Feline diabetes: yes, he can be regulated (Proceedings)

Diabetes mellitus (DM) is one of the two most common endocrine disorders in cats. While we tend to think of diabetes as a disease entity, we should remember that it really is a heterogeneous group of disorders in which insulin production is reduced or in which tissue cells are resistant to the effects of insulin, resulting in impaired glucose homeostasis. Regardless of the causes, from a clinical perspective, diabetes mellitus can be challenging to diagnose and treat in the cat because of this species' stress- induced hyperglycemia.

Pathophysiology review

Insulin is secreted after a meal, to facilitate "tissue uptake, utilization and storage of glucose, fat and amino acids in three primary tissues: liver, muscle and fat. With mild insulin deficiency, decreased transfer of ingested nutrients into tissues causes mild to moderate hyperglycemia. Severe insulin deficiency not only hampers tissue uptake of ingested fuels, but also results in marked glucose overproduction and excessive mobilization of the body's protein and fat stores. Marked insulin deficiency, coupled with a relative or absolute glucagon excess, results in an increased delivery of fatty acids to the liver and their subsequent oxidation to ketone bodies (beta-hydroxybutyrate, acetoacetate, and acetone), culminating in the clinical state of ketoacidosis." In short, there is no insulin available to deliver the glucose into the cells, resulting in cell starvation; polyphagia results with concurrent weight loss. Hyperglycemia results in glucose spilling into the urine and drawing water with it. This causes polyuria and compensatory polydypsia.

Classification and differentiation between type 1 and type 2 diabetes

In human diabetes, Type 1 refers to the condition seen in people who are generally lean, young and prone to ketogenesis. Type 2 DM usually occurs in the older human, who is often obese but is less prone to the development of ketoacidosis. Type 1 DM patients require insulin therapy, while Type 2 may be controlled, at least initially, with weight loss, diet and oral hypoglycemic agents.

In cats, the categorization is not as clear. Generally, diabetes is a disorder of the older, often overweight cat, more similar to the Type 2 human patient. However, often by the time the diagnosis of diabetes is made, these cats are insulin dependent although most are not prone to ketogenesis. In addition to these differences, cats may also develop diabetes secondary to primary pancreatic disease, endocrinopathies (acromegaly or hyperadrenocorticism), or drug therapy (glucocorticoids and progestins).

In Type 1 DM, there is beta cell depletion, resulting in absolute insulin deficiency. In Type 2 DM, the problem is one of insulin receptor and post receptor defects, causing impaired insulin uptake by tissues. This insulin resistance and associated hyperglycemia, causes the beta cells to produce more insulin, thus this state is one of a relative insulin deficiency. Obese cats appear to have a defect in insulin secretion along with a lower tissue sensitivity to insulin. Weight loss results in an imrovement in tissue sensitivity, thus weight loss, is not only helpful, but also imperative in treatment.

Another important feature about diabetes in cats is that pancreatic islet amyloid deposits are believed to interfere with insulin secretion, and that oral hypoglycemics (such as the sulfonylureas, glucatrol) may actually increase islet amyloid polypeptide (IAPP) deposition. IAPP is co-secreted with insulin. Islet amyloidosis occurs in 90% of humans with Type 2 DM.

Risk factors include body weight > 7 kg, older age (> 10 years), male gender, neutered. Unlike in humans, DM does not predispose cats to hypertension.

In the stressed patient, epinephrine release cause hyperglycemia and glucosuria. It is essential to differentiate between this stress response and diabetes. This can be done by either verifying that the hyperglycemia and glucosuria are persistent or request a fructosamine level be run on the previously collected sample. Fructosamine measures the protein bound glucose levels over the preceding 10 - 20 days. It can be affected by protein metabolism as well, hence hyperthyroidism, with more rapid muscle turnover, may result in artificially lower fructosamine values.

Therapy and management of the diabetic cat

Insulin choice: There are many types of insulin available. Insulins are derived from several sources and have several durations of action. In the United States, the FDA has eliminated any animal sourced insulin from the market. Thus, beef-pork and beef insulins are no longer available in this country for humans. They are produced from human recombinant technology, giving rise to the "humulin" insulins.

The second part of the label that affects the choice and efficacy is the speed of onset and the duration of the insulin. There are four main categories:

Regular (fast) - rapid onset of action (0.5h), max. effect (1-5h), end effect (8h)

• NPH (intermediate) - onset of action (1.5h), max. effect (4-12h), end effect (24h)

• Lente - onset of action (2.5h), max. effect (7-15h), end effect (24h)

• Semilente - onset of action (1.5h), max. effect (5-10h), end effect (16h)

• Combination: 70% NPH: 30% regular - onset of action (0.5h), max. effect (4-8h), end effect (24h)

• Ultralente (long acting) - onset of action (4h), max. effect (10-30h), end effect (36h)

Insulins glargine and detemir (ultra-long acting) once a day in humans

Remember that these values are for comparison only and that insulin responses vary with the individual and that the above listed times are in human patients. Every cat is different and will respond differently to the insulin they take in the management of diabetes.

1. Protamine zinc insulin (PZI) is a long-acting, beef-pork insulin that was considered by many to be the insulin of choice for cats because of its molecular similarity to feline insulin. Despite its long action, it still needs to be administered twice daily. It is not the perfect insulin for every cat, however it may be helpful in patients who are difficult to control with the less expensive humulin insulins. Since November, 2009, PZI-R has come on the veterinary market as ProZinc™. This is a human recombinant DNA insulin.

2. In Canada, Caninsulin™, an intermediate acting porcine insulin has been available for over 15 years. Its peak activity is ~3h and duration of 6-10h. In the United States, this product has recently been released as Vetsulin™.

3. Glargine (Lantus™) is a long-acting human recombinant DNA insulin analog that forms microprecipitates at the site of injection from which small amounts of insulin glargine are slowly released. Thus the glucose nadir occurs later than with PZI-R or a lente/ultralente insulin.

4. Insulin detemir (Levemir™) is similar to, but may be more predictable in cats than glargine (Lantus).

It is critical to know the concentration of the insulin you are using and to match the syringes to that strength. For correct dosage, insulin should be administered using syringes specially calibrated for the strength of insulin used. For example, most insulins are 100 Units/ml (U100) and micro-fine or ultra-fine U100 syringes should be used with them, however, Caninsulin™/ Vetsulin™ is a U40 insulin, and U40 syringes must be used to dose appropriately. Because only small amounts of insulin are often needed in cats, it is helpful to use a 3/10cc or 5/10cc syringe that is appropriately calibrated. This allows even the tiniest dose to be measured accurately.

While there are guidelines in choosing the starting dose of insulin for a patient, the maximum dose for that patient will be the dose that he/she needs to resolve his/her clinical signs of excessive urination and drinking, lethargy and weakness. The majority of cats require twice daily injections, regardless of the type of insulin selected.

Client counseling

Once the cat has been determined to be diabetic, client counseling becomes all-important. Initially, most clients are intimidated at the thought of administering insulin injections. Booking a discharge or demonstration appointment with the technologist works well, as, in most instances, technologists are more patient than veterinarians are at explaining and guiding the learning client.

At this appointment, review the pertinent facts about insulin storage (refrigerator), handling (gently), re suspension (gentle figure 8's), drawing up into the syringe, administration (upon exhalation of client, walk through the door of the tent, think canvas, practise on a cat using saline), single use only of insulin syringes for sterility and sharpness sake.

Show the client how to keep the 2 week diary (date, time of insulin administration, dose administered, activity level, BM, amount urinated (# and size of clumps of clumping litter), amount eaten, amount drunk (by difference, measure amount left in bowl the next morning). Counsel on diet to be fed, as determined by the veterinarian. Lower carbohydrate may be as or more effective than the traditionally fed high fiber diets. Currently there is also interest in higher protein diets to improve regulation of glycemia. Cats should have free access to a high protein, lower carbohydrate food all the time, rather than feeding twice daily.

Helpful websites for clients to use for information, support and encouragement (including teaching techniques) follow: www.petdiabetes.com, www.felinediabetes.com, www.sugarcats.com and www.cat-dog-diabetes.com/cats-diabetes-mellitus.asp

Some cats refuse to eat the diets we recommend. For those patients and for clients unwilling/unable to offer those diets, here is a website which lists the protein and carbohydrate proportions of grocery store brands: http://www.sugarcats.net/sites/jmpeerson/.

Monitoring urine parameters at home is justified for:

• cats with transient diabetes- to identify when/if glucosuria recurs

• cats on oral hypoglycemics to determine if glucosuria resolves

• previously or currently ketoacidotic kitties- to monitor for ketones

A really good chapter to use as a client handout may be found in Vet Clinics of North America: May 1995,pp 753-759, entitled: Home management of cats and dogs with diabetes mellitus: Common questions asked by veterinarians and clients, by Drs. Arnie Plotnick and Deb Greco.

Follow-up care and monitoring

At the discharge time, book an appointment for a blood glucose curve and re-evaluation for 14 days later. Let the client know that you will call daily for the first 3 - 4 days, to be supportive and available for questions, to find out how the kitty is doing, and to ascertain that they are observing the parameters you need diarized for evaluation. Let them know that it is unlikely that the initial dose will be the perfect one, and that, as they approach the "right" dose for this cat, there will initially be a marked reduction in urine output and drinking, however, after 3-4 days, these amounts will increase again as the cat's glucose homeostasis re-equilibrates.

The timeline for care that the author uses is:

• Diagnose diabetes mellitus; start insulin, diet and diary;

• 10-14 days later: in-clinic BG curve, adjust dose, teach ear prick BGs, add BID BG monitoring to diary for practice;

• Another 10-14 days later: in-clinic BG curve, fructosamine, adjust dose;

• Subsequent BG curves are performed at home, follow-up by email, phone or fax to adjust dose;

• Recheck kitty q4-6 months (exam, fructosamine, U/A) as long as he/she is stable.

At the blood glucose (BG) curve appointment, hospitalize the cat with food and water, after weighing him/her and ascertaining what time the insulin was administered and what dose the client gave. Measure BG immediately, to get a starting level. Using a 25G needle works well, as a mere drop or two of blood are needed for the portable glucometers. Plot the values on a graph for easier interpretation. Submit a serum fructosamine as well to determine how the average glycemic control has been over the past 10-20 days.

Continue measuring the BG every 1-1.5 hours over a 12 hour period. Ear sampling and a calm, reassuring manner will help to minimize the stress (and its associated BG elevations) somewhat. Nevertheless, the readings generally will be higher than what is occurring at home, therefore it is imperative to read the client's diary and take the clinical signs into consideration when adjusting the insulin dose. Once the blood glucose goes up for two consecutive measurements, the curve can be stopped. (Note this does NOT apply in the case of a cat in diabetic ketoacidosis.)

Use of the marginal ear vein is an accurate and easy technique for the measurement of BG. It is a useful technique in the clinic and, if the concept is introduced to clients with confidence and compassion, many are willing to perform curves at home. In general, these curves are more accurate as the cat's stress level is lower. Additionally, it is valuable for clients to be able to measure a spot glucose if their cat "doesn't look right" before deciding to give insulin or not.

The goals of performing a BG curve are to determine

1. whether the insulin is being absorbed

2. the glucose nadir (value and time to reach it)

3. the duration of insulin effect

4. the duration of insulin effect

5. and to assess the fluctuations of glucose levels in this individual patient!

When using glargine, the protocol for regulation and curving is somewhat different. The following recommendations come from Dr. Jacquie Rand:

• Measure glucoses every two hours for a minimum of 12 hours daily for the first three days. This is in order to determine whether hypoglycemia is occurring as well as to assess how long the insulin is lasting in the individual. After this initial three day period, dose adjustments are based on the pre-insulin BG (vs. nadir as with other types of insulin).

• If at a 7 day hospital recheck, the pre-insulin BG concentration is > 290 mg/dl (16 mmol/L), increase the dose by 1.0 U/cat. A 12h curve should be done on the following day to make sure that hypoglycemia is not occurring at this increased dose.

• Do not change the dose if the pre-insulin BG concentration is 220-290 mg/dl (12-16 mmol/L).

• The dose should be decreased by 0.5-1.0 U/cat if the pre-insulin BG concentration is < 180 mg/dL (10 mmol/L). I f biochemical hypoglycemia is present, the dose should be decreased by 1.0 U/cat. If clinical signs of hypoglycemia are present, the glargine dose should be decreased by 50%.

If a BG drops below normal range (< 80mg/dl or < 4.4 mmol/l), the staff person should notify the veterinarian after offering the cat some palatable food, as he/she may wish to administer dextrose intravenously to avoid a hypoglycemic crisis. Signs of hypoglycemia include weakness, lethargy, trembling, head tilt, ataxia, coma and death. If a hypoglycemic cat is offered food and doesn't eat right away, or if signs are severe, then corn syrup should be rubbed on the oral buccal mucosa while preparing to administer an intravenous dose of 50% dextrose.

The "Somogyi effect" is rebound hypoglycemia-induced hyperglycemia. If the cat's BG drops too low, the body reacts by releasing catecholamines (epinephrine), glucagon, glucocorticoids and growth hormone. This causes a rapid release of glucose into the serum causing this rebound to occur. It is important to not be tempted to increase the insulin dose in these individuals, as this would accentuate the problem and eventually cause a hypoglycemic crisis. "Spot checks" of BG levels should be avoided as they can be misleading and can mask a rebound effect, and be misinterpreted as needing more insulin.

Over the next month or two, by performing blood glucose curves, measuring serum fructosamine and reassessing the cat clinically and historically (diary) every 2 weeks, the insulin dose suitable for this patient will be determined. Thereafter, it is advisable to see the stable diabetic cat every 4 - 6 months for a fructosamine. Consider, also, on these rechecks, to collect a sterile urine sample for urinalysis, as diabetic cats are more prone to bacterial urinary tract infections than non-diabetic individuals. If a diabetic patient becomes ill, then a glucose curve should be run as well as any other tests appropriate to their condition.