Evaluating the array of insulin products for companion animals
Q. Please review insulin products for use in dogs and cats.
A. Dr. Anthony Abrams-Ogg, at the 2007 American College of Veterinary Internal Medicine Forum in Seattle, lectured on "Chemistry and Pharmacology of Therapeutic Insulin Preparations." Some relevant points from the lecture are provided here:
Therapeutic insulin products (insulins) appeared shortly after insulin's discovery in 1921. Since then, there has been continued extensive research into the chemistry of insulin and the improvement of therapeutic formulations. The marketed insulins represent only a small fraction of laboratory preparations, but even so the variety (and changes in variety) can be confusing. The key to understanding them is to understand their pharmacokinetics.Structure and action
Mammalian insulin is a protein consisting of a 21-amino-acid A chain and 30-amino-acid B chain, folded into a tertiary structure, with some amino-acid variations between species. Within seconds of insulin binding to the insulin receptor on fat and muscle cells, autophosphorylation occurs and complex signal transduction results in a dramatic increase in cell permeability to glucose, due to translocation of the GLUT 4 glucose-transport protein from the cytosol to the cell membrane.
The exact functional surface of insulin's tertiary structure is not known, but the differences in amino-acid structure of beef, pork and human insulin are not important with respect to receptor-binding affinity. Unless there are antibodies interfering with receptor binding, human, beef and pork insulin appear to be of equivalent potency at the receptor level in humans, and are likely so in dogs and cats as well.
Insulins follow typical pharmacokinetics involving drug liberation, absorption, distribution, metabolism and excretion. The difference between the different products is due to liberation and absorption. Insulin is secreted physiologically as a monomer (single molecule) and needs to be in that form to be metabolically active. In pharmaceutical products, insulin is present in complex forms. Insulin is absorbed in the subcutaneous space into the blood predominantly as monomers and dimers, and the different products liberate insulin monomers and dimers at various rates. Once insulin is absorbed, the product of origin is irrelevant. Furthermore, while different physiologic and pathologic states may affect distribution, metabolism and excretion, these effects are not as important on insulin's glycemic effects as are those affecting absorption.
Insulins are, therefore, classified as short, intermediate and long-acting, based on their rate of absorption. Compared to more slowly absorbed insulin, more rapidly absorbed insulin will have an earlier glycemic effect. For any given quantity of insulin, if the insulin is more rapidly absorbed, then blood insulin concentration will be higher; hence, the more rapid-acting insulins are more potent.
Because the pharmacokinetics after absorption are the same for the different insulins, a more rapidly absorbed insulin will leave the circulation sooner with respect to injection time. In addition, more rapid-acting insulins are more consistently and completely absorbed, resulting in a more predictable glycemic effect.
Traditional intermediate and long-acting insulins are suspensions of precipitated insulin. Dissolution of a precipitate is an unpredictable process, and probably is affected by different physiologic states, which accounts for some of the variability in absorption and less-consistent response than that seen with insulin solutions (e.g., regular insulin). There also is a dose effect on pharmacokinetics, in that a larger insulin dose will result in a higher, later peak, and longer duration of action.
Regular insulin is an insulin-zinc solution. When injected intravenously, the insulin concentration is rapidly diluted. After intramuscular or subcutaneous injection, the concentration is lowered by diffusion into tissues and the insulin dissociates more slowly, accounting for the longer onset and duration of action and reduced potency, as compared to the same dose given intravenously. Even as a solution, insulin is not completely absorbed when injected subcutaneously, with bioavailability of 65 percent in dogs and 45 percent in cats.
Semilente insulin is an insulin-zinc suspension of amorphous (non-crystalline) zinc-insulin precipitate. After subcutaneous injection, the amorphous particles undergo dissolution, releasing insulin monomers. The liberation of insulin is slower than in regular insulin, but more rapid than intermediate-acting insulins. Semilente insulin is available only as a component of Lente insulin.