Insulin: Pancreatic Peptide Hormone -2

Structure:

• In 1926, “ABEL” isolated crystalline insulin from pancreas.
• Insulin (insula^L =island) was first isolated in 1922 for the pancreas of dogs by Banting & Best of the university of Toranto , canada.
• It is the first hormone to be recognized as a protein. This is a Peptide hormone.
• The chemical structure of insulin has been determined by “Sanger” and his coworkers at Cambridge, England.
• The hormone consists of 51 amino acid residues dispersed in two chains.
• It contains two chains, they are A-chain & B-chain linked by disulfide bridges. A-chain contains 21 amino acids & B-chain contains 30 amino acid residues (molecular weight 5,733).
• Two Zinc atoms are always found with this hormone but is not a part of the insulin molecule. The main function of this two Zn⁺² is, it stabilizes the hormonal structure.

  

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• The position of disulfide bridges in the molecule,

  	A-chain	B-Chain x
  Inter-disulphide bridges position	7th Cys 20th Cys x	7th Cys 19th Cys x
  Intra-disulphide bridges position	6-11th Cys	Nil x

Biosynthesis:

The insulin synthesis takes place in the ER of the b-cells. The precursor molecule of the insulin is “Proinsulin”. It contains 84 amino acid residues (molecular weight 9,000). This proinsulin transfers in the granules but not in the ER. It undergoes proteolytic cleavage, consists in cleavage of a 33 amino acid, connecting peptide chain from the proinsulin molecule leaving behind insulin. Finally, the preproinsulin converts into proinsulin & into Insulin. In this synthesis process, two different enzymes participate, they are “Trypsin” & “Carboxypeptidase-B” like enzymes. (See the figure).

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Mechanism of action:

The hormone molecule acts by binding to a plasma membrane receptor on the target cells. Human insulin receptor gene is located on chromosome 19. In obesity, the number of receptors is decreases and target tissue becomes less sensitive to insulin. Insulin receptor (IR) is a glycoprotein with four subunits; two alpha and two beta subunits. The alpha units (135kD) are located on the beta subunits. The alpha units (135kD) are located on the extracellular side, to which insulin binds. The beta sub units (95kD) transverse the membrane and are exposed on the cytoplasmic side. Beta sub unit has tyrosine kinase activity.

Signal transduction: Binding of hormone causes dimerisation of the receptor. It is then internalized, so that the signal is transmitted. Then the tyrosine kinase phosphorylates tyrosine residues on the cytoplasmic side of insulin receptor. This event, in turn, phosphorylates insulin receptor substrates (IRS). IRS-1 and 2 are characterized. The message is later transmitted into a series of serine/threonine kinases. The final effect may be any one of the 3 following:

a) Gene transcription: Insulin acts at the transcription level to regulate synthesis of more than 100 proteins. This is effected through IR-2. For example; the following enzymes are induced by insulin: glucokinase, pyruvate kinase, phosphofructokinase, PFK-2, citrate cleavage enzyme, acetyl-coA carboxylase. Insulin represses the following enzymes: Glc-6-Phosphatase, PEPCK, Fru-1,6-bisphosphatase. Further the pathway through IRS-2 activates eIF-4E (eukaryotic Initiation Factor), so that protein synthesis is enhanced.

b) Activation of enzymes: The Hormone activates the exiting molecules of enzymes by covalent modification (phosphorylation or dephosphorylation). There are more than 50 enzymes activated by this mechanism.

c) DNA synthesis: Through the IRS-1 pathway, the hormone increases DNA synthesis, cell growth and anabolism.

In all above-mentioned pathways, intracellular mediators have been implicated in the hormonal action. There are Ca+2 and cAMP. Insulin activates phosphodisterase and thereby decreases cAMP. So, reactions dependent on cAMP are inhibited, e.g.: glycogen phosphorylase.

Functions:

• The hormone influences mainly on carbohydrate metabolism, by facilitates entry of glucose and other sugars into the cells, by increasing penetration of cell membranes and augmenting phosphorylation of Glucose.
• It promotes protein synthesis. At the same time, it also acts as an “antiproteolytic agent”.
• It influences on inorganic metabolism especially, that pf phosphate and potassium.
• This hormone administration lower the blood phosphate levels and facilitates absorption of inorganic phosphate appears within the cells as ATP.
• It promotes ‘Anabolic process’ (synthesis of glycogen, fatty acids and proteins) and inhibits catabolic once (breakdown of glycogen and fat).

Secretion:

After 50 units of insulin are required per day. The human pancreas stores about 250 units.

Factors stimulating the hormone secretion:

• Increased blood glucose level causes an increase in insulin secretion and decreased blood glucose level depresses insulin production.
• The hyperglycemia produced by glucagon enhances insulin production.
• The GH & glucocorticoids cause hyperglycemia. They also stimulate insulin secretion.

Factors inhibiting insulin secretions:

• “Epinephrine” is the highly effective inhibitor of insulin secretion.
• “Starvation” reduces insulin secretion.
• Magnesium also inhibits insulin secretion.

Pathophysiology of Insulin:

About 90% of persons with diabetes have non-insulin dependent diabetes mellitus (NIDOM) (type-2) such patients are usually ‘Obese’. The other 10% have insulin dependent diabetes mellitus (IDDM) (type-I). A few individuals produce antibodies directed against there insulin receptors. These antibodies prevent insulin from binding to the receptor so that such persons develop a severe insulin resistance. Tumors of b-cell origin cause hyper-insulinism there by hypo-glycemia occurs.

Reference: medical News Today