Managing diabetes in cats (Proceedings)

Overview of diabetes mellitus in cats

Like the disease in humans, diabetes in cats is a multi-factorial process combining genetic factors with environmental ones.  However, there are two factors that likely have a crucial role in determining whether or not diabetes develops, and if diabetes does occur, whether or not it is insulin dependent.  The first of these determining factors in the majority of cats is the presence of persistent hyperglycemia (either as a result of the phenomenon of glucose toxicity or due to one of many factors causing insulin resistance), which is general believed to be the first step in the development of diabetes in the majority of cats.  Second major factor that influences the course of the disease is the duration and severity of disease that ultimately results in beta cell damage or destruction.  Once islet destruction has commenced, the disease becomes less likely to have a reversible outcome and the need for chronic insulin therapy to achieve control of blood glucose is assured.  Thus, the classification of diabetic cats into Type I (insulin dependent or IDDM), Type II (non-insulin dependent or NIDDM) or transient diabetics can be very difficult, frequently confusing, and often in error, because some cats appear to not require insulin initially, and then progress to insulin dependency later.  Other cats flip back and forth between insulin dependency and not, as the severity of the impairment of beta cell function, insulin resistance, and other factors wax and wane.  These apparent flip-flops are understandable when one realizes the huge variation that occurs in these three things that are important in determining the diabetic state in cats:   1) islet pathology may be quite variable (mild to severe, static to progressive), 2) the ability of the pancreas to secrete insulin is dependent on the degree of islet pathology (which can change with time), and 3) the peripheral tissue responsiveness to insulin, which varies due to many factors (e.g. obesity, inflammatory, infectious, neoplastic or hormonal disorders).  Each of these different variables can affect the need for insulin, the dose of insulin, and the overall ease of patient management.

Feline obesity

Recent studies indicate that 25-40% of cats in the United States are overweight or obese.  There are a large number of factors that contribute to this problem, including sex (intact vs. neutered, male vs. female), age, activity (indoor vs. outdoor), and feeding style (meal feeding vs free choice).  In a recent paper studying the effects of neutering on hormones and obesity, two very important findings were uncovered:  1) after neutering a rapid increase in IGF-1 and prolactin occurs that is closely followed by an increase in body weight, and 2) dysregulation of glucose metabolism (in association with increases in leptin levels that are significant enough to cause insulin resistance).  Thus, to prevent the deleterious effects of these hormonal changes, prevention of obesity by reducing food intake and careful monitoring of body weight becomes essential.  Further, because “it is much harder to take it off, than it is to put it on” – it is important to control weight and diet from the onset (in kittens).  Another factor that is increasingly being considered, both in the development of and treatment of obesity, is the role of excess calories (especially carbs and fat) in the feline diet.  Because of their metabolic requirement to utilize protein as an energy source, CHO and fat in the diet that are not immediately used for energy (e.g. via exercise or other utilization for energy in addition to the protein they utilize for energy) will be stored as fat.  Successful weight loss requires loss of adipose tissue as well as maintenance of lean body mass, as lean body mass is the driver of basal energy metabolism (loss of lean body mass is a major contributor to weight regain as appetite is not reduced and satiety not reached).   Several recent studies have evaluated use of a high protein, low CHO diet (protein 45% or higher) for weight loss in cats, and in those studies, all cats lost weight, but maintained lean body mass.  Importantly, high protein, low carbohydrate diets not only result in sustained weight loss in these cats, but also in normalization of appetite (reduced urge to eat constantly because they are satiated).  Finally, protein is an important insulin secretagogue in cats, while reducing carbs in the diet reduces the post prandial hyperglycemia and thus, the insulin demand.                                                             

Glucose toxicity and transient diabetes

Approximately 20% (this number may be higher if the condition is recognized earlier) of cats develop “transient diabetes” – whereby within 4-6 weeks of diagnosis and initiation of insulin therapy, the clinical signs resolve, hyperglycemia and glycosuria resolves, and the insulin treatment can be discontinued.  If is suspected that these cats have subclinical diabetes (abnormal islets due to amylin deposition –see above), but the condition is uncovered when they undergo stress, receive anti-insulin drugs (e.g. prednisone or megesterol), or develop pancreatitis. 

Persistently elevated blood glucose levels also lead to development of a condition called “glucose toxicity” which is a phenomenon affecting the glucose sensing receptors on the pancreatic beta cells – the end result is a down regulation of these receptors –  whereby the beta cells simply stop responding to the glucose and stop producing insulin.  The end result is development of clinical diabetes; however, if the cause for the persistent hyperglycemia can be reversed (removal of steroids, correction of obesity, treatment of hormonal disorders, etc), and the beta cells are not permanently damaged (e.g. by amyloid deposition), the cat will regain normal insulin secretion and resolution of the diabetic state.

Sequence of events in subclinical/transient diabetes

Cat has subclinical diabetes/concurrent pancreatic pathology

↓

Insulin antagonism develops

(drugs, infection, neoplasia, pancreatitis, hormonal disorder, obesity)

↓

Carbohydrate intolerance and mild hyperglycemia develop

↓

Glucose Toxicity results in receptor down regulation and IDDM develops (months or years later)

↓

Insulin and diet therapy is instituted

Control (or correction) of initiating factors is achieved

↓

Hyperglycemia resolves

↓

Glucose Toxicity resolved

↓

Beta cells regain function

Insulin resistance is resolves

IDDM resolves

↓

Cat returns to subclinical diabetic state

The role of amylin

Amylin (or islet-amyloid polypeptide (IAPP) is the principal constituent of amyloid deposited in the pancreas of cats with diabetes.  Amylin is co-secreted with insulin by beta cells, thus insulin secretion also results in the secretion of amylin.  The role of this neuroendocrine peptide is believed to be as a glucoregulatory hormone counteracting the effects of insulin in the post-prandial state.  However, chronic increased secretion of amylin (and insulin), as a result of obesity or other insulin resistance states (e.g. glucocorticoids, acromegaly, infection, etc), results in deposition of amylin in the islet cells as amyloid.  Amyloid is toxic to beta cells, resulting in cell death, and thus decreased insulin secretion.  If the deposition of amyloid is progressive (e.g. persistent obesity), islet cell destruction progresses and eventually leads to diabetes.  It is the severity of this destruction (islet amyloid deposition) that determines (at least in part) whether the cat is insulin dependent or not.  Progressive amyloid deposition leads from subclinical or transient diabetes to non-insulin dependent diabetes and finally to insulin dependent diabetes as the islet pathology progresses.  

Treatment of the feline diabetic:  a few key points

The goals of management of diabetes in cats

• Revert a transient diabetic cat to a sub-clinical diabetic if possible

• Elimination of owner observed signs (PU/PD/PP)

• Improved quality of life and normalization of body weight and activity

• Prevention of diabetic complications (hypoglycemia, weakness, chronic infections, neuropathy)

These goals may be accomplished in some cats with diet and drugs alone, others require dietary therapy and short term insulin, other cats require life-long insulin and dietary therapy.  There is no “norm” for management of diabetic cats: each is an individual requiring individual attention and adjustments based on their response.  However, in management of most diabetic cats, insulin along with dietary therapy is the standard approach.  Insulin is important in diabetic therapy of cats, even those with transient diabetes, because it is the most effective tool to control hyperglycemia (which is essential to reversing glucose toxicity and for prevention of further amyloid deposition) – further, since it is impossible (at this point anyway) to determine whether a cat has residual beta cell function (and thus is a transient diabetic) – the most important goal is to reduce hyperglycemia and insulin resistance (reverse obesity, stop steroids).   Finally, while periodic blood glucose testing to assess the effectiveness of our therapy is ideal, many cats do not tolerate this (stress hyperglycemia also affects glucose curves!) our methods of monitoring our treatment in cats often has to be modified to balance the needs of the patient.  

Insulin therapy

Insulin therapy should be tailored to the cat as much as possible within the capabilities of the owner to provide care for their pet.  Because of the recent discontinuation of many insulins, there are fewer choices for therapy. 

• Lantus® (glargine) is a unique human insulin analogue marketed as a “peakless insulin” – meaning that it serves as a low level or baseline insulin for humans.  In cats, this insulin is not peakless, but it is a long acting, slow onset, minimal curve, insulin in cats that is proving to be highly effective for management of newly diagnosed diabetic cats.  

• Detemir (Levemir®) is a third generation analogue that is also very long acting, but appears to have a more predictable response curve than glargine, so may be a good choice in cats where glargine is not providing predictable results.  

• PZI (protamine zinc insulin, ProZinc) is available from Boehinger Mannheim.  This is a U-40 insulin that is approved for cats and is a reasonable choice due to its longer duration and generally predictable response in cats.  However, this insulin in comparison studies with the longer acting insulins requires glucose curves and is more likely to be associated with insulin induced hypoglycemia.

• Lantus, Detemir, and PZI are the insulins of choice for cats

• Most cats, at least initially –even with Lantus – require twice daily dosing of insulin to gain control of the hyperglycemia. Lantus, Detemir and PZI may be effectively used once daily in some cats.  

• Humulin® N or Novolin N (Novo Nordisk® ) are the only remaining human recombinant intermediate acting insulins available.  These are U-100 insulins and when used in cats should be used with a 1/3 cc U-100 syringe for accurate dosing.  In cats, these insulins typically have a 8-10 hour duration of action so must be given every 8-12 hours to provide adequate control.  These insulins require a glucose curve for accurate dosing and are more likely to be associated with insulin associated hypoglycemia.

The human insulin analogue, glargine, has been used in the treatment of newly diagnosed diabetic cats for several years now with impressive results.  This insulin is not peak-less in cats, as it is reported to be in humans, for which it was formulated as a “background” insulin to provide a low level, but continuous insulin source throughout the day.  Because this insulin has lower pH, it is slowly released from the sub-Q site where it is injected.  This different mechanism of action results in considerable variability in the onset, duration, and degree of action, but studies repeatedly show that is an effective insulin in cats and is the most effective insulin for achieving diabetic remission compared to other insulins studied.  Glargine should be given at a low dose (0.25U/kg 1 U/cat based on lean body weight), once or twice daily for 3-5 days (it takes several days before the effect will be seen).  The insulin dose should be based on LEAN body weight, so for most cats that means giving 1U/cat.   After 3 and 7 days, a blood glucose  check (or spot check every 3-4 hrs) is performed to determine whether the dose needs to be increased in that cat.  Typically, once the cat has been on this insulin for 7-10 days, the curve will flatten out due to its long duration and slower absorption (overlap occurs with the injections), and in some cats the dose can be adjusted (higher or lower) depending on the blood glucose levels.  At this point, the cat may only need insulin once daily or if transient diabetes is present, may not need insulin at all.  In one study, 3 of 5 cats no longer needed insulin after the first 2-3 weeks of therapy.  Careful monitoring of the cat in the first 2-4 months is necessary to prevent hypoglycemia due to the potential for clinical remission to occur.  Once the cat stabilizes on the insulin, monitoring urine glucose or water intake (reduction of intake to less than 60 ml/kg/day) along with clinical signs as assessment of an appropriate response, rather than a glucose curve, may be possible in many cats. 

Key Point:  Insulin Dosing in cats should be conservative (0.25 SC once or twice daily – (e.g. 1 U/ cat) to prevent hypoglycemia during the initial stages of therapy.  Most cats should not receive greater than 0.8 U/kg and if the dose required goes above this range, reassessment of the situation for causes of insulin resistance, including the somogyi effect are highly recommended.

Monitoring insulin regulation: cats often require creativity!

Ideally, the goal is to maintain blood glucose levels in cats between 100 – 250 mg/dl throughout the day, so that the beta cells have the greatest change of recovery of function.  However, what is more important is the owner's perception of the pet's health, the physical exam findings (including body weight), and absence of common diabetic complications (neuropathies, infections, PU/PD).  Blood glucose curves remain the best way of evaluating the insulin effectiveness – but, because of the problem of stress hyperglycemia and the tendency for some cats to lose their “happy demeanor” in the hospital, this method of monitoring the diabetic is sometimes not possible or even counterproductive.  The key is cautious interpretation of any curve that is done in the clinic (don't micromanage!) – or approach monitoring without the use of a “classic” curve at all.  The best approach for all cats is to teach the owners how to monitor blood glucose at home using a meter and lancet.  This way the owners can collect information when the cat is at home in a calm environment and the blood glucose numbers will be a more accurate reflection of what is really happening.  In my experience, any owner that can learn how to give insulin injections can easily learn how to do home glucose monitoring.  There are a number of different glucose meters available (veterinary meter is Abbott's Alpha Traq, but human meters such as the Contour, OneTouch and Accucheck – are all excellent) – and can be used according to the owners preference.  Remember, if they use human meters, the supplies can be obtained more easily for them at any pharmacy. 

Monitoring parameters

The best parameters for assessing the cat's control and quality of life are:  1) owner's subjective evaluation of improvement in signs (PU/PD, appetite) and log data, 2) weight changes (e.g. weight loss in an obese cat, weight gain in a thin cat), and 3) general appearance (hair coat, muscle mass and neuromuscular function – ability to jump, climb stairs, etc).  Measurement of urine glucose and ketones is often possible for many owners at home, and can help identify unregulated diabetics (ketonuria or persistently high urine glucose) or cats that have transient diabetes and are becoming normoglycemic (persistently negative urine glucose for more than 48 hr). Finally, for dedicated owners and are willing and able to monitor blood glucose at home, the best approach to achieve good glucose control and reversion to a pre-diabetic state is home monitoring of blood glucose.  See Table 4. 

Serial blood glucose curve generated at home

• Use marginal ear prick or pad prick technique.  There are several video examples on YouTube that can be used to show owners how to do this and we have our technicians spend time with owners showing these techniques. 

• Drop of blood collected onto glucometer strip

• Typically measure BG every 4-6 hours over day (4 times) for a complete analysis – more often if using PZI – but can measure just before insulin injection (early morning or evening) and just before bedtime (mid-point) to check for very high or very low blood sugar levels. 

• No need for restraint (a major cause of stress hyperglycemia)

• Must emphasize need for keeping a log and to seek veterinary advice in altering insulin levels and not encourage owners to make adjustments themselves. 

It is best to make changes in insulin in small increments (0.5-1 U at a time), then allow a period of adjustment before re-measuring blood glucose curves.

In cats for which home monitoring is not feasible, and for which serial blood glucose curves in the hospital are unreliable (due to stress effects), serum fructosamine (SFr) concentrations can still be used to provide a degree of information about the cat's clinical status.  Fructosamines are glycated proteins found in blood of diabetic cats.  This glycosylation is an irreversible change, it is non-insulin dependent, and results in glucose being bound to proteins that can be measured in serum.  These proteins have a circulating half-life of approximately 1-3 weeks (depending on the protein), and this is why they can be used as a measure of glycemic control.

• In cats that experience stress hyperglycemia or are unmanageable for BG curves, this test offers a method of assessing relative glucose control. 

• What this test cannot do is:  1) assess insulin effect (is it working?), 2) assess the glucose nadir (how low does the BG go?), or 3) what is the duration of insulin effect (would another insulin be better?) – only a glucose curve can do those things. 

• SFr should be normal in a cat with stress hyperglycemia, so it is a useful test to rule out this phenomenon in diagnosis of feline diabetes.

• Normal SFr = 190-365 umol/L

• Good to Excellent control, SFr = 350-450 umol/L

• Poor control, SFr  > 500 umol/L

Adverse effects of insulin therapy in cats

Hypoglycemia is a very important potential problem in diabetic cats because of the potential for their diabetes to be transient and reversible.  For this reason, it is vital that cat owners understand hypoglycemia, what it looks like (cats have more subtle signs), and what to do if it occurs.  The most overt signs of hypoglycemia are neurologic because of the obligate need for glucose in the CNS:  weakness, lethargy, and stumbling are early signs, later the signs develop into seizures, collapse or coma.   However, because many cats tend to sleep/nap a lot during the day – assessment of lethargy or weakness may be difficult.  Further, many cats do not show overt signs of hypoglycemia until the onset of seizure activity – thus, prevent of hypoglycemia is critical. 

• Hypoglycemia may be averted in some cats if food is available several times in the day (it should not be free choice) or if a mid-day snack is made available (timer food bowls work well for this purpose).  A mid-day (and mid-night) meal is especially important in recently diagnosed diabetic cats - if no one is at home most of the day – as the most likely time of reversion to normoglycemia after starting insulin therapy is in the first 2-4 months of therapy.  However, if the diabetic is obese, calorie and portion control will still be essential to allow the needed weight loss required to control the cause of the insulin resistance. 

Dietary management of diabetes in cats

For all diabetics, the goals of therapy include restoration of normal fasting blood glucose concentrations, normalization of body weight (loss or gain), and reversal or attenuation of chronic complications of diabetes (UTI, neuropathy, etc).  In cats, a combination of dietary therapy and insulin supplementation is necessary to control the disease and reverse the clinical progression.  For many years, veterinarians applied similar dietary approaches for management of diabetic cats and dogs.  However, in recent years, an approach to feeding cats based on their strictly carnivorous nature (and physiologic adaptations), has become the standard of therapy, and has had excellent results.   The reason for this is that most cats (including normal cats) fed typical feline diets (e.g. dry, CHO based foods) have mild, but prolonged (18-24 hr) post-prandial hyperglycemia.  High protein, low carbohydrate diets provide protein (which the cat needs for energy, insulin stimulation, and maintenance of lean body mass), and have very low levels of CHO (to reduce postprandial hyperglycemia, reduce excess energy from CHO and improves glucose tolerance). 

Diets with increased amounts of insoluble fiber that have been traditionally recommended for diabetic cats may reduce the glycemic load (by reducing absorption of glucose in the intestine) just as they do in dogs, but may not be as effective in inducing weight loss (without loss of lean body mass). Further, these high fiber diets are CHO based, and recent studies have shown that better glycemia control is achieved with low CHO diets.  In cats with transient or non-insulin dependent diabetes, feeding the high protein/low CHO diet along with addition of an oral hypoglycemic agent may be sufficient for management of the disease.  However, most cats require some insulin – even if it is just for a short time – and in this setting, high protein/low CHO diets provide a more appropriate nutrient profile, often result in reduced insulin requirements by 1/2 or more, and will normalize body condition (obese cats tend to lose weight, lean cats tend to normalize their weight).  A final note on feeding diabetic cats most feline diabetics respond better to feeding small meals frequently (ad libitum is only acceptable if they are not obese) as it reduces the risk of hypoglycemia and is more likely to result in more consistent blood glucose levels throughout the day.  For cats that are obese and diabetic, a high protein, low CHO and low fat (thus, lower calories overall) diet will likely be required to achieve weight loss.  The dry diabetic diets are very calorie dense, and thus feeding canned high protein foods (the calories are replaced with water) or low fat, high protein dry foods will be the best alternative. 

References

Feldman and Nelson's Canine and Feline Endocrinology and Reproduction 3rd ed.  2004.

Cowan SM, Bunch SE: Oral antidiabetic drugs for cats.  Comp Cont Ed Pract Vet 23(7): 633, 2001.

Rand J.  Understanding feline diabetes and its management. ACVIM 24: 2005.

Reusch CE, et al.  Home monitoring of blood glucose concentration in the management of diabetes mellitus.  Comp Cont Ed  23 (6): 544, 2001.