David B. Church, BVSc, PhD, MACVSc, MRCVs, ILTM
Diabetes mellitus in the dog and cat is not a single disease but a manifestation of various pathophysiological processes. Diabetes mellitus is perhaps best defined as clinically significant glucose intolerance caused by an absolute or relative lack of insulin. In any individual patient, the degree of insulin deficiency can fluctuate over time. These changes may be influenced by many factors. For example any animal with pancreatitis may develop clinically significant impaired insulin secretion. This is generally reversible and resolves as the inflammation subsides. Perhaps more obscurely, any condition resulting in chronic insulin resistance results in hyperinsulinism that may lead to so called 'islet exhaustion' in susceptible individuals. This may be variably reversible depending on the length of time the islets have been exposed to this increased secretory demand and the presence of inherent individual susceptibility to the damaging effects of chronic insulin 'hypersecretion'.
Management of Uncomplicated Diabetes Mellitus
Clearly whenever underlying explanations for insulin resistance can be identified it is important to correct these whenever practicable, as this may well result in resolution of clinical signs and indeed result in the patient no longer requiring insulin or oral hypoglycaemic therapy. For instance in cats, if megestrol acetate is suspected to be the cause of the diabetes, withdrawal of this medication may be sufficient to ameliorate glucose intolerance and clinical signs of diabetes. Additionally, some obese diabetics may initially require insulin injections but requirement may diminish or cease when their body weight normalises.
However, especially in dogs, in many cases the clinically significant glucose intolerance will not resolve with the reduction in insulin resistance-inducing factors and the clinician will have to consider alternative management strategies such as oral hypoglycemics or insulin. It is because of the phenomenon of 'islet exhaustion' that insulin therapy should be considered as a front-line treatment option in most patients with clinically significant glucose intolerance or diabetes mellitus.
In other words, the majority of diabetic cats and dogs will require insulin injections. Very occasionally oral hypoglycaemic agents may be effective for non-insulin dependent dogs and somewhat more frequently may be effective in diabetic cats. However as a possible consequence of using oral hypoglycaemic agents might be accelerated islet cell exhaustion, the use of oral hypoglycaemic agents remains a controversial method of managing both feline and canine diabetes.
Oral Hypoglycaemic Agents
In those diabetic patients with normal or elevated plasma insulin levels, some benefit may be obtained from oral hypoglycaemic therapy. A number of these so-called 'oral hypoglycemics' improve glucose tolerance by increasing the rate and amount of insulin released, as well as increasing peripheral insulin sensitivity.
Although, traditionally, oral hypoglycaemic agents were most likely to be effective in diabetic animals with some insulin secreting capacity, the possibility of glucose toxicity means they may be effective in cases which do not have significant insulin levels at presentation.
Among the variety of different compounds commercially available, glipizide or glibenclamide are probably the 'drugs of choice'. In the cat the dose is generally 5 mg two to three times daily while in the dog 0.2-0.5 mg/kg twice daily is likely to be effective.
If these drugs are going to improve glucose intolerance, they generally have significantly lowered fasting hyperglycaemia within 10-14 days.
Once the animal's insulin reserve has diminished significantly however, generally some form of exogenous insulin supplementation is required to minimise clinical signs and prevent complications developing. It is also worth remembering that generally these oral hypoglycemics increase the insulin response to a set insulinogenic stimulus. Consequently, they may accelerate the 'islet exhaustion process' and bring about an absolute insulin requirement earlier.
Insulins--What are the Differences?
There is a confusing variety of insulin preparations available that differ in their rate of absorption and duration of effect. For any insulin we use we should be comfortable we know the species of origin and the insulin's physico-chemical characteristics, as both may affect the performance in the patient.
Which Insulin is Best?
Insulins such as NPH (e.g., Isotard, Protaphane), protamine zinc and Lente insulins have been the mainstay of insulin therapy of cats and dogs for some time. Currently in the UK the only insulins registered for use in dogs and cats are Lente insulin of porcine origin, 40 IU/ml (Caninsulin®), Lente insulin of bovine origin (Insuvet Lente®) or protamine zinc insulin of bovine origin (Insuvet PZI®).
In the author's opinion protamine zinc insulin (PZI) should be considered as a reasonable first-choice for cats as it is of bovine origin and perhaps lasts a little longer than Lente insulin. An alternative form that has been recommended for these animals is Ultralente insulin although in the author's experience this insulin's performance has generally been unsatisfactory. Recently a synthetic insulin analogue, insulin glargine, has been recommended as a suitable alternative to PZI for use as a twice daily exogenous insulin in cats; generally this can be a helpful adjunct in insulin therapy for those cats that are keen to 'graze' and hence suited to the glargine's 'peakless' activity profile.
Duration of Action
Lente insulins, PZI insulins and glargine insulin generally need to be given twice daily in the vast majority of patients and certainly in almost all cats.
However, the most important point to appreciate about insulin therapy in small animals is that the time of onset, time of peak effect and duration of action will vary from animal to animal and indeed from day to day.
While recommendations can be made on the average time of peak effect and duration of action, there will be a group of patients who will not respond like the majority of animals.
Time of Peak Effect
Lente insulins (e.g., Caninsulin®) will usually have their peak effect 1-4 hours after administration and will last for approximately 12-14 hours. Protamine zinc insulin and insulin glargine also generally last for around 12-14 hours but have a less pronounced period of peak effect. It is worth remembering as a general rule most insulin preparations have a shorter duration of action in the cat.
Although it is claimed that Caninsulin® is a once daily insulin, only approximately 10% of dogs are well stabilised on once daily Caninsulin® therapy, and the majority of dogs and almost every cat require twice daily injections for there to be any chance of achieving adequate control.
These guidelines hold true for most canine and feline diabetic patients but the clinician should always consider the possibility that the insulin has a different rate of onset and duration of action if the patient proves difficult to stabilise.
Site of Injection
A frequently neglected area of diabetic therapy is the injection site. Areas that are subject to variations in movement and stretching should be avoided.
Remember the overall aim of insulin therapy is to administer the insulin so that its time of peak activity corresponds to the peak demand i.e., when the blood glucose is rising after feeding. The aim is to lower blood glucose concentration over the 24 hour period and to minimize fluctuations.
Main Reason for Problems
Many diabetic dogs and cats are usually relatively easily controlled if they really require insulin. The main problem areas that occur are:
Treating cats that have 'reversible' (at least in the short term) diabetes where the continued administration of insulin results in clinically significant hypoglycaemia.
Failure of the clinician to recognise underlying concurrent disease which will impair the animal's normal response to insulin administration. This is particularly true in cats where a subset of diabetic cats have clinically significant insulin resistance. While the explanations for this insulin resistance can be numerous, recent studies have suggested that hypersomatotropism (or acromegaly), at least in the UK is a far more common explanation for this disorder than has been previously reported. Consequently it is well worth checking any insulin resistant cat or diabetic cat with variable insulin requirements for the presence of acromegaly.
What if Twice Daily Dosing is Impossible?
If it is only possible to administer insulin once daily, use a protamine zinc preparation or insulin glargine preparation, and ensure use of a low carbohydrate diet that should be given either in small quantities frequently or only given ad libitum if the cat will 'graze' throughout the day. These efforts are all aimed at slowing any tendency for significant post-prandial hyperglycemia.
Be Aware of 'Sudden' Stabilisation
As the endogenous insulin resistance starts to diminish, diabetics often seem to suddenly stabilise i.e., blood glucose continues to be high with increasing dose then one more unit results in normal blood glucose concentration. Also remember that once the islets have been 'unloaded' there may be a return of insulin secreting capacity which can result in the animal no longer requiring insulin for some time--the so-called 'honeymoon' phase. Both these phenomenon can be responsible for hypoglycaemic episodes.
Feeding and Exercising the Diabetic Patient (Dog or Cat)
The diet must be consistent--the animal should consume the same caloric intake morning and night and from day to day. The food should be controlled and consistent:
Commercial canned preparations with variable amounts of dry food are a convenient food type for diabetics as their caloric content is relatively predictable and consistent. However they may not be attractive to all patients, particularly if they have not been a traditional part of the animal's diet.
When using relatively short duration insulins it is vital that all the offered food is consumed within a short space of time. In other words, caloric content and palatability are equally important. As a result, some diabetic dogs and cats need to be stabilised on standardised portions of their usual diets.
Whatever the form of the calories fed to the diabetic patient, the timing and the caloric content must remain consistent. Any changes in the dog's diet can only be made if the overall caloric content remains unchanged.
No snacks should be provided unless they have virtually no calories.
Feed 50-70 kcals/kg.
If the is animal underweight, increase intake. If it is overweight, decrease caloric intake.
Fibre: Good or Bad?
Additional supplementation with high fibre vegetables such as celery, turnips and cabbage or the judicial addition of soluble fibre supplements to the diet may aid diabetic control. While there is some evidence to suggest that diets high in insoluble fibre may decrease the rate of postprandial glucose elevation and daily insulin requirements, the evidence to suggest adding fibre to a diabetic's diet is likely to significantly improve poor diabetic control is lacking.
Low Carbohydrate, High Protein Diet--Good or Bad ?
Over the last few years numerous clinical trials have demonstrated improved diabetic control and reduced insulin requirements in diabetic cats fed a low carbohydrate-high protein diet. In a number of these studies the 'control' group were fed a high fibre (and hence high carbohydrate) diet of differing starch sources (which may have an impact on the glycaemic index). Certainly in the cat the results of all the studies strongly suggest feeding cats commercial diets more closely resembling the composition of their natural carnivorous diet will increase diabetic remission rates, especially in those cats with marked insulin resistance through obesity. It is certainly a more theoretically sound principle than attempting to increase the amount of fibre they are being fed. What is also likely to be particularly important is to ensure that the diet is not high in fat as there is substantial evidence to suggest a high fat diet may contribute to impaired insulin secretion and efficacy.
Generally exercise has the capacity to lower insulin requirements hence exercise should be consistent and encouraged. As diabetics are usually older animals that have been obese due to overfeeding and lack of exercise, over-exercise is not usually a problem.