Insulin therapy in cats (Proceedings)

Few diseases are as frustrating for a veterinarian as diabetes mellitus. Realistically, control of hyperglycemia is rarely accomplished, and clinical signs of diabetes often persist. The landscape is changing in feline diabetes, however, and as clinicians learn more about new insulin preparations, diets, and treatment monitoring strategies, cats with diabetes may be better controlled.

Insulin Therapy

There are many different types of insulin that vary with species of origin and with chemical modifications and formulations that affect onset and duration of action. Unfortunately, no feline insulin formulation is currently available, so human, bovine, or porcine insulin are used in treating diabetic cats. Data concerning the pharmacokinetics and pharmacodynamics of insulin in the cat are difficult to interpret. Most published studies have been conducted in normal cats, and some have been done in cats with diabetes. In either case, it is difficult to determine the effects of endogenous vs. exogenous insulin. Determinations of potency, time to peak activity and duration of activity, factors that influence choice of doses and dosing intervals, vary widely from cat to cat. In fact, there is no reasonable way to predict the kinetics of an given insulin preparation in any given patient.

The most commonly used insulin preparations in cats are Regular insulin (Humulin-R™ ), NPH insulin (Humulin-N™ ), porcine lente insulins (Vetsulin™ ), PZI, Insulin glargine (Lantus™ ), and insulin detemir (Levemir™ ). Regular insulin is not used for chronic treatment of diabetes in cats, but is commonly used in the treatment of diabetic ketoacidosis.

NPH, PZI, and Lente

NPH is considered an intermediate-acting insulin, and is available as a human recombinant product. NPH is used commonly in cats with diabetes, and is typically given subcutaneously to cats twice daily. Lente insulin uses zinc as a positively charged ion on which to base insulin polymerization. Polymers are absorbed and metabolized slowly so that the onset and duration of lente insulin are extended beyond those of regular insulin. Human recombinant lente insulin has been removed from the United States market and is not longer available for use. Porcine lente insulin, however, has gained in popularity and is the only insulin currently marketed and labelled for use in the cat. Currently available veterinary products are Vetsulin™ (U.S.) and Caninsulin™ (Europe, Australia, Canada). Porcine insulin is dissimilar in amino acid sequence when compared to feline insulin, but it is no more divergent (by 4 amino acids) than is human insulin. Lente is typically given twice daily by subcutaneous injection, and studies in cats show it is a reasonable choice for treating diabetic cats(Martin and Rand 2001). A recent study suggested the duration of porcine lente is shorter than either PZI or glargine (Marshall et al 2008).

Protamine zinc iletin (PZI) has been used extensively in feline diabetes. This insulin preparation was widely available, but was largely removed from the human market in the 1990's. Recently, PZI preparations marketed for use in cats have once again become available. One product, PZIVet™ , a preparation of 90% beef insulin and 10% pork insulin, was removed from the market last year, but PZI is still available from compounding pharmacies. PZI is still a good choice for long-term treatment of diabetes in cats, and is typically given subcutaneously twice daily.

Glargine

Insulin glargine is a genetically engineered insulin analog that has hormonal action identical to native insulin, has no known immunogenicity, and achieves long-lasting glycemic control while minimizing fluctuations in blood glucose concentration in many human diabetics. Glargine is based on human recombinant insulin with a few amino acid substitutions. Glycine is substituted for an asparagine residue at the amino terminal of the A chain, and two arginine residues are added to the end of the B chain (Figure 1). The result is a shift in the isoelectric point of the insulin molecule so that it is completely soluble at a low pH (around pH 4). The pH of interstitial fluid is approximately 7.4, and when glargine is injected into a patient, the insulin precipitates into hexamers that are inactive. These insulin hexamers are slowly broken down in the body to form active insulin monomers. The result is that the onset is gentle and the duration is long-lived. Because of the difference in pH, glargine cannot be mixed with other insulin formulations. Experience with using glargine in cats is growing (Weaver et al. 2006, Rand 2006), and many clinicians have had good success with its use. Glargine is best used twice daily subcutaneously.

Detemir

Insulin detemir has been used in Europe for several years and was just recently approved for use in the U.S. Rather than having amino acid substitutions (like insulin glargine), insulin detemir is acylated with myristic acid, which allows hexamers to form at neutral pH, and, more importantly, allows the insulin to bind to albumin (Figure 1). This results in a very slow, smooth delivery of insulin such that once daily delivery is all that is needed in many human patients. We have done some preliminary work comparing the pharmacokinetics of glargine, detemir, and regular insulin in cats (Gilor et al., 2008). Figure 2 shows a comparison of the onset of action and duration of glargine vs. detemir in one cat. In this cat, as in others we have studied, detemir is relatively "peakless" and lasts longer than does glargine. In other cats, the duration of glargine and detemir are similar. One advantage of detemir might be that, because it is bound to albumin, it reaches higher concentrations in organs with fenestrated capillaries, especially the liver. This more closely mimics circulation of insulin in normal physiology. We have observed no toxic effects of detemir in a small number of cats we have studied, and it seems reasonable that detemir could be tried if adequate glycemic control is not achieved with other types of insulin.

Insulin Dosage and Administration

Regardless of the insulin preparation used, an initial dose of 0.25 U/kg of body weight is recommended. Typically, long-acting insulin preparations have been prescribed at higher initial doses because there may be less chance of causing hypoglycemia with the slower absorption. We have, however, observed insulin-induced hypoglycemia in cats give initial doses of 0.5 U/kg glargine or PZI.

Physiologically, it makes sense to given insulin with meals. Because cats are usually fed free-choice, twice daily insulin injections coincident with meal times are usually not possible. Most insulin formulations for long-term use in cats are given every 12 hours at times that suit the owners' schedules. The exception may be with determir, as noted above, that may prove to be useful as a once daily insulin in the cat.

Monitoring Insulin Therapy

Blood Glucose Curves

Monitoring therapy can be difficult in cats with diabetes. Because stress hyperglycemia is common in cats, blood glucose concentrations measured during a veterinary visit can be misleading. Blood glucose curves have been used extensively to monitor insulin therapy in the past. There curves are generated by measuring blood glucose every hour for 12- or 24-hour periods following a dose of insulin. Blood is typically collected from an indwelling central venous catheter (to avoid repeated venipuncture) or, sometimes by repeated pricking of the marginal vein of the ear, a procedure well-tolerated by most cats. Glucose concentrations are measured using a hand-held glucose meter, of which many brands are available. Several hand-held blood glucose meters have been studied for use in cats, and all have been suitable. Conventional wisdom has dictated that adjustments in insulin therapy, whether changes in dose, frequency, or type of insulin, only be made based on serial blood glucose measurements. The validity of blood glucose curves has been called into question by several recent studies (Alt et al. 2007, Kley et al. 2004). When glucose curves are evaluated on different days in the same cat, there is very little consistency. Whether evaluation mean blood glucose concentrations, blood glucose nadir, time-to-nadir, maximum blood glucose concentration, or other parameters, variation is wide enough to result in completely different clinical recommendations in the same patient. Blood glucose curves may not be as helpful as was once thought, and other ther methods of assessing glycemic control are probably more important.

How then are blood glucose curves useful? Veterinary academicians argue as to the existence of the Somogyi phenomenon in cats, but whether some cats experience true insulin-induced hyperglycemia (from a rebound effect in response to hypoglycemia), or whether it is a simple question of insulin kinetics, wide swings reminiscent of the Somogyi effect are possible. For example, a cat receiving insulin might respond quickly with profound hypoglycemia. If the cat experiences insulin-induced hyperglycemia or if the action of the insulin is short-lived, the cat can return quickly to a hyperglycemic state. In this instance, persistent hyperglycemia and its clinical signs would persist. This might be suspected based on owner reports of signs of hypoglycemia following insulin administration. A blood glucose curve could potentially identify this situation, but could give only a rough estimate of the duration of action of insulin or the appropriateness of a given dose.

Continuous glucose monitoring using small subcutaneously implanted sensors that measure interstitial glucose concentrations have been used to some extent for serial blood glucose determinations in cats, and can be useful in monitoring therapy. These types of glucose sensors are expected to become more readily available and more affordable in the future.

Fructosamine and Glycosylated Hemoglobin

Serum proteins and hemoglobin can be glycosylated extensively in the presence of high concentrations of glucose. Serum fructosamine testing measures glycosylated serum proteins. Because the average half-life of these proteins is around 2 weeks, fructosamine concentrations in the serum reflect average blood glucose concentrations of a 2-3 week period. With red blood cell lifespan being closer to 3 months, glycosylated hemoglobin concentrations in the blood reflect glycemic control over a longer period of time. Serum fructosamine determination is used more commonly than glycosylated hemoglobin measurement to monitor insulin therapy in cats. Serum fructosamine or glycosylated hemoglobin concentrations above the reference interval are indicative of poor glycemic control.

Urine Testing

Urine chemistry test strips are readily available and easy for cat owners to use at home. Urine testing may be most useful in the beginning stages of treatment to detect ketones should they occur. Also, persistently negative urine glucose testing might indicate chronic hypoglycemia. Most cats with diabetes remain hyperglycemic during some parts of the day despite treatment, so urine glucose is usually positive. Insulin dose adjustments should not be made solely based on urine glucose measurements.

Spot Blood Glucose

Because of stress hyperglycemia and difficulty in predicting insulin kinetics in the cat, individual spot blood glucose measurements are of little use in monitoring feline diabetes. A spot blood glucose test can, however, be of value in identifying hypoglycemia.

Clinical Signs

Clinical signs of hyperglycemia (polyuria, polydipsia, appetite changes, weight loss, poor condition, etc.) may be the most useful deteriminants of glycemic control in cats undergoing insulin therapy.

Insulin Dose Adjustments

Dosages adjustments should be made based on indicators of glycemic control discussed above. In the cat, increases in insulin doses should be done conservative because a small change can have a large effect. We recommend increasing insulin doses by 0.5 to 1 U/cat. Measuring half-units is usually difficult, but should be attempted when relatively small starting doses are being adjusted upwards. Response to a dose adjustment should be evaluated after a week or more of the new dose.

References

Alt N, Kley S, Haessig M, Reusch CE. Day-to-day variability of blood glucose concentration curves generated at home in cats with diabetes mellitus. J Am Vet Med Assoc. 2007;230:1011-7.

Gilor C, Keel T, Attermeier KJ, Graves TK. Hyperglycemic-euglycemic clamps using insulin detemir and insulin glargine in health cats. (Abstract 96) J Vet Intern Med 2008; 22:729.

Kley S, Casella M, Reusch CE. Evaluation of long-term home monitoring of blood glucose concentrations in cats with diabetes mellitus: 26 cases (1999-2002).

J Am Vet Med Assoc. 2004;225:261-6.

Marshall RD, Rand JS, Morton JM. Glargine and protamine zinc insulin have a longer duration of action and result in lower mean daily glucose concentrations than lente insulin in healthy cats. J Vet Pharmacol Ther. 2008;31:205-12.

Martin GJ, Rand JS. Pharmacology of a 40 IU/ml porcine lente insulin preparation in diabetic cats: findings during the first week and after 5 or 9 weeks of therapy.

J Feline Med Surg. 2001;(1):23-30.

Rand J. Editorial: glargine, a new long-acting insulin analog for diabetic cats. J Vet Intern Med 2006;20:219-220.

Weaver KE, Rozanski EA, Mahony OM, et al. Use of glargine and lente insulins in cats with diabetes mellitus. J Vet Intern Med 2006;20:234-238.