Mechanism of Action Of Insulin

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Chapter: Essential pharmacology : Insulin, Oral Hypoglycaemic Drugs and Glucagon

Insulin acts on specific receptors located on the cell membrane of practically every cell, but their density depends on the cell type: liver and fat cells are very rich. The insulin receptor is a hetero-tetrameric glycoprotein consisting of 2 extracellular α and 2 transmembrane β subunits linked together by disulfide bonds.


MECHANISM OF ACTION OF INSULIN

 


 

Insulin acts on specific receptors located on the cell membrane of practically every cell, but their density depends on the cell type: liver and fat cells are very rich. The insulin receptor is a hetero-tetrameric glycoprotein consisting of 2 extracellular α and 2 transmembrane β subunits linked together by disulfide bonds. It is oriented across the cell membrane as a heterodimer (Fig. 19.3). The α subunits carry insulin binding sites, while the β subunits have tyrosine protein kinase activity.

 

Binding of insulin to α subunits induces aggregation and internalization of the receptor along with the bound insulin molecules. This activates tyrosine kinase activity of the β subunits pairs of β subunits phosphorylate tyrosine residues on each other expose the catalytic site to phosphorylate tyrosine residues of Insulin Receptor Substrate proteins (IRS1, IRS2, etc). In turn, a cascade of phosphorylation and dephosphorylation reactions is set into motion resulting in stimulation or inhibition of enzymes involved in the rapid metabolic actions of insulin.

 

Certain second messengers like phosphatidyl inositol trisphosphate (PIP3) which are generated through activation of a specific PI3kinase also mediate the action of insulin on metabolic enzymes.

 

Insulin stimulates glucose transport across cell membrane by ATP dependent translocation of glucose transporter GLUT4 and GLUT1 to the plasma membrane as well as by increasing its activity. Over a period of time it also promotes expression of the genes directing synthesis of GLUT4. Genes for a large number of enzymes and carriers have been shown to be regulated by insulin primarily through MAP kinases. Activation of transcription factors also promotes proliferation and differentiation of specific cells.

 

The internalized receptor insulin complex is either degraded intracellularly or returned back to the surface from where the insulin is released extracellularly. The relative preponderance of these two processes differs among different tissues: maximum degradation occurs in liver, least in vascular endothelium.

 

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