Identifying the reasons behind difficult-to-control diabetes in dogs - Veterinary Medicine
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Identifying the reasons behind difficult-to-control diabetes in dogs
In this second article of a two-part series, an internist reviews the insulin-related, client-related, and patient-related problems that can make a diabetes management regimen ineffective. Here is a step-by-step approach to identifying and addressing problems that underlie cases of poor diabetic regulation in dogs.


Patient-related problems

When insulin- and client-related problems have been ruled out, a careful hunt for problems with the patient becomes necessary. Patient-related problems are often the most challenging to identify, and a logical approach is essential. In general, patient-related issues reflect changes in energy use or intake or problems with insulin absorption, kinetics, or resistance. The clinical manifestations of these problems are variable; some dogs experience unpredictable fluctuations in their blood glucose concentrations (i.e. poor regulation), while others require excessive amounts of insulin (i.e. insulin resistance).

Although several monitoring methods may be considered in clinically stable diabetic dogs, the key to identifying and resolving patient-related problems is frequent blood glucose measurements. The best way to collect an accurate picture of the patient's glycemic control is with serial blood glucose measurements, often referred to as a glucose curve. Glucose curves may show some day-to-day variation, so it is important to correlate clinical signs with blood glucose measurements.1 With some patients, it may be worthwhile to start an at-home monitoring program so sufficient representative data can be collected quickly. After proper instruction, most clients can measure their dogs' blood glucose concentrations at home. This is more cost effective for the client and often much easier on the dog. A measurement should be obtained every two hours throughout the day, starting before insulin is administered and food is offered. It is not adequate to simply perform a few spot checks over the course of a day. The reliability of the handheld glucometers appears to be quite variable, and a veterinary-validated system is probably the best option. In a recent study comparing several different devices, the AlphaTRAK (Abbott Animal Health) had the lowest percentage of misclassified results at 2.1%, compared with 4.2% to 38.7% for the other systems evaluated.2 An alternative option is a continuous blood glucose monitor.3 Several different models are on the market, but the Guardian REAL-Time Continuous Glucose Monitoring System (Medtronic) has been evaluated most frequently in veterinary species. In general, these systems consist of a small probe that sits in the interstitial space for a few days and transmits the blood glucose reading to a small receiver. The receiver has to stay fairly close to the patient but is easily attached to a harness or collar. Daily calibration is necessary, but these systems can be helpful in poorly regulated patients.

Table 2
Poor regulation. Poorly regulated patients require frequent adjustments to their insulin dose or experience episodes of unexplained hypoglycemia (Table 2). Some poorly regulated patients respond bizarrely to insulin, with dramatic fluctuations in blood glucose concentrations throughout the day, or have "upside-down" curves, in which the blood glucose concentration rises after insulin administration. In other cases, the clinic data do not correlate well with the data obtained at home, making dose adjustment decisions increasingly difficult.

In general, poor regulation reflects problems with energy use or intake or the biological behavior of the insulin itself. As energy issues are easily identified and addressed, it is helpful to start with this possibility before moving forward.

In most cases, carefully questioning the client will highlight issues with energy utilization. Any sporadic exertion can substantially affect calorie utilization and may result in profound hypoglycemia. It's important to ask about recent changes in routine, such as a visit from grandchildren or a trip to the groomer. We may not think of it as exercise, but a day spent circling in a cage at the doggy spa has the same physiologic effects as a run in the park.

Changes in energy intake may be more difficult to identify. Some clients hesitate to admit breaking the dietary rules or feel that the occasional snack or shared sandwich will not cause problems. It is important to explain that a couple of cookies or a piece of buttered toast can provide 20% of the daily caloric needs for a small patient and can certainly impact diabetic regulation. Make sure every member of the household is onboard with the feeding plan and understands the importance of a consistent diet. The dog should be fed on a regular schedule, accompanied by daily moderate exercise.

When energy issues have been ruled out, problems with how the patient interacts with the insulin should be considered next. Problems with erratic insulin absorption are relatively uncommon. However, some animals develop thickened skin and irritation of the subcutaneous tissues if the insulin is always administered at the same site. This is a consideration in dogs with a variable or delayed onset of insulin action, often manifested by the inverted glucose curve. With these patients, serial blood glucose concentrations are markedly different if a new injection site is used. Simply teaching the owner to rotate through six or eight sites on the flanks and dorsum usually solves this problem.

Insulin kinetics problems include an unexpectedly short or long duration of effect. These patients respond to the insulin, with an appropriate decrease in their blood glucose concentration, but the duration of control is unsatisfactory. These problems are often most easily identified with 24-hour serial blood glucose measurements or with a continuous blood glucose monitor.

Table 3
Although most dogs receiving Lente or NPH insulin products require twice-daily dosing, some dogs experience a longer duration of effect and are prone to hypoglycemia with twice-daily administration (Table 3).4,5 These dogs may need once-daily dosing with a combination of insulin products to achieve acceptable control. An engineered long-acting product such as insulin detemir or glargine may be a useful option for these patients. Both insulins are designed for background glycemic control in people. In this scenario, the human patient simply administers a dose of regular insulin with each meal and relies on the background product for sustained glycemic control. These insulins have a slow onset but prolonged action and can be effectively incorporated into canine protocols, often on a once-daily basis.6 It is important to remember that these insulins are pH-balanced and cannot be mixed in the same syringe with other insulins.

Table 4
Conversely, both Lente and NPH may only last six to eight hours in some dogs, and three-times-daily dosing or the addition of a longer-acting insulin may be necessary. Again, insulin detemir or glargine can be useful in these cases. An example of a dog requiring two insulin types is provided in Table 4. Consultation with a specialist about starting doses may be helpful before beginning the use of an unfamiliar insulin.

Historically, anti-insulin antibodies have been implicated in problems with diabetic regulation. It has been suggested that antibodies may cause trapping of insulin at the injection site with subsequent erratic release from the subcutaneous tissues or overt insulin resistance (see below).7 However, the clinical impact of anti-insulin antibodies in dogs is still unclear. Recent studies have indicated that most dogs receiving heterologous exogenous insulins produce anti-insulin antibodies, although this was not associated with poor diabetic control.8,9 The only licensed insulin product for dogs in the United States is of porcine origin; porcine-origin insulin is identical to canine insulin and is not expected to trigger anti-insulin antibody production. Human insulin is highly analogous to the canine molecule and is also likely to be well-tolerated. Beef-origin insulin is much more likely to trigger antibodies in dogs. At the present time, the only beef insulin available in the United States is a PZI formulation. It is inherently a poor choice for dogs because of its biologic behavior, and it should probably be avoided for this reason alone. Patients with clinically important anti-insulin antibodies would be expected to respond appropriately to intravenous regular insulin or a switch to a homologous product.

Some drugs (e.g. beta blockers) and other diseases (e.g. hypoadrenocorticism, insulin-secreting tumors) can result in unexpected hypoglycemic episodes in diabetic dogs.10-12 A careful check of concurrent medications and a full general health evaluation are necessary to identify these uncommon causes of poor diabetic regulation.


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