INSULIN

INSULIN
INSULIN ANALOGUES
INCRETINS
DR ZAINAB KHATOON
PG 1st year
Dept of Pharmacology
Introduction
• Diabetes mellitus is a metabolic disorder characterized by
hyperglycemia, glucosuria, hyperlipidemia, negative nitrogen balance
and sometimes ketonaemia.
• Pathological change is thickening of capillary basement membrane,
increased vessel wall matrix and cellular proliferation resulting in
vascular complications like lumen narrowing, early atherosclerosis of
glomerular capillaries, retinopathy, neuropathy and peripheral
vascular insufficiency.
• Types: Type I Insulin dependant & Type II Non insulin dependant.
• Insulin was discovered in 1921 by Banting and Best.
• The endocrine tissue of pancreas called pancreatic islets which
contains 4 types of cells secreting different hormones:
1. Alpha cells: secretes glucagon.
2. Beta cells: secretes insulin.
3. Delta cells: secretes somatostatins.
4. F cell: secretes pancreatic polypeptide.
Chemistry, Biosynthesis and
secretion
• Insulin is a two chain polypeptide having 51 amino acids and MW
about 6000.
• Is composed of two chains : A chain 21 amino acids
B chain 30 amino acids
• Which are joined together by two disulphide cross bridges.
• Proteolytic
Preproinsulin cleavage by
endopeptidases
• A&B
proinsulin connected by C-
peptide chain
Proteolytic
degradation in golgi
apparatus by
proteases
Insulin + C • Stored in
pancreatic beta
peptide cells
• Glucose level > 70mg/dl stimulates insulin synthesis and release.
• Other stimulants for insulin release includes amino acids and fatty
acids.
• Acetylcholine -> stimulates insulin
• Somatostatin inhibit insulin release

Pharmacological Actions
(Rapid effects)
Carbohydrate metabolism Protein metabolism Fat metabolism

• In liver cells: decreases • In liver cells: decreases • In liver cells: increases
glycogenolysis, increases protein breakdown & inhibits lipogenesis
glycogenesis, decreases oxidation of amino acids to • In adipose tissue: increases
gluconeogenesis ketoacids fatty acid synthesis and TGs
• In muscles: it facilitates • In muscles: increases protein formation and storage,
glucose uptake by GLUT 4 synthesis, increases amino decreases lipolysis
transporters, promotes acid uptake
glycogenesis & increases
glycolysis
• In adipose tissues: facilitates
glucose uptake, increases the
synthesis of triglycerides
• Other metabolic effects: increases clearance of VLDL and
chylomicrons.
• Long term effects: it governs protein synthesis and growth regulation
as well as DNA-mediated synthesis of glucose transports(GLUT1-
GLUT5).
Mechanism of Action
• Insulin facilitates glucose transport across cell membrane.
• Insulin acts on specific receptors located on the cell membrane.
• Insulin receptor is a receptor tyrosine kinase(RTK).
• consisting of 2 extracellular a and
2 transmembrane B subunits linked
together by disulfide bonds.
Binding of insulin to a subunits induces aggregation and internalization
of the receptor along with the bound insulin molecules
activates tyrosine kinase activity of the ß subunits
expose the catalytic site to phosphorylate tyrosine residues of Insulin

Receptor Substrate proteins (IRS)
a cascade of phosphorylation and dephosphorylation reactions is set
into motion results in stimulation or inhibition of enzymes involved in
the rapid metabolic actions of insulin
second messengers like phosphatidyl inositol trisphosphate (PIP3)

mediate the action of insulin on metabolic enzymes
Insulin stimulates glucose transport across cell membrane by ATP

dependent translocation of glucose transporter
GLUT4 from cytosol to the plasma membrane
insulin also promotes expression of the genes directing synthesis of
GLUT4
Genes for a large number of enzymes and carriers are regulated by

insulin through Ras/Raf and MAP-Kinase as well as through the
phosphorylation cascade
The internalized receptor-insulin complex is either degraded

intracellularly or returned back to the surface from where the insulin is
released extracellularly
SOURCE OF INSULIN
• Beef insulin differs by three amino acid and pork insulin differs by one
amino acid. Thus, pork insulin being more homologous to human
insulin.
• Mass production of human insulin is done by recombinant DNA
techniques where in a human pro insulin gene is inserted into E coli
or yeast.
FATE OF INSULIN
• Distributed only extracellularly. If given orally gets degraded in GIT.
• Injected insulin or released from pancreas is metabolized primarily in
liver and to smaller extent in kidney and muscle.
• The plasma T1/2 is 5-9 minutes.
Types of insulin preparations
Regular (soluble) insulin: buffered neutral pH solution of unmodified
insulin stabilized by a small amount of zinc.
After s.c. injection, insulin monomers are released gradually.
Peak action is produced only after 2–3 hours and action continues up
to 6–8 hours.
Not applicable to i.v. injection.
Lente insulin (Insulin-zinc suspension): two types one is crystalline and
insoluble other is amouphous abd soluble.
Short acting.
Isophane (Neutral Protamine Hagedorn or NPH) insulin: Protamine is
added in a quantity just sufficient to complex all insulin molecules.
• On s.c. injection, the complex dissociates slowly to yield an
intermediate duration of action.
• It is mostly combined with regular insulin.
Insulin Analogues
• Using recombinant DNA technology analogues of insulin have been
produced which have modified pharmacokinetics on SC injections but
similar pharmacodynamic effects and immunogenicity. Adv: greater
stability and consistency.
• Insulin lispro: produced bu reversing proline and lysine at the carboxy

terminus B 28 & B 29 positions.
• Forms weak hexamers and dissociates rapidly after SC injections
• Quick in action with shorter duration of action.
• Injected SC 0-20 min before meals.
• Regime: 2-3 times daily meal time
• Eg- Humalog 100 units per ml.
• Insulin Aspart: The proline at B 28 of human insulin is replaced by
aspartic acid.
• Reduced tendency of cell aggregation
• Time action profile- similar to lispro
• Eg- Novolog or Novorapid 100 unit/ml
• Biphasic insulin aspart: the 70:30 mixture of isophane complex of
insulin aspart with uncomplexed insulin aspart has the advantage of
rapid and predictable onset along with intermediate duration of action.
It is called ‘biphasic insulin aspart’, and can be injected twice daily just
before each major meal.
• Eg-NOVOMIX 30 FLEXPEN 100 U/ml in 3 ml inj also as PENFIl injection
Insulin glulisine: rapidly acting insulin analogue
with lysine replacing asparagine at B 23 and glutamic acid
replacing lysine at B 29.
• Properties and advantages are similar to insulin lispro.
• particularly used for continuous subcutaneous insulin infusion (CSII)
by a pump.
Insulin glargine: long acting biosynthetic insulin has 2 additional
arginine residues at the carboxy terminus of B chain & glycine replaces
asparagine at A 21.
• remains soluble at pH4 of the formulation
• precipitates at neutral pH encountered on s.c. injection.
• smooth ‘peakless’ effect is obtained.
• suitable for once daily injection to provide background insulin action.
• mostly injected at bed time
• LANTUS OPTISET 100 U/ml in 5 ml vial and 3 ml prefilled pen injector
• Insulin detemir: Myristoyl (a fatty acid) radical is attached to the
amino group of lysine at B29 of insulin chain.
• action almost similar to that of insulin glargine
• Ex- LEVEMIR FLEXPE 100 u/mL in 3 mL prefilled pen injector
REACTIONS TO INSULIN
1. Hypoglycaemia
2. Local reactions: Swelling, erythema and stinging sometimes occur at
the injected site
3. Allergy
4. Oedema
Therapeutic uses
1. Type I diabetes mellitus
2. Type II diabetes mellitus
3. Gestational diabetes
4. Diabetic ketoacidosis
5. Non-ketonic hyperglycemic coma
6. Hyperkalemia
Incretin
Incretins are a group of metabolic hormones that stimulate a decrease
in blood glucose levels. Incretins are released after eating and augment
the secretion of insulin released from pancreatic beta cells of the islets
of Langerhans by a blood-glucose–dependent mechanism.
Some incretins (GLP-1) also inhibit glucagon release from the alpha
cells of the islets of Langerhans.
It includes glucagon like peptide(GLP-1) and glucose dependant
insulinotropic polypetide(GIP).
Released after meals and augment insulin release during phase of
nutrient absorption from GIT.

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INSULIN

• Acetylcholine -> stimulates insulin

• Somatostatin inhibit insulin release

Carbohydrate metabolism Protein metabolism Fat metabolism

activates tyrosine kinase activity of the ß subunits

expose the catalytic site to phosphorylate tyrosine residues of Insulin

second messengers like phosphatidyl inositol trisphosphate (PIP3)

Insulin stimulates glucose transport across cell membrane by ATP

Genes for a large number of enzymes and carriers are regulated by

The internalized receptor-insulin complex is either degraded

• Insulin lispro: produced bu reversing proline and lysine at the carboxy

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