Kinase linked receptors – Diabetes

It has rapid effects on metabolism, exerted via altered activity of enzymes and transport enzymes. Insulin has longer term actions via altered enzyme synthesis.

Mechanism of Action

Insulin binds to a specific receptor on the surface of its target cells. The receptor is a large transmembrane glyco – protein complex consisting of 2 α subunits and 2 β subunits. The α subunits are entirely extracellular and each carries an insulin binding site, whereas the β subunits are transmembrane proteins with tyrosine kinase activity. This activity is suppressed by the α subunits, but insulin binding causes a conformational change that depresses (activates) the tyrosine kinase activity of the β subunits which act on each other (autophosphorylation) and on other target proteins.

Activation of phosphatidylinositol 3 – kinase by interaction of its SH2 domain with phosphorylated IRS (Insulin Receptor substrate) has an important effect in the recruitment of insulin sensitive glucose transporters (Gtat- 4) from the Golgi apparatus to the plasma membrane in muscle and fat cells.

Functions of insulin: • Decreasing blood glucose by

o Increasing glucose uptake into muscle and fat via Glut-4

o Increasing glycogen synthesis

o Decreasing gluconeogenesis

o Decreasing glycogen breakdown

References:

• Pharmacology by H.P.Rang, M.M.Dale and J.M.Ritter.

• Essentials of Medical Pharmacology by K.D.Tripathi