Managing diabetes mellitues in dogs: An overview (Sponsored by Intervet/Schering-Plough Animal Health)

Diabetes mellitus is a complex disease, and managing it is equally complex. Treatment of diabetes mellitus in dogs typically includes insulin therapy, an appropriate diet, and an exercise regimen, all of which must be constantly monitored and adjusted throughout the patient's lifetime. Communicating clearly with clients and preparing them for the need to monitor and modify treatment is vital for successfully treating a diabetic dog. Clients must be committed to extensive care, monitoring, and frequent office visits. They must understand that these steps are necessary—not because you cannot provide optimal care—rather, this is simply the nature of the disease. If clients know at the onset that the dose of insulin is likely to change several times a year and that their dog will have well-regulated periods mixed with periods of suboptimal regulation, feelings of frustration they might have down the road will be replaced with understanding and patience. All of these considerations contribute to effective treatment for the patient and a long-lasting, productive relationship between you and the client.

Keys to managing, canine diabetes mellitus

Signalment and clinical signs

The average age of onset for diabetes mellitus in dogs is 7 to 9 years. Samoyeds, Australian terriers, miniature schnauzers, miniature and toy poodles, and pugs are at an increased risk for diabetes mellitus, whereas German shepherds, golden retrievers, and American Staffordshire terriers are at decreased risk for the disease.1

The classic history and clinical signs typically associated with diabetes mellitus in dogs include polyuria and polydipsia, weight loss, polyphagia, and blindness due to cataracts. Physical examination findings may vary from normal to severely compromised and can be nonspecific. Dogs with diabetes mellitus can have an underweight, normal, or obese body condition. Their hydration status can also vary from normal to dehydrated. In a stable diabetic dog, hepatomegaly and cataracts are common, whereas lethargy and weakness are observed less frequently. Diabetic dogs often have concurrent disorders that influence their history, clinical signs, and physical examination findings. The most common concurrent disorders in diabetic dogs are hyperadrenocorticism, urinary tract infection, hypothyroidism, acute pancreatitis, and neoplasia.2

Diagnosis

The diagnosis of diabetes mellitus is based on history, clinical signs, physical examination findings, and persistent hyperglycemia and glucosuria. However, because diabetic dogs are usually middle age to older animals with concurrent disorders, further diagnostics are warranted, including a complete blood count (CBC), serum biochemistry profile, complete urinalysis, and urine culture. Abdominal ultrasound and thoracic radiographs may also be warranted. Test results common in diabetic dogs include a normal CBC, and a serum biochemistry profile revealing increased alanine transaminase, aspartate aminotransferase, and alkaline phosphatase activities; lipemia; and hypercholesterolemia. The urine specific gravity may be variable, although most diabetic dogs have hypersthenuria. Glucosuria is always present in diabetic patients, and proteinuria, bacteriuria, or ketonuria may also be present. Perform a urine culture and sensitivity testing even if white blood cells are not detected in the urine sediment. Dogs with diabetes mellitus are often immunocompromised; therefore, they may have a urinary tract infection with few or no white blood cells in the urine sediment.

Diet and exercise

Treat and monitor stable diabetic patients as outpatients. You should place these patients on an appropriate diabetic diet with a high concentration of insoluble fiber and complex carbohydrates, yet limited in calories and fat. You can change from the patient's normal diet to the new diet immediately; however, if the patient is hesitant to eat the new diet (a rare problem in polyphagic diabetic dogs), mix the new diet into the old diet and gradually replace the old diet over the course of a week. The diet should contain a total daily caloric intake based on the desired body weight and should be divided into two meals offered twice a day at 12-hour intervals and just before insulin administration. Examples of such diets are Purina Veterinary Diets DCO (Nestlé Purina) or Prescription Diet w/d Canine (Hill's Pet Nutrition).

You can feed diabetic dogs the new diet regardless of weight or body condition score. Many diabetic dogs lose weight because of poor glycemic control. The new diet should improve glycemic control and ultimately result in weight gain. The diet also facilitates weight loss in diabetic and nondiabetic overweight dogs. Exercise may also promote weight loss and improve glycemic control independently of the effect on body condition, as it does in people.3

It is extremely important for clients to understand that vigorous or episodic exercise can result in adverse hypoglycemia. Therefore, you should recommend moderate and routine exercise and ask clients to alert you of any changes in the extent of exercise, which should be made gradually.

Insulin

Insulin is one of the central components of diabetic therapy in dogs and you may choose from several different insulin products. Most commercially available insulins are human analogue insulins produced by recombinant DNA techniques. Human insulin differs from canine insulin by one amino acid.

Regulation of insulin secretion

Glucose is the primary regulator of insulin secretion. Glucose that enters beta cells in the pancreas is metabolized to adenosine triphosphate (ATP), which results in the closure of ATP-sensitive potassium channels. Closure of these potassium channels decreases potassium efflux and results in beta cell depolarization and the opening of voltage-sensitive calcium channels. The increased cytoplasmic calcium concentration that follows results in insulin exocytosis.

Pattern of physiologic insulin secretion

Normal insulin secretion is biphasic. In the first phase, a large and rapid increase and decrease characterize insulin secretion. The second phase consists of a smaller, more gradual increase and decrease of insulin secretion. In dogs, the first phase of insulin secretion lasts about two to five minutes, and the second phase occurs about 45 to 60 minutes after a glucose challenge.4,5

The goal of recent insulin treatment protocols in diabetic people has been to mimic this pattern of physiologic insulin secretion. The protocols use a very short and rapid-acting insulin product that mimics phase one of insulin secretion in combination with a longer-acting insulin that mimics the second phase of physiologic insulin secretion. This pattern of insulin treatment has not yet been reported in dogs, so I do not recommend it at this time.

Short-acting insulins

The Food and Drug Administration (FDA) has approved four short-acting insulins for use in people: regular insulin (Humulin R—Eli Lilly, Novolin R—Novo Nordisk), insulin lispro (Humalog—Eli Lilly), insulin aspart (NovoLog—Novo Nordisk), and insulin glulisine (Apidra—Sanofi-Aventis).

When administered subcutaneously to people, lispro, aspart, and glulisine insulins have a faster onset (five to 15 minutes) and shorter duration of action (four to six hours) than regular insulin (in which onset is about 30 to 60 minutes and duration of action is about eight to 10 hours). The relatively slower onset of action and longer effect of regular insulin may be caused by zinc, which is present in regular insulin and promotes the formation of large insulin hexamers that are slow to diffuse from the subcutaneous tissue into circulation. Structural changes in lispro, aspart, and glulisine reduce the formation of insulin dimers and hexamers and allow for a more rapid absorption of insulin monomers from the subcutaneous tissue into circulation.6,7 All four short-acting insulin products are clear, colorless, and come in 100 U/ml (U-100) preparations.

Regular insulin may be administered intravenously, intramuscularly, or subcutaneously in dogs. In veterinary medicine, regular insulin is used mainly for the treatment of diabetic ketoacidosis and is administered intravenously as a continuous rate infusion, or intramuscularly. The clinical use of lispro, aspart, or glulisine insulins for treating diabetic ketoacidosis in dogs has not yet been reported.

Intermediate-acting insulins

Intermediate-acting insulin products are the most commonly used insulin products in diabetic dogs. These products are termed intermediate-acting because the overwhelming majority of dogs require twice daily treatment with these products. The three intermediate-acting insulin products are white and uniformly cloudy after gentle mixing.

Porcine insulin zinc. Purified porcine insulin zinc (Vetsulin [Caninsulin]—Intervet) is a lente insulin and is the only FDA-approved insulin for dogs.8 It is marketed in a 40 U/ml (U-40) preparation, and appropriate U-40 syringes must be prescribed for its use. Porcine insulin is structurally identical to canine insulin. See Use of porcine zinc insulin suspension in the management of canine diabetes mellitus for more information on porcine insulin.

Neutral Protamine Hagedorn. Neutral Protamine Hagedorn (NPH) insulin (Humulin N—Eli Lilly, Novolin N—Novo Nordisk) is an isophane suspension and is currently produced by recombinant DNA technology utilizing a nonpathogenic laboratory strain of Escherichia coli. It is identical to human insulin, and, as is the case with all insulin products marketed for use in people, it is marketed in a 100 U/ml (U-100) preparation and must be used with U-100 syringes.

Protamine zinc insulin. The production of PZI insulin by IDEXX has been discontinued, and it is recommended to switch cats currently treated with PZI to a different insuln. Protamine zinc insulin (PZI, PZI VET—IDEXX) was composed of a mixture of 90% beef and 10% pork insulin. Similar to NPH insulin, PZI insulin contained the fish protein protamine and zinc, which facilitated delayed absorption and prolong the duration of action. It was marketed in a 40 U/ml (U-40) preparation, and appropriate U-40 syringes were prescribed for its use.

During the initial process of determining the appropriate insulin dose, I recommend performing a blood glucose curve every 10 to 14 days and adjusting the insulin dose accordingly. Once you determine an appropriate insulin dose, performing a blood glucose curve every three or four months may be adequate in the absence of clinical signs suggestive of poor regulation.

The best way to determine when a dog may need a blood glucose curve or an adjustment in its insulin dose is to monitor clinical signs suggestive of poor diabetic control. Clients should keep a daily log and record the body weight and amount of drinking, urination, eating, activity and glucose, and ketones observed in the urine.

If the dog does not consume its entire meal or vomits, clients should administer half the insulin dose (a dose of insulin should not be skipped) and contact their veterinarian. Clients should also contact their veterinarian if the dog is vomiting regularly or not eating consistently.

Long-acting insulins

Insulin glargine. Insulin glargine (Lantus—Sanofi-Aventis) was introduced in the United States in 2001. It is marketed as a long-acting, peakless insulin for use in people. Glargine is also a human analogue insulin produced by recombinant DNA techniques. As with other human analogue insulins, the name is derived from the names of the amino acids used to alter human insulin. These substitutions result in a shift of the molecule's pH. Glargine insulin is injected in a clear solution with a pH of 4.0 and forms a microprecipitate at the physiologic, neutral pH of the subcutaneous space. These aggregates result in delayed, prolonged, and relatively constant absorption of insulin from the subcutaneous injection site. Because glargine is acidic, it can not be mixed with a neutral insulin (e.g., regular insulin) or with saline.

In people, glargine is used as a once-a-day, long-acting, peakless insulin that mimics the flat interprandial insulin secretion in nondiabetics. In diabetic people, the onset of action for glargine occurs two to four hours after subcutaneous injection, and its duration of action is 20 to 24 hours. Glargine is supplemented with a rapid and short-acting insulin (e.g., lispro or aspart) at meal times.

A starting glargine dose of 0.5 U/kg subcutaneously every 12 hours appears to be safe and effective in dogs. However, further studies are needed to better characterize the use of insulin glargine in diabetic dogs because reports on the subject are limited.

Insulin detemir. Insulin detemir (Levemir—Novo Nordisk) was approved for use in people by the FDA in June 2005 and has recently become commercially available in the United States. It is another long-acting human insulin analogue; however, there are no published reports on the use of detemir in dogs.

Currently, most dogs and cats require twice-a-day insulin treatment (this is the case with any insulin). Successful treatment with once-a-day insulin is rare in dogs and uncommon in cats. With increased use of glargine or detemir, more dogs and cats may do well with only once-a-day treatment.

When you combine astute, involved veterinary care with close, constant communication with the client, managing diabetes mellitus can be a success—one that's rewarding for you, the patient, and the client.

References

1. Hess RS, Kass PH, Ward CR. Breed distribution of dogs with diabetes mellitus admitted to a tertiary care facility. J Am Vet Med Assoc 2000;216:1414-1417.

2. Hess RS, Saunders HM, Van Winkle TJ, et al. Concurrent disorders in dogs with diabetes mellitus: 221 cases (1993-1998). J Am Vet Med Assoc 2000;217:1166-1173.

3. Herbst A, Kordonouri O, Schwab KO, et al. Impact of physical activity on cardiovascular risk factors in children with type 1 diabetes: A multicenter study of 23,251 patients. Diabetes Care 2007;30:2098-2100.

4. Getty L, Hamilton-Wessler M, Ader M, et al. Biphasic insulin secretion during intravenous glucose tolerance test promotes optimal interstitial insulin profile. Diabetes 1998;47:1941-1947.

5. Fischer U, Hommel H, Ziegler M, et al. The mechanism of insulin secretion after oral glucose administration. VIII. Pancreatic juice insulin excretion after glucose loading and meal ingestion in normal and vagotomized dogs. Endokrinologie 1976;68:327-337.

6. Hirsch IB. Insulin analogues. N Engl J Med 2005;352:174-183.

7. Dailey G, Rosenstock J, Moses RG, et al. Insulin glulisine provides improved glycemic control in patients with type 2 diabetes. Diabetes Care 2004;27:2363-2368.

8. U.S. Food and Drug Administration. FDA approves first insulin drug for diabetic dogs. Available at: www.fda.gov/bbs/topics/news/2004/NEW01060.html. Accessed March 25, 2008.