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Which insulin should I use? (Proceedings)

May 01, 2011

Insulin has become increasingly important in the treatment of dogs and cats with diabetes mellitus. Almost all dogs are classified with insulin-dependent or type 1 diabetes mellitus. Although up to 60% of cats are non insulin-dependent or type 2 diabetics at the time of diagnosis, early intervention with exogenous insulin is an important component to achieving remission and preserving the function of insulin-secreting beta cells. For this reason almost all of our diabetic dogs and cats will be treated with insulin so it is important to understand which insulin preparations are available and their utility in our canine and feline patients.

History

Insulin was first discovered in 1921. The original preparations were bovine and porcine pancreatic extracts. These formulations were short-acting, relatively dilute and impure. As a result, frequent administration and large volumes of insulin were required. Due to impurities, local reactions were common. Because beef and pork insulin differ from human insulin by 3 and 1 amino acids, respectively, many people developed insulin antibodies which resulted in variable and poor responses to these insulins in some diabetic people. Over time more concentrated beef and pork insulins were produced and purity improved. In the 1930's – 1950's it was discovered that the addition of protamine and zinc would cause crystallization of insulin and slow absorption. In the 1980's recombinant DNA technology led to the development of human recombinant insulin. The production of human recombinant insulin led to a dramatic decrease in the use of animal-origin insulin in man. In the 1990's insulin analogues were developed to better mimic the basal-bolus insulin requirements of man as well as to improve consistency. The premise is that a more constant (basal) amount of insulin is produced by the pancreas as a result of glucose produced by the liver. This basal production of insulin occurs in the fasted state. There is also a larger, more rapid increase (bolus) in insulin production after meals as a result of post-prandial hyperglycemia.

Ultra short and short duration insulins (Lispro, Aspart, Glulisine, human recombinant regular)

Human recombinant regular insulin was the traditional 'bolus' insulin used separately or in mixed preparations with an intermediate acting insulin. Monomers are the active form and required for absorption into the bloodstream and insulin receptor binding. When given intravenously regular insulin rapidly dissociates to monomers so there is a more rapid onset and shorter duration. When given subcutaneously, dissociation to dimers and monomers is required prior to absorption into the bloodstream. Using regular insulin subcutaneously, peak insulin levels occur at 60 minutes with a duration of up to 6 hours.

Because of the pharmacokinetics of subcutaneously administered human recombinant regular insulin in man, it requires administration 30 to 45 minutes prior to eating. This was inconvenient so ultra short-acting analogues were developed that could be administered 15 minutes before or after eating. Insulin analogues manipulate the amino acids sequences to alter absorption and dissociation. The ultra-short analogues achieved a more rapid onset, higher peaks and shorter duration. Insulin lispro (Humalog® - Eli Lilly & Co.) was created by switching proline-lysine to lysine-proline at the 28th and 29th positions on the beta chain of the insulin molecule. Insulin aspart (Novolog® - Novo Nordisk Laboratories) was created by the substitution of aspartic acid for proline at the 28th position on the beta chain. Glulisine (Apidra® - Sanofi-Aventis) was created by replacing asparagine at the 3rd position of the beta chain with lysine and replacement of lysine at the 29th position of the beta chain with glutamic acid. These substitutions prevent self-aggregation of the insulin molecules that can delay absorption.

Ultra short acting analogues have been used very little in veterinary medicine. Limited studies show that these analogues are not likely to provide a clinically significant benefit over human recombinant regular insulin in dogs and cats. A single study in dogs reported that insulin lispro was comparable to regular insulin when given by continuous rate infusion to dogs with diabetic ketoacidosis. These insulins may become important in the future if we lose human recombinant regular insulin formulations.