The Insulin Receptor
Activation of insulin receptors is directly linked to glucose uptake via many internal cellular mechanisms that determine the number and functioning of protein molecules carying glucose into the cell.
Insulin activates the external alpha units of the insulin receptor tyrosine kinase (IR). This initial binding causes a conformational change, activating the kinase domain of the intracellular beta subunits. This cascade continues to autophosphorylate and recruits IRS family of proteins as well as many other substrate adaptors. Tyrosine phosphorylated IRS then triggers numerous signaling events.
- Stimulation of glucose uptake (myocytes adipocytes): Translocation of GLUT4 vesicles to the plasma membrane.Adipocytes along with myocytes are the most heavily influenced by insulin of all the tissue types.
- Growth and mitogenic effects: Triggered by the Akt cascade and the activation of the Ras/MAPK pathway.
- Inactivation of IRS signaling: Maintained through a negative feedback signal involving Akt/PKB, PKCΖ, p70 S6K and the MAPK cascades.
- Action of Noradrenaline: This stress hormone inhibits insulin release via α2-receptors, therefore a lowering in blood glucose levels and a possible subsequent weight loss.
- Action of Adrenaline: Stimulation of β2-receptors and promotion of insulin release.
The signalling cascade:
Please see the diagram below for an integrative approach of signalling cascades.
- phosphorylated IRS-1 binds to and activates phosphoinositol 3 kinase (PI3K)
- PI3K catalyzes the reaction PIP2 + ATP → PIP3 and induces activation of the Akt/PKB and the PKCΖ cascades
- Activated Akt induces glycogen synthesis, through inhibition of GSK-3
- PIP3 activates protein kinase B (PKB)
- PKB phosphorylates glycogen synthase kinase (GSK) and thereby inactivates GSK.
- GSK can no longer phosphorylate glycogen synthase (GS)
- unphosphorylated GS makes more glycogen
- PKB also facilitates vesicle fusion, resulting in an increase in GLUT4 transporters in the plasma membrane.
- Cell survival by inhibition of pro-apoptotic agents e.g. Bad andGSK-3.