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.
• Canine insulin is identical to porcine insulin and differs from human insulin by 1 key amino acid.

Source

• 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 Diabetes mellitus, 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 Hypoglycemia (lower than normal blood glucose).

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

Administration

Further Reading

Publications

Refereed papers

• Recent references from PubMed and VetMedResource.
• Fracassi F, Corradini S, Hafner M et al (2015) Detemir insulin for the treatment of diabetes mellitus in dogs. J Am Vet Med Assoc 247 (1), 73-78 PubMed.
• Hess R S & Drobatz K J (2013) Glargine insulin for treatment of naturally occurring diabetes mellitus in dogs. J Am Vet Med Assoc 243 (8), 1154-1161 PubMed.
• Fracassi F, Boretti F S, Sieber-Ruckstuhl N S et al (2012) Use of insulin glargine in dogs with diabetes mellitus. Vet Rec 170 (2), 52 PubMed.
• Maggiore A D, Nelson R W, Dennis J et al (2012) Efficacy of protamine zinc recombinant human insulin for controlling hyperglycemia in dogs with diabetes mellitus. J Vet Intern Med 26 (1), 109-115 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 for dogs and cats. J Am Anim Hosp Assoc 46 (3), 215-224 PubMed.
• Fleeman L M, Rand J S & Morton J M (2009) Pharmacokinetics and pharmacodynamics of porcine insulin zinc suspension in eight diabetic dogs. Vet Rec 164 (8), 232-237 PubMed.
• Davison L J, Walding B, Herrtage M E et al (2008) Anti-insulin antibodies in diabetic dogs before and after treatment with different insulin preparations. J Vet Int Med 22 (6), 1317-1325 PubMed.
• Monroe W E, Laxton D J, Fallin E A et al (2005) Efficacy and safety of a purified porcine insulin zinc suspension for managing diabetes mellitus in dogs. J Vet Int Med 19 (5), 675-682 PubMed.
• Hess R S & Ward C R (2000) Effect of insulin dosage on glycaemic response in dogs with diabetes mellitus - 221 cases (1993-1998). J Am Vet Med Assoc 216 (2), 217-221 PubMed.
• Graham P A, Nash A S, McKellar Q A (1997) The pharmacokinetics of a highly purified porcine insulin zinc suspension in dogs with naturally occurring diabetes mellitus. J Small Anim Prac 38 (10), 434-438 PubMed.

Other sources of information

• Gostelow R (2015) Top 5 maintenance insulins. Clinician’s Brief. November, 53-58 Article.
• Feldman E C, Nelson R W, Reusch C E, Scott-Moncrieff J C & Behrend E  (2014) Canine and Feline Endocrinology. 4th edn, Elsevier, pp. 1-669.  
• Nelson R W (2010) Canine diabetes mellitus. In: Ettinger S J, Feldman E C, eds. Textbook of Veterinary Internal Medicine. Seventh Edition, Saunders Elsevier, pp. 1782-1795.
• Caninsulin®/Vetsulin® product information - FDA Freedom of Information Summary, www.caninsulin.com & www.vetsulin.com
• VetPen® training course