Diabetes Mellitus: Treatment Options
David Bruyette United States
Successful management of the diabetic patient involves many factors. An understanding of dietary therapy, insulin preparations, oral hypoglycemic agents, and management of concurrent illness are all required to optimize glycemic control. The goals of therapy are to control clinical signs, prevent or slow the progression of cataracts, avoid hypoglycemia, and maintain ideal body weight. The challenge is to address these concerns while attempting to help the owners deal with a time consuming, expensive, and chronic medical condition. Diabetes Mellitus in dogs and cats results from a decrease in insulin secretion from the beta cells of the pancreas and/or a decrease in insulin action.
There are three classifications of diabetes:
Type I diabetes is comparable to insulin dependent diabetes mellitus (IDDM) in humans. It results in low basal insulin concentrations with impaired insulin secretion following a glucose load. Treatment requires insulin injections. It is the most common form of diabetes in dogs.
Type II diabetes is similar to non-insulin dependent diabetes (NIDDM) in humans and is managed with dietary therapy and oral hypoglycemic. It causes normal to increased basal insulin concentrations with decreased secretion following a glucose load. Insulin may or may not be required for animals with Type II diabetes.
Type III diabetes is seen most commonly in hormonally induced diabetes in dogs and cats and is similar to impaired glucose tolerance (IGT) in humans. Diabetogenic hormones (epinephrine, cortisol, glucagon and growth hormone) or medications interfere with insulin action and cause glucose intolerance, which can lead to diabetes.
Etiology and Signalment
There are some distinct differences in the etiology of canine and feline diabetes. In dogs, it is generally thought to be an immune mediated disease with gradual destruction of beta cells. The progression from normal, to glucose intolerant, to diabetes, is generally slow so that most islets (over 90%) are lost before diabetes occurs. Other causes of diabetes in dogs include genetic predisposition, chronic pancreatitis, and medication-induced diabetes (glucocoricoids and megestrol acetate). Genetic predisposition to diabetes is most common in the following breeds: German Shepherd dogs, Schnauzers, Beagles, and Poodles. Golden Retrievers and Keeshonds are more prone to juvenile diabetes. Gender is a factor in dogs with females being three times more likely to develop diabetes than males. Generally, diabetes occurs in dogs in middle age (six to nine years) but can also present earlier for specific breeds, particularly the Golden Retriever and Keeshond.
The most common causes of diabetes in cats are obesity, pancreatitis and most commonly, amyloidosis of the pancreatic beta cells. There appears to be very little gender predisposition to this disease in cats, although it is slightly more common in males than females. As with dogs, the onset of diabetes in cats occurs most often in middle age.
The clinical signs of diabetes include PU/PD (polyuria and polydipsia) from hyperglycemia, resulting in glycosuria and a resultant osmotic diuresis. Polyphagia and weight loss is common although many animals will still be obese upon presentation. In addition to the polyphagia, there may be variable degrees of dehydration especially in the cat. Cataract formation is very common in dogs with diabetes, but rare in cats. Cats often present with icterus as a result of concurrent hepatic lipidosis and/or pancreatitis. Icterus is not common in dogs unless they have pancreatitis. Cats may also exhibit a plantigrade stance (peripheral neuropathy) that is directly related to the severity and duration of hyperglycemia. Clinical neuropathies do occur in dogs, but are extremely rare.
Differential diagnoses include: hyperthyroidism (in cats), gastrointestinal lymphoma, hepatic disease, renal disease, pancreatitis, hyperadrenocorticism, and acromegaly.
Diagnosis involves testing for persistent fasting hyperglycemia, with fasting blood glucoses greater than 200 mg/dl. Clinicians also will need to rule out transient hyperglycemia that may be due to: postprandial, diabetogenic hormones (endogenous or exogenous), and stress hyperglycemia. Stress hyperglycemia can be a problem in cats due to the release of epinephrine when stressed or handled.
The number one cause of death in diabetic dogs and cats is not the disease itself; rather, it is the owner's frustration with the disease. This is an extremely important point to remember when treating diabetic animals. Good communication with the pet owner is perhaps the most important component of managing the disease.
It is recommended that clinicians schedule a 30-minute appointment with the client at the time of discharge before sending the diabetic patient home for the first time. During this appointment, clinicians should thoroughly discuss the care required for the patient. Include the following instructions in that discussion: how to give the animal injections, how to store insulin, what types of food to feed and how often, how to recognize the signs of hypoglycemia, and how to react to this condition. Also, include information on what clinical signs to look for in terms of monitoring water intake and urine production.
The client should be given written instructions for use as a reference once they are caring for the patient at home. It is essential that the clinician and veterinary staff strive to educate the caregiver and motivate them to get involved in the care of their diabetic pet. The goals of treatment include elimination of the clinical signs of diabetes, prevention or slowing of cataract formation and resulting blindness, prevention of potentially dangerous hypoglycemia, and prevention and/or treatment of concurrent illness.
Therapy for diabetes centers on four main areas: treatment of concurrent illness (i.e., urinary tract infections, pydermas, etc.), oral hypoglycemic agents, insulin therapy, and dietary management.
Monitoring for concurrent illness is very important in effectively managing diabetic dogs and cats. Clinicians must effectively recognize and treat the other disorders because the concurrent illness will impact the diabetic regulation and many common diseases have similar clinical signs to diabetes mellitus. Even simple problems such as UTI�s and pyodermas can result in activation of stress hormones and result in insulin resistance.
Oral hypoglycemic agents have been used in the treatment of NIDDM in humans for over 30 years.� It is only in recent years however that these products have been seriously evaluated as an alternative to insulin therapy in animals.� The medical literature provides an extensive amount of information on a variety of agents used in people while research in this field in veterinary medicine is still limited mainly to sulfonylureas (e.g., glipizide).
In one study, glipizide was effective in improving clinical signs and blood glucose concentrations in 65% of cats. The degree of response in these cases varied greatly however, which is to be expected when the type of DM is unknown (IDDM vs. NIDDM). Unlike in people, distinguishing between the two forms of diabetes has proven difficult, as routine insulin secretagogue testing in cats is unreliable although it is currently believed that 50-70% of diabetic cats are insulin dependent diabetics. In a more recent study, glycemic control in diabetic cats was monitored over a 50-week period in which glipizide monotherapy was instituted at a dose of 5 mg orally twice daily. Overall, 22 out of 50 cats (44%) treated were considered to have had a positive response to therapy. The effectiveness of the drug however, waned in three of these cats prior to the end of the study decreasing the success rate to 38%.
Unfortunately, there were no consistent factors in either study that would indicate which patients would respond well to glipizide therapy. When considering treatment with oral hypoglycemics in our feline patients however, careful patient selection based on our knowledge of the disease as well as information from the medical literature, will ensure a better success rate. Current initial dose recommendations for treating cats with glipizide are 2.5 mg orally twice daily.
Animals determined to be responding favorably to glipizide therapy typically show resolution of clinical signs, blood glucose levels < 200 mg/dL and absence of glucosuria. These cases should be routinely evaluated, as they may not require life-long therapy. Based on the severity of the underlying pancreatic pathology, complete response may not be seen in all cases and an initial favorable response does not preclude the possibility of insulin supplementation in the future. Acarbose (Precose): alpha--Glucosidases (i.e., sucrase, maltase, lactase) are made in the brush border of the small intestine and are involved in the digestion of complex carbohydrates into mono-saccharides (i.e., glucose). Acarbose acts by competitively and reversibly inhibiting these enzymes therefore delaying hydrolysis and subsequent absorption of ingested carbohydrates. It is also thought that acarbose may inhibit pancreatic alpha--amylase which is a catalyst in the digestion of starch. The overall effect of these actions is to reduce post-prandial hyperglycemia. A dose of 12.5�20 mg q8-12h with meals has been proposed for use in cats. Based on its mechanism of action, it is also possible to consider using acarbose in patients who are receiving daily insulin injections. Decreasing the post-prandial rise in glucose may help to stabilize the patients glucose levels throughout the day in conjunction with exogenous insulin. In a recent study in dogs, acarbose was thought to be useful as an adjunct treatment in patients where the cause for poor glycemic control could not be found and insulin treatment alone was not effective. The suggested dose was 12.5 to 25 mg/meal regardless of body weight. The dose was gradually increased every two to four weeks until clinical signs and glycemic control improved or side effects (diarrhea) developed.
There has been a considerable amount of confusion over the various insulin preparations available. In general, animal origin insulins are being discontinued as the desire and ability to treat people with human derived insulin preparations has progressed. There is concern that animals receiving human insulin will develop antibodies resulting in decreased insulin activity and/or effectiveness. Dogs receiving any insulin product that is not derived from pork will make antibodies. However, studies have shown that those antibodies do not interfere with the glucose control. In fact, dogs that made antibodies against insulin had a longer duration of action, which actually enhanced the effect of the insulin rather than decreased its efficacy. Cats however, due to the amino acid sequence of their insulin, which is completely different than any other species, will make antibodies against all the available insulin preparations so the clinician must decide what type of insulin to use.
The options with human insulin include: short acting, intermediate acting, and long-acting insulins. The short acting insulins are primarily used for ketoacidosis, and therefore, are not covered in this article. The intermediate acting insulins are classified as either NPH or Lente. It is important to note, however, that even though they are classified as intermediate, they do not behave the same way in the dog or cat. Lente is actually a mixture of semi-lente and ultra lente, which results in a bimodal onset of actions. This is helpful in some patients because is helps block post- prandial hyperglycemia. Conversely, lente insulin is not recommended for use in an animal that does not develop postprandial hyperglycemia. It is recommended that NPH be used in the majority of dogs and cats with diabetes and it is also understood that most patients will require two injections a day to achieve glycemic control. Ultralente insulin is available and a percentage of cats will do well on once a day dosing of this preparation. However, approximately 25 percent of cats will not absorb ultralente, especially humulin-U origin ultralente. In these cases, an intermediate acting insulin can be used or the animal can switched to PZI. PZI is a controversial insulin, primarily because it is compounded in limited quantities by all but one manufacturer (Blue Ridge Pharmaceuticals), which can result in variances from batch to batch. The variances make it much more difficult to control the diabetic patient using PZI, than with those insulins produced in large batches. All insulins are quite variable from patient to patient as well as within a given patient with respect to how quickly the drug acts and its duration of the action. Therefore, in the initial management of a diabetic patient, it is advisable to choose a conservative initial dose of insulin to stabilize the animal. It will then be necessary to rely on serial blood glucoses and clinical signs in order to determine the proper dose.
There is no other way to regulate a dog or cat other than to do serial blood glucose curves initially because of the inherent variability between products. In dogs we like to start with Humulin-N at 0.5 units/kg q12h. In cats, we start with either PZI or NPH at 1-3 units once a day. One unit for thin cats and three units for fat cats. Ultimately, q12h dosing is necessary in most cats.
For patients taking under five units of insulin per dose, it is no longer necessary to dilute the insulin. It is more advisable to use a one-third or one-fourth strength insulin syringe. These syringes, along with insulin pens (which accept an insulin cartridge) are easier for the client to use and help ensure client compliance. In addition, clinicians should advise clients to change the site of the injection periodically. Over time, the skin at the site of the injection will thicken which results in poor absorption at those sites.� Clients also should initially monitor their pet's urine sugars at home, especially in dogs, and keep a logbook to bring with them to the next examination.
There is a considerable amount of reliable research data showing that diets high in carbohydrates, low in fat and high in fiber are helpful in regulating diabetic dogs. These types of diets also lowers the average insulin dose, lowers the average blood sugar, lowers the amount of urine being produced and lowers glycosolated hemoglobins and fructosamine levels. The carbohydrates in these diets are complex carbohydrates. It is important to avoid diets high in simple sugars, which includes any commercial diet semi-moist food, primarily those packaged in foil packets. Diets high in sugars are absorbed very rapidly before the insulin has time to work. The goal in controlling the diabetes with diet is to balance the absorption of sugar with onset of action of the insulin. A high carbo-hydrate/low fat diet also decreases plasma free fatty acids, increases the number of insulin receptors, increases insulin action at the receptors, and finally, it decreases cholesterol. High fiber diets reduce insulin resistance. The fiber acts to decrease postprandial hyperglycemia, primarily because it delays gastric emptying. A high fiber diet also decreases absorption of glucose and increases insulin action at the receptor.
Some recent evidence suggests that high protein rather than high fiber diets may be more useful in cats with diabetes. Ongoing studies suggest that such diets (canned kitten diets) result in a decrease in insulin dosage and even remission of the diabetes. This may be due in part to the high protein requirement of cats coupled with the high CHO content of most commercial cat foods.
Ideally, the feeding schedule should be coordinated with the onset of action of the insulin. With dogs, this is fairly easy to regulate, but with cats, it is nearly impossible due to their �grazing� style of eating. For cat owners who may not be able to follow a strict feeding schedule or those with multiple pet households, insulin therapy will have to be adjusted to meet the owner's needs. The most important component of the dietary plan is to stress consistency in the diet.
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