In addition to demonstrating the highly variable absorption kinetics, these results suggest that beef/pork PZI is more completely
absorbed than Ultralente. Although the initial recommendation was to use beef/pork PZI once daily, resulting in acceptable
glycemic control in some cats, the current recommendation is to give it twice daily.
Beef/pork PZI is not recommended as initial treatment in dogs because intermediate-acting insulins have an adequate duration
of action in dogs, and intermediate-acting insulins have more consistent absorption.
Beef insulins also are more immunogenic in dogs, and antibody formation has resulted in inconsistent absorption and action.
Some cats have had adequate glycemic control with beef/pork and human NPH insulin given twice daily, but in other cats the
duration of action is too short. Currently only human NPH is available. The main advantage of NPH insulin over beef/pork PZI
is that, as expected, the former has greater and more consistent absorption.
NPH insulin has been a mainstay of the treatment of diabetes mellitus in dogs for years, with a shift from beef/pork to human
because of product availability. Once-daily administration was the initial approach, but there is cumulating evidence that
twice-daily administration results in more acceptable glycemic control.
Ultralente insulin is an insulin-zinc suspension of crystalline zinc-insulin precipitate. The crystals are more stable than
the amorphous zinc-insulin precipitate of Semilente; therefore, monomers are more slowly released in the subcutaneous space.
As with PZI, beef insulin-zinc crystals are more stable than pork and human insulin-zinc crystals. Prior to its discontinuation,
beef Ultralente insulin had the longest duration of action in humans and was considered a peakless insulin, similar to insulin
glargine. Human Ultralente insulin also was discontinued recently, presumably because it did not have the same peakless duration
of action of beef Ultralente insulin; basal insulin therapy now may be provided with insulin glargine and insulin detemir.
Lente insulin is mixture of 30 percent Semilente and 70 percent Ultralente insulin. Because the amorphous and crystalline
precipitates are formed under different physical conditions, the mixture does not result in interconversion between the two.
While the overall insulin effect of Lente is close to NPH, Lente in principle has a faster onset of action and is superior
at controlling post-prandial hyperglycemia because of the Semilente component, and has a slighter longer duration of action
than NPH because of the Ultralente component.
Human Lente is no longer available, but veterinary pork Lente is available. Pork insulin has the same structure as dog insulin.
Immunogenicity could still occur due to impurities, but, given modern purification techniques, reduced immunogenicity of pork
insulin in humans, and lack of evidence of antibody formation in dogs given pork insulins, significant immunogenicity is unlikely.
Lente insulins can achieve acceptable glycemic control in dogs with once-to twice-daily injections, with a likelihood of better
control with twice-daily injection, and in cats with twice-daily injection.
Insulin glargine is created by replacing asparagine with glycine at position A21 and adding two arginines to the C-terminal
portion of the B chain. This results in insulin that is soluble at a pH of 4.0 but insoluble at neutral pH.
When injected into subcutaneous tissue with a neutral pH, the insulin precipitates, and insulin monomers are then slowly released
from the insulin aggregates and absorbed. Glargine has a slightly reduced affinity for the human insulin receptor (86 percent).
It may be injected by syringe or pen. The use of glargine is increasing in cats as a long-acting substitute for human Ultralente
and alternative to beef and beef/pork PZI. Its use results in improved glycemic control when used once or twice daily, but,
as with other long-acting insulins in cats, glycemic control is best with twice-daily administration. Pharmacokinetic studies
in normal dogs demonstrate erratic absorption.
Insulin detemir recently was released in the United States and Canada as another basal insulin. It is a neutral, soluble insulin
analogue in which B30 threonine is removed and B29 lysine is acylated with a 14-carbon fatty acid. The fatty-acid modification
allows insulin detemir to reversibly bind to human albumin. Because the insulin remains soluble in the subcutaneous space
and does not form a precipitate, it appears to be more consistently absorbed. The duration of action is less than with glargine,
and in humans it is used both once and twice daily.