Persistent hyperglycemia is a frustrating and all too common problem in diabetic dogs and cats treated with insulin. Numerous factors might contribute to poor glucose regulation in treated diabetics. Some of these factors are related to management, such as improper insulin administration, while others have a physiological basis, such as biologic variability of insulin action. In this session, possible causes for persistent hyperglycemia in dogs and cats receiving diabetes treatment will be reviewed, along with suggested diagnostic and therapeutic approaches to achieve resolution.
For the purposes of this discussion, persistent hyperglycemia should not be considered synonymous with insulin resistance, although the latter is one cause of persistent hyperglycemia in diabetics. Rather, persistent hyperglycemia (PH) as used here refers to a condition of chronically elevated serum glucose in a treated diabetic dog or cat, regardless of the cause.
Identifying the Patient with PH
Diabetic dogs and cats with PH are typically classified as a poorly-regulated diabetics when examined by a veterinarian. Owners may report that clinical signs of diabetes persist in these pets and that the recommended at-home treatment is not working as well as expected. Physical examination may reveal findings compatible with metabolic disease and diabetes, such as hepatomegaly, cataracts, and poor body condition. Poor glycemic control is reflected in the laboratory evaluation as elevated fructosamine levels and abnormal glucose curves.
Once a diabetic patient is identified as having PH, careful reviews of the history, physical examination, and current therapeutic protocol may reveal possible causes or suggest a possible diagnostic work-up. A sequential approach to evaluating PH patients is warranted but in the author's experience, problems related to diabetes management are the most frequent causes of PH in dogs and cats. For this reason, it is important to completely rule out problems with the management protocol before beginning an extensive investigation to search for additional medical problems.
Troubleshooting the Diabetes Treatment Protocol
Review the Patient History
It is important to determine whether some factor(s) related to the pet's home environment or daily habits may be responsible for poor diabetes control. In humans, glycemic control can be upset by stress or emotional strain as well as seemingly innocuous departures from the patient's ordinary routine, such as unusual exposure to sunlight or increased physical activity. Presumably, similar factors could affect diabetic control in dogs and cats, so careful questioning of the pet's owner is warranted. Hunting or service dogs, for example, might experience increased insulin needs when working. Similarly, it is conceivable that a cat with a preference for a particular window sill might absorb insulin more rapidly on especially sunny days. In addition to routine questions about appetite, water consumption, urinary and defecation habits, and general attitude, the owner should be questioned about the diet, administration of non-prescribed medications or supplements, changes in the home environment or any unusual events. Owners often do not realize the importance of these factors and will not offer the information unless specifically asked.
Non-prescribed dietary changes, feeding excessive amounts of treats or table scraps, and some dietary supplements all have the potential to alter the patient's daily carbohydrate intake. Some herbal medications have been associated with glycemic dysregulation in humans and might have the same effects in animals. Self-prescribed medications or medications provided by another veterinarian, especially topical preparations, may not be seen as problematic by owners. However, topical ocular or otic medications containing steroids may produce systemic effects in some dogs and cats and antagonize diabetes regulation. Changes in the home environment or daily routine might also disrupt glucose control. Some events are clearly stressors on the patient, such as new pets or people in the household, a recent move to a new home, recent illness or surgery, but others are less obvious. One diabetic cat treated by the author developed PH after a newly installed glass door allowed it to encounter neighborhood cats on the other side of the glass. While it is important to consider any change in the patient's environment as potentially contributing to PH, it is equally important to resist placing too much emphasis on relatively minor changes unless all other causes of PH have been thoroughly investigated and ruled out.
Review the Diabetes Treatment Protocol
Review of the treatment protocol entails evaluation of all aspects of therapy including the insulin protocol, diet therapy, and management of any concurrent illness. When evaluating the insulin protocol, it is important to establish that the animal is receiving insulin at the prescribed dose and that the injection is performed properly. The first step is to confirm that the insulin and syringes being used are the prescribed products. Mismatch between the insulin product and the syringe used to administer it (e.g., using U-100 syringes to administer U-40 insulin) is a relatively common error that can lead to profound problems with diabetes regulation. Use of non-prescribed, degraded or outdated insulin are other potential causes for poor glycemic control that are easily remedied. Once insulin type and syringes are ruled out as possible sources of errors, the owner's insulin handling and injection techniques should be evaluated.. Many veterinarians accomplish this by observing the owner draw up and inject the insulin dose during an office visit. This can eliminate gross errors in insulin dosage, improper injection site selection (e.g., into adipose tissue), poor patient restraint and related errors, as possible causes of the problem.
Review the Glucose Curve
At this point, if a cause for PH has not been uncovered, a metabolic basis for PH should be considered. Investigation of metabolic causes of PH begins with documentation of the magnitude and duration of hyperglycemia over the course of the day. The glucose curve is the simplest way to document whether a dog or cat truly has PH throughout the day. The traditional serial glucose curve is useful for monitoring blood glucose concentrations over time but recent studies have highlighted the low reproducibility of this technique, even when performed under ideal conditions. As the technique can yield vastly different results even when performed only 12-hrs apart under the exact same conditions, care must be taken not to place too much weight on a single glucose curve result. Glucose curves are usually performed in the hospital. However, techniques for teaching owners to generate at-home glucose curves in dogs and cats have also been described. Blood samples should be obtained q 1-2 hr so that rapid changes in glucose will not go undetected. A portable glucometer is suitable for measuring blood glucose in most circumstances. The glucometer used should provide accurate and reliable results; several models have been shown to perform well in dogs and cats. Continuous blood glucose monitoring (CBGM) is another technique that has recently been used with success in dogs and cats. CBGM uses a subcutaneous sensor and a portable receiver to measure and record interstitial glucose concentration in real time (every 5 minutes) over the course of the day. A number of recent studies have shown the CBGM technique to be reliable in cats and dogs. Either the traditional or CBGM glucose curve techniques can be useful for establishing the diagnosis of PH and both provide useful information about the magnitude and pattern of hyperglycemia, provided the clinician is aware of the limitations of the tests.
Delayed insulin absorption may lead to PH. Insulin absorption from a subcutaneous site in humans can vary as much as 50% from day-to-day, even if the same insulin, dose, and injection site are used. As alluded to earlier, insulin absorption and action in humans can also be affected by variations in countless factors associated with daily life, including physical exercise, body temperature, and the emotional state. While there are few studies in dogs and cats examining variables that alter insulin absorption and action, it is likely that there is a high degree of true day-to-day biologic variability in these species as in humans. Biologic variability is distinct from the variability introduced by human error and the technology used for insulin administration and glucose measurement. Other potential causes of delayed insulin absorption include interference by insulin antibodies, which develop in response to exogenous insulin, and poor blood flow at the site of injection, which can occur when the injection is administered in adipose tissue. Anti-insulin antibodies have been detected in diabetic dogs and cats but there is not convincing evidence that these antibodies interfere with insulin absorption.
Insulin resistance is probably the most common metabolic cause of PH in dogs and cats but is not a specific diagnosis. By its simplest definition, insulin resistance is an inadequate biologic response to endogenous or exogenous insulin. However, a definitive diagnosis of insulin resistance is difficult to achieve and commonly used diagnostic methods are too cumbersome to be practical in most clinical settings. In veterinary medicine, insulin resistance is usually a clinical diagnosis made on the basis of PH, an unusually high insulin requirement, and the presence of a condition associated with insulin resistance. Insulin resistance should be considered if PH exists despite an insulin requirement of >1.5 U/kg/injection or an insulin dose >2.2 U/kg/injection is needed to control hyperglycemia. Common causes of insulin resistance include obesity, bacterial/fungal infection, and concurrent endocrinopathies. Additionally, ketosis, hyperlipidemia, cardiac insufficiency, chronic pancreatitis, renal disease, hepatic insufficiency, and neoplasia can potentially lead to insulin resistance and poor glycemic control. Any condition that activates counterregulatory hormones (cortisol, catecholamines, and glucagon), such as stress, trauma, major surgery, and pregnancy, can induce an insulin resistant state. Insulin resistance is best treated by through specific treatment of underlying disorders:
Obesity is probably the most common cause of mild to severe insulin resistance in dogs and cats and has been shown to be associated with glucose intolerance. Obesity, hypertension, and insulin resistance commonly occur together in humans with type 2 diabetes mellitus, but this metabolic complex is not well-defined in veterinary patients. Insulin resistance due to obesity is reversible with sufficient weight loss and exercise.
Secondary bacterial and fungal infections may cause PH in diabetic dogs and cats. Infection may occur in any tissue but infections of the urinary tract, skin, intervertebral disk, cardiac valves, lungs, abdominal organs (especially the liver), and reproductive tract are most common in diabetic animals. The organism should be identified whenever possible by bacterial or fungal culture or by cytologic exam (fungus). Treatment with broad-spectrum antibiotics or antifungals should be initiated when an infection is suspected and treatment adjusted based on culture and sensitivity. Surgery may be required when an abscess has formed.
Hyperadrenocorticism is a common cause of PH in dogs but is rare in cats. Overproduction of adrenal glucocorticoids can exacerbate hyperglycemia and impair glucose control in diabetic dogs and cats via the induction of insulin resistance in target tissues. Dogs and cats with hyperadrenocorticism often require very large amounts of insulin to maintain reasonable control of glycemia. The diagnosis is made using routine adrenal testing. Treatment options are those for non-complicated hyperadrenocorticism.
Growth hormone (GH) excess can exacerbate diabetes and cause PH in dogs and cats. Acromegaly (caused by a pituitary tumor) causes severe insulin resistance, diabetes and PH in cats. Recent investigations have suggested that feline acromegaly may be more common than previously thought. In dogs, acromegaly typically affects intact females and is caused by stimulation of GH secretion from mammary tissue by exogenous or exogenous progestins. Definitive treatment of PH due to GH excess is difficult to accomplish in cats with pituitary tumors, which may not respond well to any therapeutic modality, but can be addressed in dogs by ovariohysterectomy or by discontinuation of exogenous progestin treatment.
Hyperthyroidism in cats and hypothyroidism in dogs have both been reported to be associated with insulin resistance. Cats with experimental hyperthyroidism have fasting hyperinsulinemia and impaired glucose tolerance, which suggest insulin resistance. The pathophysiology underlying insulin resistance in hypothyroidism may result from the obesity that develops in affected dogs but elevated growth hormone secretion is also known to occur in hypothyroid dogs. Treatment involves normalizing thyroid function and options are the same for non-complicated hyperthyroidism and hypothyroidism in non-diabetic cats and dogs, respectively.