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Insulin: pharmacology and formulations

ISSN 2398-2950

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Introduction

History

  • Insulin Insulin (Latin insula meaning island) is produced by the Islets of Langerhans (by Paul Langerhans in 1869).
  • Destruction of the insulin-producing cells leads to diabetes (by Eugene Opie in 1901).
  • Pancreatic extract was shown to lower blood glucose in diabetic dogs in 1916 (by Nicolae Paulescu).
  • Further research in the 1920s (by Frederick Banting and Charles Best) led to the first treatment of diabetes in humans in 1922 and manufacture of insulin by the company Eli Lilly.

Structure

  • Insulin was the first human protein to be sequenced (by Frederick Sanger in 1955).
  • Insulin is a high molecular weight (human insulin 5808 Da) polypeptide hormone composed of 110 amino acids.
  • Insulin is a dimer and consists of a 21-amino acid A chain and a 30-amino acid B chain linked by disulfide bonds.
  • There is little variation in insulin structure between species – it is highly conserved.
  • Variations in insulin structure between species alter the potency (blood glucose lowering effect) of insulin.
  • Feline insulin is identical to porcine insulin and differs from human insulin by 1 key amino acid.

Source

  • Feline diabetes Diabetes mellitus is not an immune-mediatd disorder, and anti-insulin antibodies are not found commonly in diabetic cats.
  • Insulin can be of animal origin, synthetic (recombinant) or a synthetic analog.
  • Animal derived insulin is usually derived from swine pancreas. Animal derived insulin is highly purified (contains little or no other protein).
  • Recombinant human insulin, made in bacteria, was first commercialized by Eli Lilly in 1982.
  • Alteration of the amino acid sequence has been used to produce analogs of have insulin. Human insulin analogs can be shorter or longer acting than human insulin due to differences in pharmacokinetics (eg absorption).

Route of administration

  • Insulin cannot be administered orally because it is a peptide and would be broken down in the intestinal tract.
  • Insulin is administered by injection.
  • Most insulin products are administered by subcutaneous injection.
  • A few (regular insulin) insulin products are suitable for intravenous infusion.

Aim of treatment

  • Insulin is administered for the treatment of relative or absolute deficiency of insulin leading to diabetes, which is characterized by chronic elevation of blood glucose (hyperglycemia) and associated clinical signs.
  • The goals of insulin treatment are to reduce hyperglycemia and associated clinical signs, and to avoid hypoglycemia (lower than normal blood glucose), and, where appropriate, to achieve clinical remission.

Formulation

  • Insulin is short acting.
  • Formulating insulin to slow its absorption from the injection site and/or bloodstream is used to prolong its duration of action. This is achieved by including zinc, with or without protamine, in the formulation or by altering the insulin structure to create a basal analog.
    • Zinc insulin crystals create a depot effect at the injection site. The absorption rate depends on the size of the zinc-insulin crystals. Larger crystals slow the rate of absorption, whereas smaller crystals allow faster absorption.
      • Lente insulin combines rapid acting and long acting crystalline zinc insulin.
    • Protamine is a large protein from fish sperm that also delays absorption. Protamine was shown, by Hans Christian Hagedorn in 1936, to prolong insulin action by delaying absorption. It is used in combination with zinc.
      • Neutral protamine Hagedorn insulin and protamine zinc insulin contain both protamine and zinc-insulin crystals.
    • Insulin glargine Insulin glargine is less soluble at the pH found in the body than insulin meaning that it forms microprecipitates at the site of subcutaneous injection, which delay absorption.
    • Insulin detemir Insulin detemir forms a stable soluble depot at the injection site and binds to albumin in the bloodstream, both of which delay absorption.
  • In general, increasing the duration of insulin action decreases the onset of action and the potency of the insulin and increases the variability in the duration of action.

Properties

Onset, peak and duration of action

  • Insulins are categorized as rapid, intermediate or long acting.
  • Onset, peak and duration of insulin action are not fixed between or within a species or individual.
  • There is considerable overlap between rapid, intermediate or long-acting insulin preparations.
  • The onset, peak and duration of action in any individual of any species depends on many factors following each injection, including absorption from the injection site, blood glucose at the time of treatment, health status, feeding and exercise. 
Rapid, eg regular insulin
Onset <1 h Peak 1-4 h Duration <8 h
Intermediate, eg insulin zinc suspension, neutral protamine Hagedorn (NPH)
Onset <2 h Peak 4-8 h Duration 12-24 h
Long, eg protamine zinc insulin, insulin glargine, insulin detemir
Onset 2-6 h Peak 6-10 h Duration 12-24 h
 

Rapid-acting insulin (also called soluble, neutral or regular)

  • Used under close verterinary supervision where a rapid effect is required (eg in the management of diabetic ketoacidosis).
  • Rapid onset of action (<1 h).
  • Peak effects 1-4 h after administration.
  • Short duration of action (<8 h).
  • Can be administered by subcutaneous, intramuscular or intravenous routes.

Intermediate- and long-acting insulin

Neutral protamine Hagedorn (NPH) insulin

  • Classified as an intermediate-acting insulin.
  • Contains recombinant human insulin as zinc insulin crystals plus protamine.
  • Human insulin differs from canine insulin at one of the key amino acid sites.
  • Duration of action is too short to make it suitable for use in cats.
  • Not approved (100 IU/mL) for use in cats.

Lente insulin

  • Classified as an intermediate-acting insulin.
  • Contains porcine insulin as zinc insulin crystals. (Products for use in humans contain human recombinant insulin as zinc insulin crystals.)
  • Combination of rapid acting (around 30%) amorphous and long acting (around 70%) crystalline zinc insulin sometimes known as lente insulin.
  • Porcine insulin differs from feline insulin at 3 of the key amino acid sites. (Human insulin differs from feline insulin at all four of the key amino acid sites.)
  • Onset of action within 2 h, peak action around 4-6 h and up to 12 h duration of action in cats.
  • Requires twice daily in cats to provide adequate glycemic control.
  • Porcine insulin zinc suspension (40 IU/mL) is widely used in cats in many countries. (Human insulin zinc suspension (100 IU/mL) also available.)
  • Porcine insulin zinc suspension is approved for use (40 IU/mL) in cats (and dogs).

Protamine zinc insulin (PZI)

  • Classified as a long-acting insulin.
  • Contains recombinant human insulin as zinc insulin crystals with protamine.
  • Human insulin differs from feline insulin at all 4 of the key amino acid sites.
  • Onset of action is within 2 h, peak action around 6 h and at least 9h duration of action in cats.
  • Requires twice daily administration in cats to provide adequate glycemic control. 
  • Protamine zinc insulin is approved for use (40 IU/mL) in cats.

Insulin glargine

  • Classified as a long-acting basal insulin analog.
  • Contains recombinant human insulin that has been altered structurally by replacement of asparagine at A chain position 21 with glycine and arginine added to B chain positions 31 and 32.
  • Human insulin differs from feline insulin at all 4 of the key amino acid sites.
  • Less soluble at the pH found in the body than insulin meaning that it forms microprecipitates at the site of subcutaneous injection, which delay absorption.
  • Onset of action is variable but usually within 6 h and duration of action is around 13 h but variable at 8-24 hours.
  • Requires twice daily administration in cats to provide adequate glycemic control
  • Not approved for use in veterinary species (100 IU/mL), but twice daily administration used quite commonly in diabetic cats.

Insulin detemir

  • Classified as a long-acting basal insulin analog.
  • Contains recombinant human insulin that has been altered structurally by omission of threonine at B chain position 30 and addition of a 14 carbon fatty acid chain attached to lysine at B chain position 29.
  • Human insulin differs from feline insulin at all 4 of the key amino acid sites.
  • Forms a stable soluble depot at the injection site and binds to albumin in the bloodstream, both of which delay absorption.
  • Onset of action within 2 h, peak action around 5 h and duration of action of 11-16 h in most cats, but can be up to 18-21 h.
  • Requires twice daily administration in cats to provide adequate glycemic control.
  • Less potent in cats than in dogs - standard insulin doses are recommended in cats.
  • Not approved for use in veterinary species (100 IU/mL) - not used commonly in diabetic cats.

Insulin concentration

  • Insulin is measured in 'international units' (abbreviated to IU).
  • 1 IU is defined as biological equivalent of 34.7 µg of pure crystalline insulin, corresponding to the amount of insulin required to reduce the blood glucose concentration of a fasting rabbit by 45 mg/dl (2.5 mmol/L).
  • Insulin preparations are available at a concentration of 40 IU/mL for veterinary use and 100 IU/mL for human use.
  • The lower concentration preparations are invaluable for facilitating accurate dosing in dogs and cats.
  • Dilution of insulin is rarely necessary in cats (and dogs), particularly if insulin preparations for veterinary use (40 IU/mL) are used and/or if injection is carried out using an injection pen device.

Injection

  • Insulin is administered using specialized insulin syringes  or injection devices (‘insulin pen’) that are calibrated in international units rather than volume (mL).
  • Syringes are available in 2 mL, 1 mL, 0.5 mL and 0.3 mL sizes .
  • It is essential to use the correct insulin syringe for the insulin concentration.
  • The small insulin syringes allow relatively accurate dosing of even 100 IU/mL insulin without dilution.
  • Insulin syringes are designed to measure insulin accurately. However, there can be considerable variation between doses, particularly at lower doses.
  • Specialized insulin syringes have ultra-fine needles intended for single use only. These needles minimize tissue trauma and discomfort on injection.
  • Insulin injection devices (U40) for veterinary use are available in two sizes:
    1. Maximum dose of 8 units in increments of 0.5 units.
    2. Maximum dose of 16 units in increments of 1 unit.
  • It is essential to use the correct insulin injection device for the insulin concentration.
  • Insulin pens are designed to measure insulin doses accurately and precisely, meaning that dosing is consistent between injections, particularly at doses of 8 IU or less.
  • Insulin pens have ultra-fine needles intended for single use only. These needles minimize tissue trauma and discomfort on injection.

Administration

Dose

  • The dose of insulin required to maintain blood glucose within an acceptable range obviously varies widely between individuals and depends on factors such as type of insulin, diet, exercise, obesity  Obesity, concurrent illness and individual variability.
  • The general rule of thumb is that the insulin dose should be between 0.5 and 1.0 U/kg once or twice daily.
  • It is essential to titrate the dose for every patient on an individual basis.
  • The dose of insulin required may change with time.
  • It is advisable to wait up to 1-3 weeks after starting treatment before increasing the insulin dose to see whether insulin requirements come down.
  • In the long term insulin requirements may increase due to progressive loss of beta-cell function as well as concurrent illness.

Frequency

  • In human diabetics insulin is administered with each meal and blood glucose concentrations are measured at the same time to provide an accurate insulin dose which mimics the physiological response in a non-diabetic.
  • In most diabetic cats, adequate glycemic control can be provided by twice daily administration of insulin. Claims that any single insulin produces better glycemic control in cats have not been proven in randomized, controlled and masked studies. To date, there is no one insulin that has been consistently shown to produce higher rates of clinical remission in cats. 

Location of injection

  • Owners will be administering insulin subcutaneously but the choice of site has influence on the ease of injection and absorption.
  • Absorption from the scruff of the neck is usually satisfactory and the quantity of loose skin makes injection safe and easy. However, absorption is much better from the subcutaneous sites over the flank. Rotation of the injection site is suggested.
  • Daily fluctuations in absorption may also occur due to changes in exercise, external temperature, and whether the injection site was massaged or not.
  • It is very important to aim for a consistent routine in every part of diabetes management.

Further Reading

Publications

Refereed papers

  • Recent references from PubMed and VetMedResource.
  • Hoelmkjaer K M, Spodsberg E M & Bjornvad C R (2015) Insulin detemir treatment in diabetic cats in a practice setting J Feline Med Surg 17 (2), 144-151 PubMed.
  • Sparkes A H, Cannon M, Church D et al (2015) ISFM consensus guidelines on the practical management of diabetes mellitus in cats J Feline Med Surg 17 (3), 235-250 PubMed.
  • Gostelow R, Forcada Y, Graves T et al (2014) Systematic review of feline diabetic remission: separating fact from opinion. Vet J 202 (2), 208-221 PubMed.
  • Caney S M (2013) Management of cats on Lente insulin: tips and traps. Vet Clin North Am Small Anim Pract 43 (2), 267-282 PubMed.
  • Gilor C & Graves T K (2010) Synthetic insulin analogs and their use in dogs and cats Vet Clin North Am Small Anim Pract 40 (2), 297-307 PubMed.
  • Rucinsky R, Cook A, Haley S et al (2010) AAHA diabetes management guidelines.​ J Am Anim Hosp Assoc 46 (3), 215-224 PubMed.
  • Nelson R W, Henley K, Cole C et al (2009) Field safety and efficacy of protamine zinc recombinant human insulin for treatment of diabetes mellitus in cats J Vet Intern Med 23 (4), 787-793 PubMed.
  • Norsworthy G D, Lynn R & Cole C (2009) Preliminary study of protamine zinc recombinant insulin for the treatment of diabetes mellitus in cats. Vet Ther 10 (1-2), 24-28 PubMed
  • Michiels L, Reusch C E, Boari A et al (2008) Treatment of 46 cats with porcine lente insulin - a prospective, multicentre study. J Feline Med Surg 10 (5), 439-451 PubMed.
  • Martin G J & Rand J S (2007) Control of diabetes mellitus in cats with porcine insulin zinc suspension. Vet Rec 161 (3), 88-94 PubMed.
  • Weaver K E, Rozanski E A, Mahony O M et al (2006) Use of glargine and lente insulins in cats with diabetes mellitus. J Vet Intern Med 20 (2), 234-238 PubMed.
  • Martin G J & Rand J S (2001) Pharmacology of a 40 IU/ml porcine lente insulin preparation in diabetic cats: findings during the first week and after 5 or 9 weeks of therapy. J Feline Med Surg (1), 23-30 PubMed.

Other sources of information