Synthesis and Pharmacological Properties of Insulin

Islets of langerhans of pancreas contains 4 types of cells –

I. α / A cell	20%	Secretes glucagons ( increase blood glucose level)
II. β/ B cell	68%	Secretes insulin ( decreases blood glucose level)
III. δ / D cell	10%	Secretes somatostatin ( inhibit both insulin and glucagons release)
IV. PP/ F cell	2%	Secretes pancreatic polypeptide ( stimulation of gastric and intestinal enzymes and inhibition of intestinal motility)

   

Insulin is a large polypeptide hormone. It is synthesized in beta cell of pancreas. It consists of 51 amino acid & they are arranged in A chain & B chain. A chain contains 21amino acid & B chain contains 30 amino acid. A chain & B chain are linked together by disulfide bond. In addition, A chain contains another disulfide bond. Disulfide bond are essential for biological activity. Oral administration of insulin; disulfide bond are destroyed by proteolytic enzyme pepsin not by HCl.

Source:

a. Human.

b. Porcine.

c. Bovine

Synthesis of insulin:

Site: Rough endoplasmic reticulum of β cell.

Steps:  Glucose enters in to the cell → converts into glucose metabolites → stimulates RER (rough endoplasmic reticulum)→ synthesis of preproinsulin → which converted to proinsulin → proinsulin transported into golgi complex → & converted into insulin by the enzyme trypsin like enzyme.(These trypsin like enzyme are transmitted genetically into the individual , the person had lack of these enzyme who has suffer  DM). Then insulin is packaged into the granules→ granule fused with cell membrane →exocytosis of insulin →release of insulin into the capillary blood.

Insulin exists in our body in 3 forms:

1. Monomers-single molecule active form.

2. Dimer –double molecule inactive form.

3. Hexamer- It is storage form of insulin in granules of β cell. It is stored in the form of crystal & consists of 2 molecule of zinc & 6 molecule of insulin.

Daily release of insulin is 18- 40 units.

It is metabolized by enzyme insulinase.

M/A of insulin (cellular/molecular mechanism):

Insulin receptor is a tetramer made up of two alpha (α) & two beta (β) glycoprotein subunits & binds by disulfide bonds. The a subunit binds with insulin extra cellularly & β subunit is transmembrane protein & its intracellular end has tyrosine kinase activity. Binding of insulin triggers the tyrosine activity of the β subunits producing autophosphorylation of the β subunits on the tyrosine residue.

Autophophorylation of the β subunit leads to phosphorylation of some enzyme in the cytosol .The activated enzyme then produce action.

Pharmacological properties of insulin

Insulin promotes storage of fat, as well as glucose (both are sources of energy) in target cell & influences growth of cells & metabolic function of tissue.

A. Action of insulin on glucose transports: Insulin has an important effect on several transport molecules that facilitates glucose transport or movement across the cell membrane. These transporters play a role in etiology as well as manifestation of diabetes. There are 5 types of transporters.

GLUT -4 is important for lowering blood glucose.

Defect in GLUT-2 mediates transport of glucose into pancreatic β-cells may cause reduced insulin liberation that characterized NIDDM.

B. Action of insulin on liver:

1. Decreased blood glucose level by –

a. Increase glycogenesis by increase glucose uptake & increase deposition of glycogen.

b. Decreased glycogenolysis by decrease phospholipase & increased cAMP.

c. Decreased neoglucogenesis by decrease enzymes concerned with neoglucogenesis

2. Decrease TG synthesis & VLDL formation?

3. Decrease protein catabolism.

4. Increased K⁺ & phosphate uptake by liver.

5. Inhibit formation of keto acid, fatty acid & protein.

C. Action of insulin on muscle:

1. Increase protein synthesis by amino acid transport & increased ribosomal protein synthesis.

2. Increase glycogen synthesis by glucose transport. Induce glycogen synthetase & inhibit phosphorylase.

D. Action of insulin on adipose tissue:

Decrease circulating free fatty acid & promotes TG storage in adipose tissue by-

1. Lipoprotein lipase is induced & activated by insulin to hydrolyze TG from lipoprotein.

2. Glucose transport into cell to form glycerophosphate as a metabolic product which permits esterification of fatty acid.

3. Intracellular lipase is inhibited by insulin & inhibition of lipolysis of stored TG