Insulin

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Insulin production and secretion

Insulin production

Insulin is produced as preproinsulin in the rough Endoplasmic Reticulum

It is then cleaved to proinsulin, and stored in vesicles in the Golgi apparatus – here it undergoes further cleavage to C-peptide and insulin

C-peptide is a useful marker in determining endogenous insulin production, especially in patients on exogenous insulin replacement

Insulin secretion

Glucose is absorbed in the small intestine and transported via the hepatic portal vein to the liver

Liver cells contain insulin-independent glucose transporters (GLUT-2) and so acquire glucose from hepatic circulation

Once inside the cell, glucose is phosphorylated to glucose-6-Phopshate (gluc-6-P), which commits it to use by the body

Gluc-6-P enters into glycolysis and the TCA cycle – this increases the number of ATP’s in the hepatocyte

Increased ATP caused closure of K+ channels, leading to depolarisation of the cell. This leads to opening of Ca2+ channels and Ca2+ influx. Influx of Ca2+ causes the movement of insulin vesicles from the cytosol to the membrane and then release into the bloodstream

This potassium channel can also be blocked by sulphonylurea drugs – this is useful for diabetic patients with residual β-cell function

Insulin release can also be stimulated by vagal nerve stimulation

Β-cells also express insulin receptors – thus insulin acts back on the producing β-cell (autocrine action) to enhance transcription and translation of genes, including insulin itself

Two insulin peaks appear following glucose intake – the first is an initial and rapid release (spike) from the release of pre-formed insulin (caused by increased glucose), and the second sustained release (plateau) is from newly synthesised insulin (stimulated by cytosolic long-chain Acetyl CoA from lipogenesis)

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Mechanism of action of Insulin

Insulin has multiple effects on the metabolism of carbohydrates, fats and proteins

Insulin regulates the various processes

promotes transport of glucose into cells and its utilization in cells

increases hepatic glycogen formation and inhibits gluconeogenesis

inhibits lipolysis

increase protein synthesis and decreases protein breakdown

Promotes glucose uptake:

In muscle and adipose tissue – insulin causes GLUT-4 (glucose transporting) channels to move from the Cytosol to the cell membrane – this facilitate glucose uptake by the cell

Once inside the cell glucose is phosphorylated and converted to glycogen or used for energy (phosphorylation traps and commits glucose to further metabolism inside the cell)

Promotes Glycolysis

Insulin stimulates the formation of fructose-2, 6-bisphosphate (a glucose metabolite)

This compound activates PFK-1 and inhibits fructose-1, 6-bisphosphate (enzyme which catalyse the reverse reaction of PFK-1).

This all means that glucose metabolised to pyruvate cant be converted back to glucose (So basically Glycolysis is up regulated and No Gluconeogenesis can occur)

Increases glycogen synthesis

In the liver insulin promotes glucose uptake by stimulating its storage as glycogen

This is done by activating glycogen synthase (enzyme which catalyses glycogen synthesis) and by deactivating glycogen phosphorylase (enzyme which causes glycogen breakdown).

So basically this ensures that glycogen synthesis takes place and it prevents glycogen breakdown simultaneously.

Increase triglyceride synthesis

Insulin activates Acetyl CoA carboxylase which will catalyse the formation of malonyl CoA (1st step of Fatty acid synthesis)

Malonyl CoA inhibits the breakdown of fatty acids, by inhibiting the fatty acid transporter protein from transporting fatty acids into the mitochondria where B-oxidation occurs.

Newly formed fatty acids are esterified and packaged into VLDL particles – then exported into blood to be used by muscle or stored in adipose. This uptake is stimulated by Insulin – insulin activates Lipoprotein lipase.

In adipose tissue the triacylglycerides are hydrolysed to fatty acids and glycerol by hormone sensitive lipase – but this is activated by hormones which are antagonistic to Insulin

If fatty acids are not re-esterified they will be released into the blood. Re –esterification however requires alpha-glycerol-phosphate, which is produced from DHAP (dihydroxyacetone phosphate). Insulin also inhibits fatty acid efflux by promoting entry of glucose into adipocytes.)

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Types of Insulin

Short acting insulin (eg soluble insulin)

Standard insulin is for use in multiple dose regimens and for continuous IV infusion in labour and during medical emergencies.

Limitations are that it enters the circulation too slowly (due to delay in absorption)

Time to peak action: 2-4 hours

Duration of action: 6-12 hours

Also the effect persists for too long after meals – which predispose the patient to hypoglycaemia.

Short acting insulin-analogues – is insulin which structure has been modified in order to change the pharmacokinetics without altering the biological effect. So it is absorbed quicker, enters the circulation more rapidly and disappears from the circulation more rapidly as well.

Time to peak action: 1-2hours

Duration of action: 4-6 hours

Intermediate acting insulin (e.g. isophane insulin)

Takes longer to reach time of peak action – 3-8hours.

Duration of action is of intermediate length – 12-20 hours.

Typically used in combination with a short-acting insulin given in the morning and evening

The short-acting insulin can control the periods immediately after the injection and the afternoon and evening can be controlled by the intermediate acting insulin.

Longer acting insulin (e.g. insulin zinc suspension)

Time to reach peak action: 6-12hours

Duration of action: 16-30 hours

Used particularly in patients who prefer only one injection per day(e.g. elderly), they use one long acting insulin injection in the morning only

They rarely achieve normal blood glucose concentrations throughout the day though.