INSULIN

1
INSULIN

• M.Prasad Naidu
• MSc Medical Biochemistry,
• Ph.D.Research Scholar

2
PANCREAS

• Both endocrine and exocrine
• Endocrine function is localized in the islets of
  Langerhans, epithelial cells that are dispersed
  throughout the entire organ.
• 3 distinct types of cells namely
• Alpha?Glucagon
• Beta ? Insulin
• Gama? not known
• Delta? secretes stores somatostatin

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Insulin -- Introduction

• Plays imp role in metabolism causing
• Increased Carbohydrate Metabolism
• Glycogen storage
• Fatty acid synthesis
• Amino acid uptake and
• Protein synthesis
• Thus imp anabolic hormone which acts on variety
  of tissues including liver, fat and muscle.

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chemistry

• Protein hormone produced from the islets of
  Langerhans which make up1 of the pancreas.
• Crystallization requires Zn , which is a
  constituent of stored insulin since normal islets
  are relatively rich in this element.
• Insulin is made up of 51 AAs arranged in 2 PP
  chains(AB) having a mol.wt of 5734.
• 2 inter chain and 1 intra chain S-S- bonds
• Insulin can not be administered orally
• The pork pancreas is the most similar to human
  insulin. The 2 insulins diff only in the terminal
  AA no of B chain(30)
• This terminal AA in porcine insulin is Ala and
  Thr in Hum.

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Chemistry

• This terminal AA can be removed easily with
  CP.(retains the biologic activity)
• Thus it is possible to convert porcine insulin
  into a Human ( 1 AA shorter)
• Insulins from the pig, whale and dog are
  structurally identical.
• Those from the sheep, horse and cow differ form
  porcine insulin only in 3 AAs under the S-S
  brige in the A chain.
• Other species may differ in as much as 29 out of
  the 51 AAs.
• Two structurally diff insulins isolated a
  single rat pancreas, diff by a single AA(Lys/Met)
  in the A chain.
• The pancreas of certain fishes more than one
  insulin

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Structure of Insulin

• Despite the wide variation in 10 structure , the
  bio. Activity per unit wt is remarkably constant
  for all insulins.
• It exists in Zn crystals as hexamers and dimers.
• When diluted in the circulation, insulin exists
  as a monomer.
• The m-RNA for preproinsulin has been isolated
  from islets, the complementary DNA synthesized
  and active insulin has been sucessfully cloned in
  bacteria.
• Therefore insulin is the first high mol.wt
  hormone to be made by the process of molecular
  engineering.

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Structure of Insulin

• The 2030 structures of Bovine insulin have been
  determined by X-ray crystallography.
• These studies indicate that the A chain portion
  of the molecule is the more exposed, including
  the 6-11-S-S- bond possibly involved in hormonal
  activity.
• The B chain in in the internal portion of the
  molecule.
• Non covalent binding b/n B chain is respible for
  the formation of insulin dimer higher polymers.

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Structure of Insulin

• Removal of the terminal octapeptide on B chain /
  removal of Asn on A chain inactivates insulin.
• Removal of terminal carboxy AA of the B chain and
  some AAs in the N-ter portion of the molecule
  does not affect the activity.
• The OH groups of Ser, Thr can be modified by
  sulfation with little loss of potency.
• Destruction of His by photo-oxidation results in
  complete inactivation.
• Increasing iodination of Tyr causes progressive
  inactivation.

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Structure of Insulin

• Sulfated bovine insulin, porcine insulin and fish
  insulins are sometimes used in the resistant
  diabetics because of their reduced antigenicity
  and cross-reactivity with circulation antibody.
• Other modifications reduce the absorption of
  insulin from the injected sites, resulting in
  prolonging the axn of insulin.

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Structure of Insulin

• Protamine Zn insulin is a combination of insulin
  with protamine which is absorbed more slowly than
  the ordinary insulin.
• 1 injection of protamine Zn insulin may lower the
  blood glucose for more than 24hrs, whereas 2or3
  injections of regular (crystalline) insulin might
  be required for the same effect.

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Structure of Insulin

• Globin insulin , combination with a protein has
  an effect of 12-15 hr duration of action
• Ultralente insulin is a slow-acting insulin
  prepared by controlled crystallization in the
  presence of high conc of Zn and acetate in order
  to produce large crystals which are therefore
  slowly absorbed.
• Lente insulin is a 73 mixture of ultralente and
  regular insulin which has a duration of effect
  between the two.