Canine & Feline Diabetes Mellitus: Insulin & Non-Insulin Therapies
ACVIM 2008
Kirk Ryan, DVM, DACVIM (Internal Medicine)
Baton Rouge, LA, USA

Diabetes in Humans

Diabetes mellitus is an incredibly common disease in people. In the United States, data from 2005 indicates that diabetes affects roughly 20.8 million people (or 7% of the population).The frequency of diabetes in humans is expected to increase over the next several decades due to lifestyle and demographic changes in our society. An abstract presented to the American Diabetes Association in 2003 estimated a one in three (33%) chance that children born in the year 2000 will develop diabetes during their life time. Known risk factors for diabetes mellitus in people include genetic factors, age, pregnancy and numerous lifestyle factors (diet, exercise, obesity). The lifestyle factors associated with diabetes raise the risk of diabetes in developing countries and especially in modern American culture. Classically, human cases of diabetes are classified as either Type 1 or Type 2 diabetes. Type 1 diabetes (previously called "insulin dependent" or "juvenile onset") is generally associated with immune mediated destruction of the pancreatic beta cells which produce insulin. Type 2 diabetes (previously called "non-insulin dependent or "adult onset") may have many causes which culminate in insulin resistance and hyperglycemia. Approximately 90% to 95% of human cases are classified as type 2 diabetes.

Diabetes in Cats and Dogs

For veterinary species, data is more difficult to find, less well publicized and difficult to verify. Estimates on the prevalence of diabetes in cats range from 1 in 50 to 1 in 400 (a prevalence of 2% or less).5 In one study of dogs presented to veterinary teaching hospitals, the prevalence of canine diabetes in 1999 was estimated at 64 cases out of every 10,000 (a prevalence of less than 1%). Anecdotal experience and perception of many veterinarians point to an increasing prevalence of diabetes in veterinary species, and the disease remains a common diagnosis for both cats and dogs. In cats, proposed risk factors for the development of diabetes include breed, age, diet, obesity, activity level, concurrent illness, and possibly drug therapy. Disorders associated with diabetes in both cats and dogs include pancreatitis, pancreatic neoplasia, and numerous endocrinopathies (Cushing's disease, thyroid disorders, acromegaly). With few exceptions, all dogs are considered to have Type 1 diabetes, whereas most cats would be defined as having Type 2 diabetes. Understanding the "type" of diabetes is relevant in veterinary medicine because it relates to both the underlying causes and the treatments for diabetes.

Non-Insulin Treatment of Diabetes

As the saying goes: "An ounce of prevention is worth a pound of cure". Avoidance of risk is probably the most overlooked and underappreciated therapy for diabetic animals. Although some factors are unavoidable (i.e., age, genetic predisposition), many factors can be reduced or eliminated by diligent pet owners. Proper diet, exercise and weight loss make intuitive sense, but can be complicated by species differences.

Exercise Therapy

Many owners are perplexed at the prospect of exercising a lackadaisical and obese cat. Nonetheless, obesity in cats is a well accepted risk factor for diabetes and a bit of creativity devoted to exercise and weight loss may provide numerous health benefits. Some examples include cat toys, tag with a laser pointer, and environmental changes that encourage climbing (cat walks, towers, etc.). Fortunately, dogs, in general, are more amenable to exercise than cats and dog owners more naturally engage in walks or other play exercise (fetch, Frisbee, swimming, etc.) with their pets. Perhaps the most difficult component of an exercise plan is ensuring that planned activities correspond to the pet's natural athletic ability. Previously sedentary animals should be acclimated to exercise to avoid inadvertent injury or stress. Elderly animals at risk for diabetes may not be able to go for that one mile jog in the morning.

Dietary Therapy

The relationship between diabetes mellitus and diet/obesity is a complex one. Although many diabetic animals suffer from obesity, we also recognize that a significant number of diabetic patients present for weight loss. Therefore, reflexively prescribing a typical weight loss diet to all diabetic animals is inappropriate. Additionally, the dietary needs of cats and dogs are quite different. Therefore, there is no single diet that works well for all diabetic patients.

For obese dogs, a low calorie weight loss diet containing reduced amounts of fat and higher levels of complex carbohydrates and fiber may be beneficial. These diets slow digestion, limit the postprandial glucose spike, promote weight loss, and reduce the risk of acute pancreatitis. Rival pet food companies provide the veterinary profession with many excellent choices. Diets used in a weight loss program should be balanced for long term use or eliminated/substituted once weight loss goals have been met. Weight loss should be monitored to enhance the success through informed owner compliance and safety.

Unfortunately, the same nutritional strategies used in dogs do not work well for obese cats. Current conventional wisdom holds that cats have evolved as true carnivores with a "feast or famine" eating pattern. The ancestors of domestic felines may have developed selective insulin resistance to maintain hyperglycemia during prolonged periods between meals while maintaining the ability to store dietary fats. This sort of metabolism worked well for cats eating diets traditionally low in carbohydrates and high in protein. Postprandial glucose elevations were limited because their metabolism was not challenged by the absorption of large amounts of simple sugars. Instead, blood glucose is maintained primarily by liver metabolism of fats and protein (gluconeogenesis).

A parallel exists between the popular Atkins diet for people and a comparable high protein-low carbohydrate feline diet. For instance a diet composed entirely of mice is estimated to contain 45-50% protein, 3-5% carbohydrate and 40-45% fat. Under these conditions, the body's metabolism shifts towards using fat substrates as the primary energy source rather than carbohydrates. The end result is a trend of fat breakdown, weight loss, improved insulin sensitivity and overall better glycemic control. In previous decades, however, commercially prepared cat foods contained much higher values of carbohydrates (> 50 % carbohydrates). Based on the rationale presented above, feeding inappropriately high carbohydrate diets may result in beta cell burnout and metabolic changes that raise the risk of feline diabetes. Fortunately, numerous pet food manufacturers have formulated scientifically sound feline diets that incorporate these nutritional principles. Examples of high protein-low carbohydrate diets appropriate for the management of feline diabetes and obesity include Purina DM diet and Hill's prescription MD diet. Diabetic cats fed these diets may have a dramatic reduction in the need for insulin injections.

Regardless of the diet chosen, a consistent diet is the basis for proper diabetes management. Many pet owners inadvertently interfere with proper dietary management of their animal's disease by providing high calorie treats or by frequently switching diets based on palatability perceptions. Pet owners should be educated on the benefits of a consistent diet and provided with suitable guidelines for treat selection. Finicky animals or animals with inconsistent appetites should be fed a palatable diet that encourages regular eating. In some cases, the benefits of a good appetite supersede the benefits of an otherwise "ideal" prescription diet.

Non-Insulin Drug Therapy

Given the prevalence of diabetes mellitus in people, the pet owning public has a wide and varied experience with the disease. Pet owners often ask about differences and similarities between veterinary and human strategies for treating the disease. People with non-insulin dependent diabetes often manage their disease with a combination of diet changes, exercise, and oral medications. Sometimes oral medications are appropriate as part of the treatment plan for diabetic cats. In contrast, oral medications are usually not helpful for managing canine diabetes. Most oral hypoglycemic medications are drugs that lower blood glucose concentrations by stimulating insulin secretion or by enhancing the sensitivity of insulin receptors. A large number of these medications are for human diabetics and could be used in cats as well. Despite their theoretic benefits in the treatment of Type 2 diabetes, veterinary experience with oral hypoglycemic drugs remains limited. Limiting factors include: (1) difficulty in orally medicating cats, (2) drug cost, (3) potential for side effects, and (4) off-label use.

At this time, the oral hypoglycemic drug glipizide (Glucotrol®) remains the oral medication with the most widespread veterinary acceptance. Glipizide belongs to a class of drugs called sulfonylureas which bind pancreatic beta cell receptors to cause insulin release. Glipizide is the treatment of choice for stable diabetic cats when insulin therapy is not possible (usually due to owner refusal or patient sensitivity). Glipizide should not be used to treat diabetic emergencies (such as diabetic ketoacidosis). Potential side effects of glipizide in cats include hypoglycemia, hepatotoxicity, gastrointestinal side effects and blood dyscrasias (anemia, thrombocytopenia, neutropenia).

Since the introduction of glipizide in 1955, numerous other oral hypoglycemic drugs have been developed and used in people. Biguanides are a class of drug that reduce blood glucose concentrations by inhibiting gluconeogenesis and increasing glucose uptake by muscle cells. Metformin (Glucophage®) may be the best recognized biguanide medication, but reports of metformin use in cats demonstrated numerous side effects and poor efficacy. Avandia® (rosiglitazone) belongs to a third class of drug known as the thiazolidinediones. These drugs act via mechanisms similar to the biguanides. In late 2007, rosiglitazone was linked to an increased risk of heart attack and death in human patients compared to placebo and other oral hypoglycemic drugs. Detailed information on the use of these drugs in the clinical treatment of diabetic cats and dogs is currently lacking.

Acarbose is a drug which inhibits pancreatic and gastrointestinal enzymes (alpha glucosidases) involved in the digestion and absorption of carbohydrates. Acarbose has been used in diabetic small animals to limit hyperglycemia. In most instances, however, proper diet selection and other more common therapies make acarbose use unnecessary. Potential side effects of acarbose include flatulence, diarrhea and abdominal discomfort.

Insulin Selection in Diabetes

All dogs require insulin injections to treat diabetes. Although close to 90% of cats have type 2 (classically, non-insulin dependent) diabetes, the majority of these patients are managed with insulin therapy (primarily or in conjunction with other non-insulin treatments). Understandably, the market for diabetes related health care products is driven by the needs of the human medical profession. As such, products available to treat veterinary patients sometimes become available or unavailable based on trends in human medicine. Numerous products and sources of insulin create confusion for veterinary professionals and pet owners.

Insulin Source

Traditionally, insulin was derived from pancreatic extracts of livestock animals (primarily beef and pork). Beef-origin insulin is biologically similar to cat insulin, whereas porcine insulin is biologically similar to dog insulin. These insulins worked well for small animal and humans with diabetes. However, animal-origin insulin was not ideal for human patients. Human recombinant insulin was developed almost 30 years ago through technological advances and soon dominated the insulin market. Fortunately, diabetic cats and dogs generally responded well to human insulin products, and these products became standard in veterinary medicine. Occasionally, diabetic animals develop immune reactions to human insulin resulting in insulin resistance due to antibody clearance. In these instances, porcine or bovine insulin (similar to the species being treated) should be used.

Insulin Type

Regardless of the source of insulin, management of different individual patients requires numerous insulin types with varying properties regarding onset, duration and potency. Traditionally, insulins were classified as short acting, long acting, or intermediate acting. These different insulin types were created by formulating insulin mixed with other compounds that affected the absorption, distribution and elimination of the injected hormone. See the Table 1 below for a review of this classic outline. More recently, genetically engineered insulin analogs have been developed with amino acid sequence changes that alter the chemical characteristics of insulin. Insulin analogs are widely used in the treatment of humans with diabetes.

Table 1. Traditional insulin outline.

Duration/onset category

Insulin types

Concentration

Rapid acting

Regular

U-100 (100 units/ml)

Intermediate acting

NPH

U-100

Lente (Vetsulin® by Intervet)

U-40 (40 units/ml)

Long acting

PZI (Idexx)

U-40

Ultralente

U-100

Glargine insulin analog

U-100

Traditionally, veterinarians have used rapid acting insulin only for emergency situations (e.g., diabetic ketoacidosis, hyperkalemia, etc). Dogs are usually treated with intermediate acting insulin, and cats are often treated with long acting insulin. Human products were often used in both species because mass production made them cheap and convenient (stocked in nearly every pharmacy). Over time, manufacturers have stopped producing some insulin products used commonly by veterinarians but no longer used in treating human diabetic patients. Since 2005, lente and ultralente insulin products were discontinued by one of the primary insulin manufacturers (Eli Lilly). This left open niche markets for growing veterinary pharmaceutical companies to continue to produce and market insulins specifically intended for small animal medicine. Vetsulin® is a porcine origin lente insulin approved for use in dogs. PZI, which has had limited availability as a human insulin, has been distributed as a veterinary product by Idexx Laboratories (PZI-Vet®) for use in cats. PZI may also be obtained from numerous compounding pharmacies; physical properties of compounded insulin may differ from brand-name products. Because of the small size of veterinary patients, most veterinary products are less concentrated than their human counterparts. This allows for small doses to be measured in more practical volumes. Insulin syringes are manufactured for use with specific concentrations of insulin. It is extremely important to verify that the insulin syringes match the prescribed insulin.

Glargine

Glargine (Lantus®, Sanofi Aventis) is a long-acting insulin analog that has gained popularity in the treatment of feline diabetes in cats. The long acting affects of glargine stem from its ability to crystallize in subcutaneous tissues at physiologic pH, which delays insulin absorption and prolongs the duration of action. Hence, glargine insulin cannot be diluted. The protocol for the use and monitoring of glargine insulin in cats is significantly different than the protocol used for traditional insulins. Veterinarians and technicians are encouraged to review references on the use of glargine in diabetic cats prior to starting such treatment.

References

1.  United States Centers for Disease Control 2005.

2.  K.M. Venkat Narayan, MD. Scientific Sessions of the American Diabetes Association, June 2003.

3.  Courtney CH, Olefsky, JM, LJ DeGroot, JL Jameson, eds. Endocrinology, 5th ed, 2006, pp 1093-1117.

4.  Gilliam LK, Lernmark A, LJ DeGroot, JL Jameson, eds. Endocrinology, 5th ed, 2006, pp 1073-1091.

5.  Rand J, Marshall R. Vet Clin Small Anim 35 (2005) 211-224.

6.  Rand JS, et al. J. Nutr. 134: 2072S-2080S, 2004.

7.  Kirk CA. Vet Clin Small Anim 36 (2006) 1297-1306.

8.  Nelson R, et al. J Vet Intern Med 2004;18:18-24.

9.  Rosen CJ. NEJM 357 (9): 844-846.

10. Rand JS, Marshall RD. 23rd Annual ACVIM Forum, Baltimore, MD, 2005. p. 483-4.

11. Heinemann L, et al. Diabetes Care 23:644-649, 2000.

Speaker Information
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Kirk Ryan, DVM, DACVIM (Internal Medicine)
Baton Rouge, LA


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