Insulin lispro is a human insulin analogue made by reversing the order of B28 proline and B29 lysine of human insulin. Insulin
aspart is made by substituting aspartic acid for proline at B28. These substitutions reduce insulin self-association so the
insulin remains monomeric/dimeric and, therefore, is absorbed twice as quickly after subcutaneous injection as regular insulin.
Receptor binding affinity is similar to human insulin. Because of the rapid onset of action and lack of precipitation, these
insulins are currently the products of choice for prandial injection (to control post-prandial hyperglycemia) by injection
and in insulin pumps. A major advantage of these insulins in humans is allowing a flexibility in diet, as post-prandial hyperglycemia
may be addressed. They have no advantage over regular insulin for intravenous use. Pre-clinical studies have been performed
on dogs and cats, mostly as toxicity studies, but acceleration of absorption may not be as pronounced.
Regular insulin is used primarily in veterinary medicine in treatment of diabetic ketoacidosis, and occasionally to treat
post-prandial hyperglycemia in dogs. Owner convenience has taken preference historically over tight glycemic control.
Once-daily injection has been preferred, with a gradual shift toward twice-daily injection, and the duration of regular insulin
is too short for such a purpose. Given that it is easy to control diet in dogs, that post-prandial hyperglycemia is mild and
prolonged in cats, that regular insulin is unlikely to be withdrawn, and that these analogues may not be faster-acting in
dogs, they are unlikely to be extensively used.
Intermediate and long-acting insulins
Neutral protamine Hagedorn (NPH) insulin and protamine-zinc insulin (PZI) are suspensions of protamine-zinc-insulin crystals
at a neutral pH. Protamine, a fish protein usually of salmon or trout origin, acts as the retarding agent. It is presumed
that subcutaneous proteolytic activity cleaves the protamine from the insulin, resulting in crystal dissociation and release
of insulin monomers. A small amount of zinc is present as a stabilizing agent that prolongs the action by inhibiting protaminases.
In NPH insulin, insulin and protamine are present in at a 1:5 ratio. A small amount of phenol/cresol is also required. In
PZI, the protamine and zinc are present in excess, which further prolongs the action. PZI for human use was discontinued in
1991. A 90 percent beef/10 percent pork insulin (PZI-VET, IDEXX) for use in cats is now available in the United States. Pure
beef PZI for cats is also available from some compounding pharmacies.
The stimulus to produce beef PZI is the perception that it is a superior insulin to use in cats because: 1) beef insulin is
structurally the closest to cat insulin; 2) the duration of action of insulins in cats compared to humans and dogs is short;
therefore a long-acting insulin is desirable; and 3) PZI is more completely and consistently absorbed than Ultralente insulin.
Concerning insulin structure, beef, pork, and human insulin probably all bind with similar affinity to the insulin receptor
of the cat. The only concern with different insulin structure would, therefore, be one of immunogenicity, which does not appear
to be an important problem in cats.
Cats are unpredictable in their response to insulin, although the reason for this is not understood. Compared to dogs and
humans, insulin in cats is less completely absorbed, and perhaps this is at least in part responsible for the observation
that duration of insulins in cats is short.
It has been proposed that the short duration is the result of a counter-regulatory phenomenon. In a study of normal cats measuring
insulin concentration and blood glucose following administration of 1 U/kg, mean (range) peak insulin concentration was 763
(262-2758) pmol/L for beef/pork PZI vs. 318 (126-804) pmol/L for beef-pork Ultralente insulin. Mean (range) peak insulin concentration
over baseline was reached in four (one to 12) hours for beef/pork PZI vs. eight (two to 20) hours for beef-pork Ultralente.
Mean (range) duration of increase in insulin was 24 (22-24) hours for beef/pork PZI vs. 21 (14-24) hours for beef/pork Ultralente.
Mean (range) blood-glucose nadirs were achieved at eight (three to 20) hours for beef/pork PZI vs. 10 (five to 24) hours for
beef/pork Ultralente. Degree of blood glucose reduction was similar.