What is Insulin?
- Insulin is a naturally occurring peptide hormone produced by the pancreas, specifically by beta cells in the islets of Langerhans.
- It’s a protein hormone composed of two chains (A and B) linked by disulfide bonds.
- First successfully isolated and used in 1921 by Frederick Banting and Charles Best, revolutionizing diabetes treatment.
How Insulin receptor mediated signaling works?
Phase 1: The Master Switch
(Initiation)
Ligand Binding: Insulin (or IGF-1/2) binds to
the extracellular alpha subunits of the insulin receptor (IR).
Conformational Change: Binding triggers a shape change
across the membrane, activating the tyrosine kinase (Tyr-K) domains on
the intracellular beta subunits.
Autophosphorylation: The receptor performs trans-autophosphorylation,
where the two beta subunits phosphorylate each other to create docking sites
for signaling proteins.
Phase 2: The Docking Station
(Substrate Recruitment)
The activated IR recruits several primary substrates,
which act as a hub for the signal to split into two distinct directions:
1. IRS (Insulin Receptor
Substrates): The
primary mediators for metabolic signals family of signalling proteins specifically
phosphorylating IRS-1 and IRS-2
2. SHC: A protein that primarily
initiates the growth-related signaling cascade.
Pathway
1: The Metabolic Pathway (PI3K/AKT)
Function: Responsible for glucose, lipid, and
protein management.
Activated insulin
receptor upon insulin binding activates IRS by phosphorylating specifically
IRS-1 and IRS-2
1. PI3K Activation: Phosphorylated IRS
recruits Phosphoinositide-3-Kinase (PI3K).
2. Lipid Conversion: PI3K converts the membrane lipid
Phosphatidylinositol 4,5-bisphosphate (PIP2) into PIP3 (Phosphatidylinositol
4,5-bisphosphate).
3. Kinase Recruitment: PIP3 activates and pulls PDK1
and AKT (Protein Kinase B) to the cell membrane.
4. AKT Activation: PDK1 phosphorylates AKT, making
it fully active to move throughout the cell.
5. Glucose
Uptake: Stimulates GLUT4 translocation to the plasma membrane. In muscle
and fat cells, majority of GLUT4 are held in intracellular vesicles.
6. Activated AKT Phosphorylates a
substrate called AS160.
7. This
Activates small GTPases (RAB proteins) involved in exocytosis
of GLUT4 Storage Vesicles (GSVs)
8. GSVs fuses and embed GLUT4 in the plasma membrane thus enhances cells capacity of glucose uptake
Metabolic Actions triggered by
this pathway
- Glucose Uptake: Stimulates GLUT4
translocation to the plasma membrane.
- Glycogen Synthesis: Inhibits GSK3 to promote
sugar storage.
- Protein Synthesis: Activates mTOR.
- Gluconeogenesis Inhibition: Phosphorylates FoxO transcription factors to prevent the liver from making excess sugar.
To prevent over-activation, which can lead to disease, the signal is terminated by:
- Phosphatases: PTP1B dephosphorylates the IR, while PTEN and SHIP2 dephosphorylate PIP3 to stop the AKT branch.
- Stress Kinases: JNK and IKK add inhibitory serine phosphates to IRS, blocking its connection to the receptor.
- Internalization: The receptor is physically removed from the surface via endocytosis.