INSULIN
Discovered by Banting and Best in 1921, this hormone has gained popularity all over the world for obvious reasons.
Insulin is secreted from the beta cells of pancreas as a
single chain peptide which is called the pre- pro insulin. This is a 110 AA
peptide having A, B and C chains as shown.
24 AAs are removed to form Proinsulin; the connecting C peptide is them cleaved off resulting in –
21 AA –A chain and 30 AA – B
chain.
WHAT
REGULATES THE LEVELS OF INSULIN IN OUR BODY?
We must know that approx. 1 U of insulin is secreted by our pancreas per hour. Regulation is by chemical, hormonal and neural mechanisms.
·
CHEMICAL REGULATION:
Glucose induces a brief pulse of insulin output within 2 minutes (phase 1) followed by a delayed but a more sustained second phase of insulin release. Food induces insulin release by generating signals- incretins from the gut which act on beta cells of pancreas which causes anticipatory release of insulin. Few incretins are- glucagon like peptide -1 (GLP-1), glucose dependent insulinotropic polypeptide (GIP), vasoactive intestinal peptide (VIP), pancreozymin- cholecystokinin (PZ-CCK).
Glucagon and few other peptides enhance insulin release by increasing cAMP levels in beta cells.
·
HORMONAL
REGULATION- Several hormones modify insulin action depending on glucose
levels of the body. Somatostatin inhibits insulin release; glucagon stimulates
release of both insulin and somatostatin; insulin inhibits glucagon secretion.
NEURAL REGULATION – Adrenergic alpha-2 receptor activation decreases insulin release. Adrenergic beta-2 stimulation increases insulin release. Cholinergic activation by Ach or vagal stimulation causes insulin release (IP3-DAG: increased intracellular Ca++ in beta cells).
WHAT DOES
INSULIN DO IN OUR BODY?
MECHANISM
OF ACTION
Insulin receptors are present on virtually all cells in our
body; however their density depends on the cell type: - liver and fat cells are
very rich.
As shown, the insulin receptors have two alpha subunits and
two beta subunits bound by disulphide bonds. Binding of insulin to the alpha
subunit, internalises the receptor along with the bound insulin. This in turn
activates the beta subunits to play their tyrosine kinase activity. Once the
beta subunits are activated, they phosphorylate IRS (Insulin receptor
substrate) proteins. Following this, a cascade of phosphorylation and
dephosphorylation takes place that causes the various insulin related
metabolisms to occur in the body.
Insulin causes shifting of the glucose transporter from the
cytoplasm to the plasma membrane. This is an ATP dependent process; Second
messengers like PIP3 play a crucial role in this process.
Over a period of time, insulin also promotes GLUT4 producing
genes. Genes are also stimulated by MAP-Kinase and the phosphorylation cascade.
This complete process is shown in a simplified way in the
image below-
Now, we shall dive into the pharmacological aspect of our
discussion-
INSULIN ANALOGUES: Using recombinant DNA technology, analogues
of insulin have been produced; they pose the advantage of being more stable and
consistent.
Insulin lispro- Created by reversing proline and
lysine at carboxy terminus B28 and B29 positions. It forms very weak hexamers,
hence when given subcutaneously, they rapidly dissociate. It is best given 0-20
min before a meal. Fewer hypoglycaemic episodes are marked.
Insulin lispro is used to treat type-1 diabetes.
Insulin
aspart- The
proline at B28 of human insulin is replaced by aspartic acid. This change
reduces the tendency for self aggregation of the insulin molecule. This
preparation acts similar to lispro.
Insulin glulisine- By replacing aspargine with lysine at B23; and lysine with glutamic acid at B29.
Insulin glargine- This preparation has two additional arginine residues at the carboxy terminal of B chain; and glysine replaces aspargine at A 21. This analogue remains soluble at an acidic pH but precipitates at a neutral pH as is encountered on s.c. injection. Thus a depot preparation is made. This preparation can be taken at any time of the day-mostly injected at bed time. Insulin glargine has a slow onset of action, but a relatively low blood insulin level is maintained over 24hrs. Has better tolerability compared to isophane insulin. However, it does not control meal time glycemia and hence a rapid acting analogue is used along side.
It is a buffered solution having neutral pH of unmodified
insulin stabilised by a small amount of zinc. On subcutaneous administration,
insulin monomers are released gradually (slow onset of action). When given just
before meal, it produces a mismatch in insulin levels, i.e. early postprandial hyperglycaemia
and late post postprandial hypoglycaemia. Thus administration approximately 1
hour before meal prevents this mismatch.
LENTE INSULIN
(Insulin zinc suspension)
Two types of such suspensions are known;
The one with large particles is crystalline-ULTRALENTE
One with amorphous particles - SEMILENTE
This form of insulin is rarely used now.
ISOPHANE INSULIN
(Neutral Protamine Hagedrone- NPH)
Protamine is complexed with insulin in such a way that
neither insulin nor protamine is in free form. On s.c. injection, the complex dissociates
slowly. Generally taken twice daily before breakfast and before dinner.
REACTIONS
TO INSULIN
CURRENT MODES OF
INSULIN DELIVERY
Insulin has long been used in the subcutaneous route .Insulin injected subcutaneously (s.c.) at least twice a day is having many inherent disadvantages including local pain, inconvenience of multiple injections, and occasional hypoglycemia as a result of overdose, itching, allergy, hyperinsulinemia, and insulin clinical trials have shown that even on injectable insulin treatment, a significant percentage of patients fail to attain lasting glycemic control due to noncompliance. Though this is the currently used method, several challenges have paved way for many advancements in insulin delivery.
Needle and syringe
A common way of administering is with the needle and syringe. Syringes come in range of capacities (1ml, 0.5ml, 0.3ml) with different needle types. Needles have very fine points and special coating to make injections pain free. Nevertheless, it is not convenient for people having needle phobia to inject insulin 2-4 times a day. Hence, it poses not much advantage over the s.c. route.
Insulin pens
Insulin pen injectors are convenient and discreet way of administering insulin. They have a built-in dial that allows us to determine the amount of insulin to be injected, a short needle one end and a plunger at the other. Insulin pens are particularly useful if we need to take premixed insulin. As such insulin pens are more accurate, convenient, less painful and patient friendly but associated with higher cost in comparison with vial and syringe.
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| Insulin pens |
Insulin jet injectors
Insulin jet injectors offer an alternative to needles and work by sending a fine spray of insulin into the skin (transcutaneously) using a pressurized jet of air instead of a needle. This route is advantageous in terms of causing less infections; however the costs and size of these jet injectors pose a considerable drawback.
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| Insulin jet injector |
Insulin pump
Insulin pumps are small devices of size of a pager that can be attached to our belt or placed in our pocket. They are made up of an insulin reservoir connected to a tube, ending in a cannula or catheter, which is inserted under the skin of our abdomen. They can be set to deliver insulin at a slow, continuous rate throughout the day, or to release larger quantities at meal times or when blood sugar is high. The main advantage of a pump is that it closely mimics the slow but continual release of insulin by the pancreas. CGM (continuous glucose monitors) readings are used to adjust insulin delivery through insulin pump, it is known as sensor-augmented pump (SAP) therapy.
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| Insulin pump |
Insulin patches
Insulin patches are also currently under development, but it is difficult for insulin to be absorbed through the skin. Insulin delivery is gradual and dose can be adjusted. Sustained physiological levels of basal insulin in a pain-free manner is injected. The patch makes tiny holes on the skin surface and to deliver insulin.
Insulin inhalers
Insulin inhalers are a new way of delivering premeal time insulin. Insulin inhalers work like an asthma inhaler, but deliver dry powdered insulin into the bloodstream via the lungs.
Advantages of the pulmonary route include a vast and well perfused absorptive surface, absence of certain peptidases that are present in the gastrointestinal (GI) tract that breaks down insulin, and the ability to bypass the “first pass metabolism''.
Exubera was found to reduce postprandial blood glucose and A1c significantly. However, Exubera was contraindicated in smokers as it increased the risk of hypoglycemia due to greater absorption compared to nonsmokers.
Another promising inhaled insulin is Afrezza (Sanofi and MannKind) based on Technosphere dry powdered formulation. The onset of action is quick and lasts for 2-3 hrs. Transient nonproductive cough and a modest reduction in lung function initially are the common side-effects
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| Insulin inhalers |
FUTURE
TRENDS FOR INSULIN DELIVERY SYSTEMS
· Islet cell transplantation
· Insulin nanopump
· Gene therapy
SOURCE
International Journal of
Therapeutic Applications, Volume 7, 2012, 25-31
Well, i tried keeping this vast topic simple, once you are done reading this post, its going to be fun as we engage in the uses of insulin in the next post.
Thank you!😄
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