Canine Diabetes Mellitus

Chapter 44

Canine Diabetes Mellitus

Definition, Epidemiology, and Pathophysiology

Diabetes mellitus in dogs is a persistent defect of carbohydrate metabolism associated with an absolute deficiency of insulin in nearly all cases. Almost every affected dog requires administration of exogenous insulin for management of the disease. The underlying cause in dogs is poorly understood but is likely multifactorial, including genetic predisposition; infectious, toxic, or inflammatory damage to the pancreatic islets with progressive immune-mediated destruction; or predisposing conditions, such as natural or iatrogenic endocrine disorders, obesity, and hyperlipidemia that cause insulin resistance with subsequent β-cell exhaustion. The prevalence in North American teaching hospitals seems to have increased between 1970 (19 dogs per 10,000) and 1999 (64 dogs per 10,000) (Guptill et al, 2003). The prevalence in Europe is similar, although perhaps slightly variable depending on location. Females, neutered or intact, and neutered males are overrepresented, although female predisposition may be declining. The peak age of occurrence is 7 to 11 years, with 70% of patients older than 7 years at the time of diagnosis. Diabetes occurs rarely in dogs younger than 1 year of age.

Absolute insulin deficiency associated with canine diabetes mellitus is also associated with an increase in glucagon concentration. Together these changes lead to hyperglycemia, both from increased hepatic glucose production and from lack of peripheral use. When blood glucose concentration exceeds the renal threshold (180 to 220 mg/dl), osmotic diuresis occurs, leading to polyuria with secondary polydipsia. There is also fatty acid mobilization with consequent increased production of ketoacids by the liver because the peripheral tissues become energy starved. In addition, ketoacid production is increased because of the lack of the effects of insulin on lipoprotein lipase and hormone-sensitive lipase to facilitate the storage of fatty acids in adipocytes. As ketoacid production exceeds the quantity used for energy metabolism, acidemia occurs, and spillover of ketones into the urine contributes to polyuria. Without insulin, the ability of cells to use glucose is markedly diminished. Insulin deficiency reduces fatty acid deposition in adipocytes and decreases the incorporation of amino acids into protein. These metabolic abnormalities create a catabolic state with resultant weight loss despite adequate or excessive food consumption.

Diagnosis and Management Plan

The diagnosis of diabetes mellitus is based initially on a combination of clinical signs that generally include polyuria and polydipsia, weight loss despite a good appetite, and the demonstration of persistent hyperglycemia with glucosuria. Repeat blood and urine glucose testing to confirm the persistence of hyperglycemia is unnecessary if the clinical signs of polyuria, polydipsia, and polyphagia have been noted. Ketonuria may be present in 66% of dogs with uncomplicated diabetes mellitus. Increased serum alkaline phosphatase and alanine transaminase and hypertriglyceridemia are also common.

Once the diagnosis of diabetes mellitus has been established, it is important to determine if the dog has complicated diabetes (see Web Chapter 13). This determination is critical because diabetic ketoacidosis requires aggressive management in the hospital. Conversely, uncomplicated cases are better managed as outpatients. The major clinical criteria for determining if a dog requires aggressive management relate to clinical findings: Is the patient ill, anorexic, or vomiting, or, conversely, is the dog eating and drinking well and exhibiting a generally healthy attitude? Dogs that appear generally well and show a good appetite can be managed as uncomplicated diabetics even in the presence of ketonuria. Morbidity in these patients is rarely severe enough to require hospitalization and intensive care.

Before initiating therapy, it is important to discuss the effort and cost of management of a diabetic dog with the owner and identify comorbid conditions. Lifestyle or financial circumstances may prevent some owners from successfully managing a diabetic pet. Foremost, it is important that the clinician have a clear understanding of the owner’s lifestyle and daily schedule so that a feasible treatment and monitoring protocol can be developed. Additionally, many older dogs manifest concurrent disease that can affect control of the diabetes or may influence the owner’s decision to treat or not. A thorough medical evaluation should be conducted to identify concurrent diseases. In addition to the history and physical examination, recommended studies include a complete blood count, serum chemistries (including canine pancreatic lipase immunoreactivity), urinalysis, urine culture, thoracic radiographs, and abdominal ultrasonography or radiography.

Diet, Feeding Schedule, and Exercise

Diets that are high in fiber, low in simple sugars, and moderately restricted in fat and protein are generally recommended for diabetic dogs, although they may not provide an advantage over diets with moderate fiber and low carbohydrates (see Chapter 46). However, the most important aspect of diet for diabetic dogs is that it be a balanced diet that the dog will eat consistently.

If dogs receive insulin twice daily, it is recommended to feed two equal meals at the time of insulin administration. Some clinicians recommend that the dog be fed before injecting insulin and withholding the insulin injection anytime the dog does not eat its entire meal. Although this may work well for a dog that is a gluttonous eater, it is less effective for finicky eaters or dogs that eat small amounts throughout the day. The latter type of eaters may be given insulin routinely without having eaten their entire meal after it has been established that their eating pattern is consistent and glucose curves have confirmed hypoglycemia does not occur.

Even when insulin is given once daily, it is recommended that the dog be fed twice daily. The second meal should approximately coincide with the glucose nadir depending on when the owner can be home to feed. For patients that have a variable time to glucose nadir, the second meal of the day should be fed at a consistent time that approximates the average time of the nadir. Alternatively, the second meal should be presented 12 hours after the insulin injection. Feeding a larger portion of the daily diet around the time of the glucose nadir may lead to a glucose curve with less fluctuation. However, if Lente insulin given once daily provides adequate control, the glucose response can be improved in some cases by feeding the larger meal at the time of the insulin injection. Lente insulin contains 30% short-acting insulin (Semilente) and 70% long-acting insulin (Ultralente) and is absorbed in many dogs such that there are two peaks of insulin activity, with the earlier peak leading to the higher insulin concentration.

Exercise affects both the absorption of insulin and the metabolic use of glucose. Consequently, exercise levels should be kept constant with activity provided at the same times every day.

Insulin Therapy

As stated previously, virtually all diabetic dogs require insulin therapy. Both recombinant human insulin and porcine insulin have been advocated for canine diabetes. There is very little experience or published information about the use of synthetic insulin analogs in dogs (see later). The use of compounded insulin products is not recommended because of a lack of both consistency between batches and stringent control of the formulation.

The recommendation for insulin treatment in dogs involves administration of an insulin with intermediate duration of action twice daily. The only currently available intermediate-duration product is recombinant human neutral protamine Hagedorn (NPH) insulin (used extralabel for dogs). Porcine Lente insulin (Vetsulin) has been approved for use in dogs but cannot be sold in the United States at the present time because of concerns with stability and bacterial contamination associated with the manufacturing process. It is uncertain when or if the product will again be available in the United States. There is some experience with this product because it has been and remains in use in Canada and many European countries under the brand name Caninsulin. Using Vetsulin, most dogs require injections every 12 hours for adequate control of blood glucose, with a median dose between 0.75 and 0.78 U/kg per injection (range, 0.28 to 1.4 U/kg) for dogs receiving insulin every 12 hours (Monroe et al, 2005). Using recombinant human NPH insulin, most dogs also appear to require two injections per day, with a median time to glucose nadir of 4 hours (range, 1 to ≥10 hours) and a range for duration of action 4 to 10 hours or longer. The median dose reported for well-controlled dogs is 0.63 U/kg every 12 hours (range, 0.4 to 0.97 U/kg) (Palm et al, 2009).

The long-acting protamine zinc insulin made with recombinant human insulin and approved for veterinary use in cats (ProZinc) may be useful for dogs for which intermediate-duration insulins provide too short of a duration of action (<8 hours) to provide adequate glycemic control when given twice daily.

Insulin glargine (e.g., Lantus, Aventis) is a human insulin analog in which the amino acid asparagine has been replaced by glycine within the α-chain and two arginine molecules have been added to the C-terminus of the β-chain. It is intended to be used as a long-acting, basal insulin in humans. There is little clinical information about the use of this product in dogs. It may be useful as a longer acting insulin in patients for which NPH or Lente insulins have too short a duration of action to provide adequate glycemic control with two daily injections. In a small number of dogs, insulin glargine was shown to be safe, providing good to moderate control in most of the patients with a median dose of 0.6 U/kg (range 0.11 to 1.07 U/kg) given every 12 hours. However, the time to glucose nadir was quite variable, and duration of action was not determined (Fracassi et al, 2012). Insulin detemir (Levemir) is a long-acting insulin that is used in humans as a basal insulin. The fatty acid myristic acid replaces threonine at position 30 on the β-chain, which causes strong binding between insulin detemir molecules and binding to albumin to prolong its metabolism. There is very little information about use of insulin detemir in dogs, but, similar to insulin glargine, it may be useful for dogs that need a long-acting product. An equivalent dose of detemir in dogs appears to be 25% of the dose of NPH insulin, and the duration of action may be too long to require dosing every 12 hours (Sako et al, 2011). Evidence-based information about the use of detemir or glargine in dogs is too sparse to make a clear recommendation for dosing frequency. It is very important to determine the duration of action and appropriate dose for each patient by performing glucose curves, which may need to be continued longer than 12 hours.

Determining Insulin Dose and Frequency of Administration

In dogs with uncomplicated diabetes, it is recommended to initiate treatment with an insulin product with intermediate duration of action, such as recombinant human NPH or porcine Lente, at a dose of 0.25 U/kg every 12 hours administered subcutaneously starting at a time in the morning that fits the client’s schedule. Blood glucose is measured two or three times at 3-hour intervals during the first day to ensure that the dose is not so high as to create hypoglycemia. If the blood glucose decreases to less than 100 mg/dl at any time during the first day, the dose should be reduced by 25%, and blood glucose should again be monitored to ensure hypoglycemia does not develop before the dog is sent home. Because it can take several days for the dog to adjust to any change in insulin dose or product type, it is sent home to receive insulin injections for 5 to 7 days before the first recheck to monitor the response to the insulin. To prevent tissue irritation from injecting insulin at the same site while maintaining consistent absorption of insulin from each injection, it is recommended to alternate injections at approximately 1 to 2 inches on either side of the midline. The suggested level is over the thorax from just caudal to the scapulae to the last rib, alternating from side to side; this allows for injection sites with similar blood supply, skin thickness, and muscular activity.

Because each dog may react uniquely to any insulin product, the appropriate dose and number of injections per day must be determined by monitoring the blood glucose response to the product (see Chapter 45). A careful history should be taken and a thorough physical examination, including body weight, should be performed to determine if clinical signs have resolved or are resolving. In addition, one should perform a glucose curve at 5- to 7-day intervals until the appropriate protocol is determined, which often takes 4 to 6 weeks. Performing one or two blood glucose measurements after the morning injection to titrate the insulin dose is inadequate and often leads to poor glucose control and hypoglycemia. To provide adequate information, the glucose curve should be performed after feeding the same food and giving the same insulin product and dosage at the usual times on the morning of the test. Blood glucose is determined every 2 hours for 10 to 12 hours, beginning either just before the dog is fed and given insulin or within 1 hour of doing so, if possible, depending on the owner’s schedule. Deciding to feed and give insulin to the dog at home before coming to the hospital depends on the following practical factors: (1) the time in the morning that the dog is usually fed and treated and (2) whether or not the dog is likely to eat normally in the hospital setting. It is best to keep feeding and insulin administration within 1 hour of the usual schedule while beginning the curve at a time that is practical for the owner and veterinarian.

Glucose concentration can be determined using a point-of-care analyzer or handheld glucose meter to reduce the amount of blood drawn and the associated trauma to the patient. Handheld glucose meters intended for use with human blood generally underestimate the serum or plasma glucose concentration by 10% to 15% compared with a reference laboratory. A relatively new meter (AlphaTRAK) intended for use in dogs and cats may be the most accurate for use with dog blood. The AlphaTRAK both overestimates and underestimates blood glucose concentration, but the degree of inaccuracy is small. However, when blood glucose is relatively low, it occasionally may overestimate the value, failing to identify hypoglycemia.

Based on the clinical response of the patient and the results of the blood glucose curves, the insulin dose is adjusted by 1 to 5 U per injection, depending on the size of the dog and blood glucose concentrations measured every 5 to 7 days. The dose is adjusted to obtain a blood glucose nadir concentration of 80 to 150 mg/dl and to attempt to maintain the blood glucose concentration less than 250 to 300 mg/dl. It is important to perform glucose curves to determine the duration of insulin activity, defined as the time after insulin injection when the blood glucose exceeds 250 mg/dl after a nadir of 80 to 150 mg/dl. To determine the duration of insulin activity accurately, the blood glucose nadir must decrease sufficiently (range, 80 to 150 mg/dl) so that glucose concentrations greater than 250 mg/dl can be considered as representing near-complete loss of the administered insulin effect. In addition, it is important that the blood glucose nadir concentration remain greater than 65 mg/dl; otherwise, counterregulatory hormonal responses may stimulate blood glucose concentrations to increase to more than 250 mg/dl prematurely, before the true duration of insulin activity has been exceeded. If the blood glucose concentration just before the next scheduled insulin injection is less than 150 mg/dl and the glucose nadir was appropriate, the dog should be fed without giving the next injection of insulin, and the glucose curve should be continued until the blood glucose exceeds 250 mg/dl to determine if the duration of activity of the insulin product is longer than 12 hours. If the blood glucose exceeds 250 mg/dl within 1 to 2 hours of feeding without giving insulin, the duration of insulin activity is likely very close to 12 hours. Some dogs do not have an increase in blood glucose for some time after the injected insulin has been completely metabolized unless they are fed to provide a glucose source. If the glucose increases after feeding without giving insulin as indicated, it is generally safe to continue giving the same dose of insulin every 12 hours.

If the duration of insulin activity is longer than 14 hours but shorter than 16 hours and an extended glucose curve or clinical signs indicate the blood glucose concentration becomes too low overnight, administering a dose of intermediate-duration insulin in the evening that is 25% to 50% lower than the morning dose provides safe and adequate control in most cases. If the duration of insulin activity is longer than 16 hours, the dog may be adequately controlled with one daily injection of the product.

If the duration of action of an intermediate-duration insulin that is given once daily is longer than 16 hours but the dog continues to have clinical signs of polyuria and polydipsia, particularly during the night, a different intermediate-acting preparation could be tried every 12 hours, or a longer acting product, such as protamine zinc insulin, insulin detemir, or insulin glargine, could be given once or twice daily. It cannot be overemphasized that when starting a diabetic dog on any insulin once or twice daily, the duration of the response to that product must be determined by means of an adequate glucose curve. There is great variation among dogs in the duration of action of insulin products; for example, an insulin that is considered of long duration may have an effect of less than 12 hours in certain dogs. Treating with once-daily insulin without adequate glucose monitoring often leads to hypoglycemia. This occurrence is explained by the tendency to continue to increase the daily insulin dose in response to continued polyuria and polydipsia when the actual problem is not an inadequate dose but an inadequate duration of activity.

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Jul 18, 2016 | Posted by in PHARMACOLOGY, TOXICOLOGY & THERAPEUTICS | Comments Off on Canine Diabetes Mellitus

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