinase enzyme activity. The insulin receptors are present as tetramers i.e they have 4 polypeptides or subunits which assemble to form the receptor. Two of these subunits are alpha subunits while the other two are beta subunits. Alpha subunits project outside the membrane i.e form the extracellular part of the receptor which has the binding site for insulin. The beta subunits traverse through the membrane and protrude into the cytoplasm and has intrinsic tyrosine kinase activity i When insulin is not bound to the receptors, the tyrosine kinase is inactive. When the insulin binds to its receptors, the tyrosine kinase activity of beta subunits activates which then crossphosphorylate tyrosine residues of each other. This receptor then binds to insulin receptor substrates. Once that happens this insulin receptor substrate becomes a docking site for other kinases and adaptor proteins.

PI3Kinase pathway:

Phosphotidylinositol3 kinase phosphorylates phosphatidylinositol 45 biphosphate. For this, initially it binds to IRS. This brings it close to its substrate which is present on the membrane and also activates it by phosphorylation. Then, it phosphorylates, PIP2 forming phosphotidyinositol 3,4,5 triphosphate. Now this triphosphate also acts as a docking site for 2 other kinases i.e phosphoinositide dependent kinase 1 and Protein kinase B. Now PDK1 phosphorylates protein kinase B or AKT thus activating it. It is this protein kinase B which now dissociates and moves into the cytoplasm which then causes insertion of GLUT 4 receptors on the membrane, activates glycogen synthase for conversion of glucose to glycogen, inactivates glycogen phosphorylase for preventing glycogenolysis and hence causes varied effects on metabolism.

2. RASMAPK pathway

Monomeric Gproteins have the ability to bind GDP and GTP. In inactive state , they are bound to GDP while when active they bind to GTP just like our trimeric G proteins. For activating it, insulin receptor substrate binds with another adaptor protein GRB2 which in turn binds and activates a Guanine exchange factor protein SOS which replaces Ras GDP with GTP causing its activation. The activation of Ras inturn leads to activation of kinase cascade including Raf, MEK and then ultimately leading to the activation MAPKinase. After activation, MAP kinase translocates into the nucleus and phosphorylates many transcription factors that regulate expression of important cellcycle and differentiationspecific proteins. So that’s how insulin has effects on cell proliferation, growth and differentiation.

In summary, insulin acts by 2 signal transduction pathways: PI3Kinase pathway responsible for its metabolic actions and some survival actions also and Ras MAP kinase pathway responsible for its effects on cell proliferation, growth and differentiation.

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