Mechanism of Action of Insulin

Mechanism of Action of Insulin

Mechanism of Action of Insulin

Insulin, a major pancreatic hormone, acts on many tissues and organs in the body, including the Liver, Fat, Muscle to regulate blood glucose levels. Insulin Receptor plays a major role in maintaining glucose homeostasis.

It is a transmembrane receptor, form by four glycoprotein subunits 2 alpha subunits, and two beta subunits linked to each other by a disulfide bond. It has an extracellular receptor domain for binding with insulin. It has an extracellular receptor domain, for binding with insulin. And intracellular part, which has a catalytic domain, and has intrinsic enzyme activity as they have tyrosine kinase enzyme. Thus they belong to receptor tyrosine kinase, part of large receptor superfamilies called Kinase Linked Receptor.

What is Kinase?

Protein kinases are the enzymes, that transfer the phosphate group onto a target protein, thereby changing the protein function from inactive to active.
Usually, Adenosine Triphosphate, ATP is used as a source of phosphate donor. But, phosphorylation may not always activate the protein. Phosphorylated protein can either be Activated, Deactivated, Or, passes signals (forming signal cascade).

Protein Kinase can be classified according to the amino acid they phosphorylated. There are usually 3 amino acids upon which they act.

One is Receptor Tyrosine Kinase - which phosphorylates the tyrosine amino acid. The second one is Serine/Threonine Kinase - which phosphorylates the serine & threonine amino acids. Insulin Receptor is the example of Receptor Tyrosine Kinase

Key points to remember here are:

Receptors are the protein molecules, which are the polymer of amino acids.

Similarly, the Beta-subunit of the insulin receptor contains:

Tyrosine amino acids (called as tyrosine residues) &
Tyrosine Kinase enzyme - which phosphorylates the tyrosine amino acid.

 

Mechanism of action of insulin

In summary, insulin acts by two signal transduction pathways.

PI3K Kinase pathway - responsible for its metabolic actions.
Ras MAP kinase pathway - responsible for its effects on cell proliferation, growth, and differentiation.

Here, we will look over the PI3K kinase pathway.

Insulin is an agonist at this receptor. After a meal, the concentration of glucose in the body, increases. In response, the pancreas secretes more insulin.

The binding of insulin to an alpha-subunit chain of the insulin receptor causes conformational changes, and transmembrane domains get closer, which active and increases, the intrinsic tyrosine kinase enzyme activity present in the catalytic domain, & phosphorylate the tyrosine residues of another domain and the process called cross phosphorylation, or Auto-phosphorylation of tyrosine residues of insulin receptor - as insulin has it own intrinsic tyrosine kinase enzyme for phosphorylation.

This, in turn, leads to phosphorylation of no. of an intracellular substrate which initiates many different signaling cascades. One of those, intracellular substrates is the protein, IRS-1, which once phosphorylated recrudesce & activates the lipid kinase, PI3K. PI3K is a key enzyme in insulin signaling, phosphorylate the specialized phospholipid, PIP2 - converting it to PIP3.

PIP3 activates the enzyme, PDK-1. PDK-1 leads to the activation, of the enzyme, AKT.  AKT initiates a series of steps - that leads to the translocation of vesicles containing the glucose transporter, GLUT 4. The vesicles move to the cell surface, where they fused to the cell membrane.  Once translocated, to the membrane, GLUT 4 transports glucose into the cell, where depending on the cell types, it can be stored, or used for energy.

In Type-1 diabetes, insulin production is absent or diminished. And the signaling cascade - cannot occur. As a result, glucose remains outside of the cell. To treat, Type-1 diabetes, insulin may be delivered - by injection, initiating the signaling pathway, and allowing glucose to enter the cell, restoring homeostasis.
 
In contrast, individuals with Type-2 diabetes, don't have diminished or absent insulin production. Instead, the signaling cascade downstream of the receptor is impaired. This reduced response to insulin in the cell.