Insulin

Mechanism of action

Insulin is a polypeptide protein produced by beta cells distributed in clusters in the pancreas (known as islet of langerhans). 

Insulin is released by the pancreas when blood sugars are high and binds to insulin receptors, leading to:

• Increased uptake of glucose into skeletal muscle and adipose tissue 
• Stimulation of glycogenesis (conversion of glucose to glycogen in the liver) inhibiting  hepatic glucose output
• Decreased glycogenolysis and gluconeogenesis 
• Inhibition of lipolysis in the adipocyte
• Inhibition of proteolysis and enhances protein synthesis 

In diabetes, pancreatic dysfunction means insulin may need to be administered to regulate blood sugars.

• All patients with type 1 diabetes require insulin (autoimmune destruction of beta cells).
  
• Some patients with type 2 diabetes and gestational diabetes also require insulin.

Insulin must be administered parenterally. If given orally, it would be inactivated by gastrointestinal enzymes.

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Fig 1: Insulin and glucagon regulate blood glucose levels.

Insulin requirements

The table below describes factors that may increase or reduce insulin requirements. Diseases affecting the adrenal, pituitary or thyroid gland may also affect a patient’s insulin requirements. Hyperthyroidism and hypothyroidism can lead to insulin resistance. Hypothyroidism can also precipitate hypoglycemia. Furthermore, insulin antibodies may be formed with insulin administration, which may necessitate adjustment of the insulin dose 

Cautions

Administration errors have been reported with insulin devices, increasing the risk of hypoglycemia. 

• Always write “units” in full (never abbreviate).
  Insulin should never be withdrawn from a pen device using a needle and syringe.
• The strength of insulin in pen devices can vary, but insulin syringes have graduations which are only suitable for calculating doses of standard 100units/mL.

Interactions 

Special cases:

• Beta blockers may mask the symptoms of hypoglycaemia (e.g., tremor)
• Alcohol may intensify or reduce the hypoglycaemic effect of insulin.
• Pioglitazone + insulin: risk of cardiac failure (discontinue if oedema/weight gain occurs).

Administration 

Insulin is generally given via subcutaneous injection into the abdominal wall, thigh, gluteal region or deltoid region. 

• Abdomen → fastest absorption
• Thigh/buttock → slower absorption

The needle should be kept under the skin for at least 6 seconds. 

Devices:

• Pre-filled pens and reusable pens (with cartridges).
  
• Vials with insulin syringe and needle (less common; vials also used for continuous infusions).
  
• Cloudy insulins must be gently rolled and inverted 10 times until milky white.

Adverse events

• Hypoglycaemia: due to overdose, missed meals, or excessive exercise
• Hyperglycaemia and DKA: from inadequate dosing
• Lipodystrophy & cutaneous amyloidosis from repeated injections at the same site; rotate sites to prevent.
  • If these conditions occur there is a potential risk of delayed insulin absorption and worsening of glycaemic control.  
• Injection site reactions: pain, redness, hives, inflammation, bruising, swelling and itching (usually mild and transitory)
• Oedema 

Types of insulin

There are three different types of insulins available in the UK: human insulin, human insulin analogues and animal insulin. Animal insulins such as hypurin porcine neutral are no longer initiated, but some patients may still use them when they do not wish to or cannot switch to human insulins. 

Human insulin is a type of insulin that is identical to the insulin produced by the human body.

• Short acting (e.g. actrapid, humulin S, humulin R) 
• Intermediate acting human insulin is called neural protramine hagedorn (NPH) insulin, or isophane insulin, and has protamine added to slow its absorption. 

Human insulin analogues are insulins where there have been modifications made to change the absorption profile. Examples include lispro, glulisine, aspart, glargine, and detemir. 

• Fiasp and novorapid are common brands of insulin aspart, but are not completely bioequivalent. Fiasp has the addition of nicotinamide (vitamin B3) resulting in a faster initial absorption of insulin; generally Cmax of fiasp is reached 5 minutes earlier than novorapid. 
• Insulin glargine has low solubility at neutral pH, and is completely soluble in the injection solution (acidic pH). Once injected into the subcutaneous tissue, the acidic solution is neutralised and micro-precipitates are formed, which small amounts of insulin glargine are continuously released from. This leads to a smooth and peakless concentration time profile with a prolonged duration of action. 

Insulin in the blood stream has a half-life of a few minutes, therefore the time-action profile is dependent on absorption. Absorption of insulin can be affected by the dose, route and site, thickness of subcutaneous fat, blood flow and type of diabetes. The absorption from limb site can vary substantially day to day, especially in children. 

The tables below describe key pharmacokinetic parameters for different types of insulin, onset of action, peak action and duration are all related to the subcutaneous route of administration.

Short and intermediate acting insulins 

Long acting insulins

Insulin regimens

1. Basal bolus regimens = intermediate/long acting (basal) + rapid/short acting before meals (bolus). This regimen allows flexibility to tailor the insulin dose depending on carbohydrate content of meals.
2. Mixed (biphasic) regimen = multiple daily doses of biphasic insulin OR patient mixes insulin preparations at the time of injection
3. Insulin pump = usually rapid acting insulin analogue or soluble insulin delivered by pump, regularly or continuously

References 

1. Insulin | Treatment summaries | BNF | NICE
2. Fiasp 100 units/mL FlexTouch solution for injection in pre-filled pen – Summary of Product Characteristics (SmPC) – (emc)
3. Actrapid 100 international units/ml, Solution for Injection in a vial – Summary of Product Characteristics (SmPC) – (emc)
4. Apidra 100 Units/ml solution for injection in a vial – Summary of Product Characteristics (SmPC) – (emc)
5. Humalog 100 units/ml KwikPen, solution for injection in a pre-filled pen – Summary of Product Characteristics (SmPC) – (emc)
6. Actrapid 100 international units/ml, Solution for Injection in a vial – Summary of Product Characteristics (SmPC) – (emc)
7. Insulatard 100 international units/ml suspension for injection in vial – Summary of Product Characteristics (SmPC) – (emc)
8. HUMULIN M3 KwikPen (Mixture 3) 100IU/ml suspension for injection – Summary of Product Characteristics (SmPC) – (emc)
9. Humalog Mix25 100 units/ml suspension for injection in vial – Summary of Product Characteristics (SmPC) – (emc)
10. ABASAGLAR 100 units/mL KwikPen solution for injection in a pre-filled pen – Summary of Product Characteristics (SmPC) – (emc)
11. Tresiba 100 units/mL Pre filled (FlexTouch) – Summary of Product Characteristics (SmPC) – (emc)
12. Levemir FlexPen 100 units/ml solution for injection in pre-filled pen – Summary of Product Characteristics (SmPC) – (emc)