Etiology

Hyperglycemia is present if the blood glucose concentration is greater than 130 mg/dl, although clinical signs of hyperglycemia do not develop until the renal tubular threshold for the resorption of glucose is exceeded. In dogs this typically occurs whenever the blood glucose concentration exceeds 180 to 220 mg/dl. The threshold for glucose resorption appears to be more variable in cats, ranging from 200 to 280 mg/dl. Glycosuria causes an osmotic diuresis, which in turn causes polyuria and polydipsia, the hallmark clinical signs of severe hyperglycemia (greater than 180 mg/dl in dogs and greater than 200 to 280 mg/dl in cats). The most common cause of hyperglycemia and glycosuria is diabetes mellitus. Severe hyperglycemia without glycosuria also occurs commonly in cats with stress-induced hyperglycemia, presumably resulting from the secretion of catecholamines and possibly lactate. Transient glycosuria (typically less than 1% on urine glucose test strips) may occur in some cats with severe or prolonged stress-induced hyperglycemia.

Clinical Features

Hyperglycemia of between 130 and 180 mg/dl (possibly as high as 280 mg/dl in cats) is clinically silent and is often an unsuspected finding encountered during blood testing for another reason. If a dog or cat with mild hyperglycemia (less than 180 mg/dl) and no glycosuria is seen because of poly uria and polydipsia, a disorder other than overt diabetes mellitus should be suspected. Mild hyperglycemia can occur in some dogs and cats up to 2 hours after consumption of diets containing increased quantities of monosaccharides and disaccharides, corn syrup, or propylene glycol; during intravenous (IV) administration of total parenteral nutrition fluids; in stressed, agitated, or excitable cats and dogs; in animals in the early stages of diabetes mellitus; and in animals with disorders and drugs causing insulin resistance (Box 52-1). A diagnostic evaluation for disorders causing insulin resistance is indicated if mild hyperglycemia is found to persist in a fasted, unstressed dog or cat, especially if the blood glucose concentration is increasing over time (see p. 783).

Etiology

Hypoglycemia is present if the blood glucose concentration is less than 60 mg/dl. It typically results from the excessive use of glucose by normal cells (e.g., during periods of hyperinsulinism) or neoplastic cells, impaired hepatic gluconeogenesis and glycogenolysis (e.g., portal shunt, hepatic cirrhosis), a deficiency in diabetogenic hormones (e.g., hypocortisolism), an inadequate dietary intake of glucose and other substrates required for hepatic gluconeogenesis (e.g., anorexia in the neonate or toy breeds), or a combination of these mechanisms (e.g., sepsis; Box 52-2). Iatrogenic hypoglycemia is a common problem resulting from overzealous insulin administration in diabetic dogs and cats.

Prolonged storage of blood before separation of serum or plasma causes the glucose concentration to decrease at a rate of approximately 7 mg/dl/h. Glycolysis by red and white blood cells becomes even more apparent in dogs and cats with erythrocytosis, leukocytosis, or sepsis. Therefore whole blood obtained for the measurement of the glucose concentration should be separated soon after collection (within 30 minutes), and the serum or plasma should be refrigerated or frozen until the assay is performed to minimize artifactual lowering of the blood glucose concentration. Glucose determinations from separated and refrigerated plasma or serum are reliable for as long as 48 hours after the separation and refrigeration of the specimen. Alternatively, plasma can be collected in sodium fluoride tubes. Unfortunately, hemolysis is common in blood collected in sodium fluoride-treated tubes, which can result in slight decrements in glucose values owing to methodologic problems in laboratory determinations. Blood glucose values determined by many portable home blood glucose–monitoring devices are typically lower than actual glucose values determined by bench-top methodologies, and this may result in an incorrect diagnosis of hypoglycemia. Finally, a laboratory error may also result in an incorrect value. It is wise to confirm hypoglycemia by determining the blood glucose concentration from a second blood sample and using bench-top methodology before embarking on a search for the cause of hypoglycemia.

Clinical Features

Clinical signs of hypoglycemia usually develop when the blood glucose concentration is less than 45 mg/dl, although this can be quite variable. The development of clinical signs depends on the severity and duration (acute versus chronic) of hypoglycemia and the rate of decline in the blood glucose concentration. Clinical signs are a result of neuroglycopenia and hypoglycemia-induced stimulation of the sympathoadrenal nervous system. Neuroglycopenic signs include seizures; weakness; collapse; ataxia; and, less commonly, lethargy, blindness, bizarre behavior, and coma. Signs of increased secretion of catecholamines include restlessness, nervousness, hunger, and muscle fasciculations.

Depending on the cause, the signs of hypoglycemia may be persistent or intermittent. The hallmark clinical sign of hypoglycemia (i.e., seizures) tends to be intermittent, regardless of the cause. Dogs and cats usually recover from hypoglycemic seizures within 30 seconds to 5 minutes as a result of activation of counterregulatory mechanisms (e.g., secretion of glucagon and catecholamines) that block the effects of insulin, stimulate hepatic glucose secretion, and promote an increase in the blood glucose concentration.

Diagnostic Approach

Hypoglycemia should always be confirmed before beginning diagnostic studies to identify the cause. Careful evaluation of the animal’s history, physical examination findings, and results of routine blood tests (i.e., complete blood count [CBC], serum biochemistry panel, urinalysis) usually provides clues to the underlying cause. Hypoglycemia in the puppy or kitten is usually caused by idiopathic hypoglycemia, starvation, liver insufficiency (i.e., portal shunt), or sepsis. In young adult dogs or cats hypoglycemia is usually caused by liver insufficiency, hypoadrenocorticism, or sepsis. In older dogs or cats liver insufficiency, β-cell neoplasia, extrapancreatic neoplasia, hypoadrenocorticism, and sepsis are the most common causes.

Hypoglycemia tends to be mild (greater than 45 mg/dl) and is often an incidental finding in dogs and cats with hypoadrenocorticism or liver insufficiency. Additional clinical pathologic alterations are usually present (e.g., hyponatremia and hyperkalemia in animals with Addison’s disease or increased alanine aminotransferase [ALT] activity, hypocholesterolemia, hypoalbuminemia, and a low blood urea nitrogen [BUN] concentration in animals with liver insufficiency). An adrenocorticotropic hormone (ACTH) stimulation test or liver function test (i.e., preprandial and postprandial bile acids) may be required to confirm the diagnosis. Severe hypoglycemia (less than 40 mg/dl) may develop in neonates and juvenile kittens and puppies (especially toy breeds) and in animals with sepsis, β-cell neoplasia, and extrapancreatic neoplasia, most notably hepatic adenocarcinoma and leiomyosarcoma. Sepsis is readily identified on the basis of physical examination findings and abnormal CBC findings, such as a neutrophilic leukocytosis (typically greater than 30,000/μl), a shift toward immaturity, and signs of toxicity. Extrapancreatic neoplasia can usually be identified on the basis of the physical examination, abdominal or thoracic radiography, and abdominal ultrasonography findings. Dogs with β-cell neoplasia typically have normal physical examination findings and no abnormalities other than hypoglycemia identified on routine blood and urine tests. Measurement of baseline serum insulin concentration when the blood glucose is less than 60 mg/dl (preferably less than 50 mg/dl) is necessary to confirm the diagnosis of a β-cell tumor.

Treatment

Whenever possible, therapy should always be directed at eliminating the underlying cause of the hypoglycemia. If the disorder cannot be eliminated and the clinical signs of hypoglycemia persist, long-term symptomatic therapy designed to increase the blood glucose concentration may be necessary to minimize clinical signs (see Box 52-12). Such therapy is usually required for animals with metastatic β-cell or extrapancreatic neoplasia.

Symptomatic therapy for animals with severe hypoglycemia of acute onset relies on the administration of glucose (Box 52-3). If the dog or cat is having a hypoglycemic seizure at home, the client should rub a sugar mixture on the pet’s buccal mucosa. Most animals respond within 1 to 2 minutes. Clients should be instructed never to place fingers in, or pour the sugar solution down, the pet’s mouth. Once the dog or cat is sternal and cognizant of its surroundings, it should be fed a small meal and brought to the veterinarian.

If collapse, seizures, or coma develops in the hospital, a blood sample should be obtained to measure the glucose concentration and other variables before reversing the signs with the IV administration of 50% dextrose. Dextrose should be administered in small amounts slowly rather than in large boluses rapidly. This is especially important in dogs with suspected β-cell neoplasia in which aggressive glucose administration can result in severe hypoglycemia after excessive insulin secretion by the tumor in response to the glucose. Commonly, 2 to 15 ml of 50% dextrose is required to alleviate the signs. Dogs and cats with hypoglycemia usually respond to glucose administration within 2 minutes. Recurrence of hypoglycemia is dependent on the ability to correct the underlying etiology.

Occasionally, a dog or cat with severe central nervous system signs (e.g., blindness, coma) does not respond to initial glucose therapy. Irreversible cerebral lesions may result from prolonged severe hypoglycemia and the resultant cerebral hypoxia. The prognosis in these animals is guarded to poor. Therapy is directed at providing a continuous supply of glucose by administering a 2.5% to 5% solution intravenously or increasing hepatic gluconeogenesis with a constant rate infusion of glucagons (see p. 805). Seizure activity is controlled with diazepam or a stronger anticonvulsant medication. Glucocorticoids and mannitol may be necessary to combat cerebral edema.

Etiology

Virtually all dogs with diabetes have insulin-dependent diabetes mellitus (IDDM) at the time of diagnosis. IDDM is characterized by hypoinsulinemia, essentially no increase in the endogenous serum insulin concentration after the administration of an insulin secretagogue (e.g., glucose or glucagon) at any time after the diagnosis of the disease, failure to establish glycemic control in response to diet or treatment with oral hypoglycemic drugs (or both), and an absolute need for exogenous insulin to maintain glycemic control. The cause of diabetes mellitus has been poorly characterized in dogs but is undoubtedly multifactorial. A genetic predisposition, infection, insulin-antagonistic diseases and drugs, obesity, immune-mediated insulitis, and pancreatitis have been identified as inciting factors. The end result is a loss of β-cell function, hypoinsulinemia, impaired transport of circulating glucose into most cells, and accelerated hepatic gluconeogenesis and glycogenolysis. The subsequent development of hyperglycemia and glycosuria causes polyuria, polydipsia, polyphagia, and weight loss. Ketoacidosis develops as the production of ketone bodies increases to compensate for the underutilization of blood glucose (see p. 794). Loss of β-cell function is irreversible in dogs with IDDM, and lifelong insulin therapy is mandatory to maintain glycemic control of the diabetic state.

Unlike cats, dogs very rarely have a transient or reversible form of diabetes mellitus. The most common scenario for transient diabetes mellitus in dogs is correction of insulin antagonism after ovariohysterectomy in a bitch in diestrus. Progesterone stimulates secretion of growth hormone in the bitch. Ovariohysterectomy removes the source of progesterone, plasma growth hormone concentration declines, and insulin antagonism resolves. If an adequate population of functional β cells are still present in the pancreas, hyperglycemia may resolve without the need for insulin treatment. These dogs have a significant reduction in β-cell numbers (i.e., subclinical diabetes) compared with healthy dogs, before the development of hyperglycemia during diestrus, and are prone to redevelopment of hyperglycemia and diabetes mellitus if insulin antagonism recurs for any reason after ovariohysterectomy. Although uncommon, a similar situation can occur in dogs with subclinical diabetes treated with insulin-antagonistic drugs (e.g., glucocorticoids) or in the very early stages of an insulin-antagonistic disorder (e.g., hyperadrenocorticism). Failure to quickly correct the insulin antagonism will result in IDDM and the lifelong requirement for insulin treatment to control the hyperglycemia.

A honeymoon period occurs in some dogs with newly diagnosed IDDM. It is characterized by excellent glycemic control in response to small doses of insulin (less than 0.2 U/kg/injection), presumably because of the presence of residual β-cell function. However, glycemic control becomes more difficult and insulin doses usually increase within 3 to 6 months of starting treatment as residual functioning β cells are destroyed and endogenous insulin secretion declines. It is very uncommon for non–insulin-dependent diabetes mellitus (NIDDM) to be recognized clinically in dogs, despite the documentation of obesity-induced carbohydrate intolerance in dogs and the identification of residual β-cell function in some diabetic dogs.

Clinical Features

Diagnosis

The diagnosis of diabetes mellitus is based on three findings: appropriate clinical signs, persistent fasting hyperglycemia, and glycosuria. Measurement of the blood glucose concentration using a portable blood glucose–monitoring device and testing for the presence of glycosuria using urine reagent test strips (e.g., KetoDiastix; Ames Division, Miles Laboratories) provides rapid confirmation of diabetes mellitus. Concurrent documentation of ketonuria establishes a diagnosis of diabetic ketosis (DK), and documentation of metabolic acidosis establishes a diagnosis of DKA.

It is important to document both persistent hyperglycemia and glycosuria to establish a diagnosis of diabetes mellitus because hyperglycemia differentiates diabetes mellitus from primary renal glycosuria and glycosuria differentiates diabetes mellitus from other causes of hyperglycemia (see Box 52-1), most notably epinephrine-induced stress hyperglycemia that may develop around the time of blood sampling. Stress-induced hyperglycemia is a common problem in cats and occasionally occurs in dogs, especially those that are very excited, hyperactive, or aggressive. The reader is referred to p. 792 for more information on stress-induced hyperglycemia.

A thorough evaluation of the dog’s overall health is recommended once the diagnosis of diabetes mellitus has been established to identify any disease that may be causing or contributing to the carbohydrate intolerance (e.g., hyperadrenocorticism), that may result from the carbohydrate intolerance (e.g., bacterial cystitis), or that may mandate a modification of therapy (e.g., pancreatitis). The minimum laboratory evaluation should include a CBC, serum biochemistry panel, measurement of serum pancreatic lipase immunoreactivity, and urinalysis with bacterial culture. Serum progesterone concentration should be determined if diabetes mellitus is diagnosed in an intact bitch, regardless of her cycling history. If available, abdominal ultrasound is indicated to assess for pancreatitis, adrenomegaly, pyometritis in an intact bitch, and abnormalities affecting the liver and urinary tract (e.g., changes consistent with pyelonephritis or cystitis). Measurement of baseline serum insulin concentration or an insulin response test is not routinely done. Additional tests may be warranted after obtaining the history, performing the physical examination, or identifying ketoacidosis. Potential clinical pathologic abnormalities are listed in Box 52-4.

Treatment

The primary goal of therapy is elimination of client-observed clinical signs of diabetes. Persistence of clinical signs and development of chronic complications (Box 52-5) are directly correlated with the severity and duration of hyperglycemia. In the diabetic dog establishing control of hyperglycemia can be accomplished with insulin, diet, exercise, prevention or control of concurrent insulin antagonistic diseases, and discontinuation of medications that cause insulin resistance. The veterinarian must also guard against development of hypoglycemia, a serious and potentially fatal complication of therapy. Hypoglycemia is most apt to occur as the result of overzealous insulin therapy. The veterinarian must balance the benefits of tight glucose control obtainable with aggressive insulin therapy against the risk of hypoglycemia.

Techniques for Monitoring Diabetic Control

The basic objective of insulin therapy is to eliminate the clinical signs of diabetes mellitus while avoiding the common complications associated with the disease (see Box 52-5). Common complications in dogs include blindness caused by cataract formation, weight loss, hypoglycemia, recurring ketosis, and recurrence of polyuria and polydipsia. The devastating chronic complications of human diabetes (e.g., nephropathy, vasculopathy, coronary artery disease) require several decades to develop and are uncommon in diabetic dogs. As such, the need to establish nearly normal blood glucose concentrations is not necessary in diabetic dogs. Generally speaking, most clients are happy and most dogs are healthy and relatively asymptomatic if blood glucose concentrations are kept between 100 and 250 mg/dl.

Protocol for Generating the Serial Blood Glucose Curve at Home

Hyperglycemia induced by stress, aggression, or excitement is the single biggest problem affecting accuracy of the serial blood glucose curve, especially in cats (Fig. 52-5). The biggest factors inducing stress-induced hyperglycemia are hospitalization and multiple venipunctures. An alternative to hospital-generated blood glucose curves is to have the client generate the blood glucose curve at home using the ear or lip prick technique and a portable home glucose-monitoring device that allows the client to touch the drop of blood on the ear or lip with the end of the glucose test strip. This technique is usually reserved for diabetic dogs in which the reliability of blood glucose results generated in the veterinary hospital is questionable. The reader is referred to p. 792 for more information on monitoring blood glucose concentrations at home.

FIG 52-5 Blood glucose concentration curves in a fractious Terrier-mix. The same dose of NPH insulin was given for each curve. One glucose curve (blue line) was obtained with the dog in an agitated state requiring physical restraint each time a blood specimen was obtained; blood for the other glucose curve (red line) was obtained through a jugular catheter with minimal-to-no restraint and the dog in a quiet state. ↑, Insulin administration and food.

Interpreting the Serial Blood Glucose Curve

An overview of interpreting results of a serial blood glucose curve is provided in Fig. 52-6. The ideal goal is to maintain the blood glucose concentration between 100 mg/dl and 250 mg/dl throughout the day and night, although many diabetic dogs do well despite blood glucose concentrations consistently in the high 100′s to low 300′s. Typically, the highest blood glucose concentrations occur at the time of each insulin injection, but this does not always occur. If the blood glucose nadir is greater than 150 mg/dl, the insulin dose may need to be increased, and if the nadir is less than 80 mg/dl, the insulin dose should be decreased.

FIG 52-6 Algorithm for interpreting results of a blood glucose concentration curve.

Duration of insulin effect can be assessed if the glucose nadir is greater than 80 mg/dl and there has not been a rapid decrease in the blood glucose concentration after insulin administration. Assessment of duration of insulin effect may not be valid when the blood glucose decreases to less than 80 mg/dl or decreases rapidly because of the potential induction of the Somogyi response, which can falsely decrease the apparent duration of insulin effect (see p. 780). A rough approximation of the duration of effect of insulin can be gained by examining the time of the glucose nadir. For most well-controlled diabetic dogs, the initial blood glucose concentration near the time of insulin administration is less than 300 mg/dl and the glucose nadir occurs 8 to 10 hours after injection of insulin. An initial blood glucose concentration greater than 300 mg/dl, combined with a glucose nadir occurring less than 8 hours after insulin administration and subsequent blood glucose concentrations exceeding 250 mg/dl, is supportive of short duration of insulin effect (see p. 781). A glucose nadir occurring 12 hours or longer after insulin administration is supportive of prolonged duration of insulin effect (see p. 781). Dogs may develop hypoglycemia or the Somogyi response if the duration of insulin effect is greater than 14 hours and the insulin is being administered twice a day (Fig. 52-7).

FIG 52-7 Blood glucose concentration curves obtained from three diabetic dogs treated with recombinant human lente insulin twice a day, illustrating a difference between dogs in the duration of insulin effect. The insulin is effective in lowering the blood glucose concentration in all dogs, and the blood glucose nadir is between 100 and 175 mg/dl for the dogs. However, the duration of insulin effect is approximately 12 hours (solid line) in one dog with good control of glycemia (ideal duration of effect), approximately 8 hours (dotted line) in one dog with persistently poor control of glycemia (short duration of effect), and greater than 12 hours (dashed line) in one dog with a history of good days and bad days of glycemic control (prolonged duration of effect)—a history suggestive of the Somogyi response (see Fig. 52-8).

Role of Serum Fructosamine in Aggressive, Excitable, or Stressed Dogs

Blood glucose curves are unreliable in aggressive, excitable, or stressed dogs because of problems related to stress-induced hyperglycemia. In these dogs the clinician must make an educated guess as to where the problem lies (e.g., wrong type of insulin, low dose), make an adjustment in therapy, and rely on changes in serum fructosamine to assess the benefit of the change in treatment. The reader is referred to p. 792 for more information on the use of serum fructosamine in diabetic pets with stress-induced hyperglycemia.

Hypoglycemia

Hypoglycemia is a common complication of insulin therapy. Signs of hypoglycemia are most apt to occur after sudden large increases in the insulin dose, with excessive overlap of insulin action in dogs receiving insulin twice a day, after prolonged inappetence, during unusually strenuous exercise, following sudden improvement in concurrent insulin resistance, and in insulin-treated cats that have reverted to a non–insulin-dependent state (see p. 785). In these situations severe hypoglycemia may occur before glucose counterregulation (i.e., secretion of glucagon, epinephrine, cortisol, and growth hormone) is able to compensate for and reverse hypoglycemia. The occurrence and severity of clinical signs is dependent on the rate of blood glucose decline and the severity of hypoglycemia. In many diabetic dogs signs of hypoglycemia are not apparent to clients, and hypoglycemia is identified during evaluation of a serial blood glucose curve or suspected when a low serum fructosamine concentration is identified. Clinical signs and treatment of hypoglycemia are discussed on p. 765. If clinical signs of hypoglycemia have occurred, insulin therapy should be stopped until hyperglycemia and glycosuria recur. The adjustment in the insulin dose is somewhat arbitrary; as a general rule of thumb, the insulin dose initially should be decreased 25% to 50% and subsequent adjustments in the dose based on clinical response and results of blood glucose measurements. Failure of glycosuria to recur after a hypoglycemic episode suggests reversion to a non–insulin-dependent diabetic state or impaired glucose counterregulation.

Recurrence of Clinical Signs

Recurrence or persistence of clinical signs is perhaps the most common complication of insulin therapy in diabetic dogs. This is usually caused by problems with client technique in administering insulin; problems with insulin therapy relating to the insulin type, dose, species, or frequency of administration; or problems with responsiveness to insulin caused by concurrent inflammatory, infectious, neoplastic, or hormonal disorders (i.e., insulin resistance).

Insulin overdosing and the Somogyi response.

The Somogyi response results from a normal physiologic response to impending hypoglycemia induced by excessive insulin. When the blood glucose concentration declines to less than 65 mg/dl or when the blood glucose concentration decreases rapidly regardless of the glucose nadir, direct hypoglycemia-induced stimulation of hepatic glycogenolysis and secretion of diabetogenic hormones, most notably epinephrine and glucagon, increase the blood glucose concentration, minimize signs of hypoglycemia, and cause marked hyperglycemia within 12 hours of glucose counterregulation. The marked hyperglycemia that occurs after hypoglycemia is due, in part, to an inability of the diabetic dog to secrete sufficient endogenous insulin to dampen the rising blood glucose concentration. By the next morning the blood glucose concentration can be extremely elevated (greater than 400 mg/dl), and the morning urine glucose concentration is consistently 1 to 2 gm/dl as measured with urine glucose test strips. Unrecognized short duration of insulin effect, combined with insulin dose adjustments based on morning urine glucose concentrations, is historically the most common cause for the Somogyi response in dogs.

Clinical signs of hypoglycemia are typically mild or not recognized by the client; clinical signs caused by hyperglycemia tend to dominate the clinical picture. The insulin dose that induces the Somogyi response is variable and unpredictable. The Somogyi response is often suspected in poorly controlled diabetic dogs in which insulin dosage is approaching 2.2 U/kg body weight/injection but can also occur at insulin dosages less than 0.5 U/kg/injection. Toy and miniature breeds of dogs are especially susceptible to development of the Somogyi response with lower-than-expected doses of insulin.

The diagnosis of the Somogyi response requires demonstration of hypoglycemia (less than 80 mg/dl) followed by hyperglycemia (greater than 300 mg/dl) after insulin administration (Fig. 52-8). The Somogyi response should also be suspected when the blood glucose concentration decreases rapidly regardless of the glucose nadir (e.g., a drop from 400 to 100 mg/dl in 2 to 3 hours). If the duration of insulin effect is greater than 12 hours, hypoglycemia often occurs at night after the evening dose of insulin and the serum glucose concentration is typically greater than 300 mg/dl the next morning. Unfortunately, the diagnosis of the Somogyi response can be elusive, in part because of the effects of the diabetogenic hormones on blood glucose concentrations after an episode of glucose counterregulation. Secretion of diabetogenic hormones during the Somogyi response may induce insulin resistance, which can last 24 to 72 hours after the hypoglycemic episode (Fig. 52-9). If a serial blood glucose curve is obtained on the day glucose counterregulation occurs, hypoglycemia will be identified and the diagnosis established. However, if the serial blood glucose curve is obtained on a day when insulin resistance predominates, hypoglycemia will not be identified and the insulin dose may be incorrectly increased in response to the high blood glucose values. A cyclic history of one or two days of good glycemic control followed by several days of poor control should raise suspicion for insulin resistance caused by glucose counterregulation. Serum fructosamine concentrations are unpredictable but are usually increased (>500 μmol/L)—results that confirm poor glycemic control but do not identify the underlying cause.

FIG 52-8 Blood glucose concentration curves obtained from three poorly controlled diabetic dogs treated with recombinant human lente insulin twice a day, illustrating the typical blood glucose curves suggestive of the Somogyi response. In one dog (solid line) the glucose nadir is less than 80 mg/dl and is followed by a rapid increase in the blood glucose concentration. In one dog (dashed line) a rapid decrease in the blood glucose concentration occurs within 2 hours of insulin administration and is followed by a rapid increase in the blood glucose concentration; the rapid decrease in blood glucose stimulates glucose counterregulation, despite maintaining the blood glucose nadir above 80 mg/dl. In one dog (dotted line) the blood glucose curve is not suggestive of the Somogyi response, per se. However, the insulin injection causes the blood glucose to decrease by approximately 300 mg/dl during the day, and the blood glucose concentration at the time of the evening insulin injection is considerably lower than the 8 AM blood glucose concentration. If a similar decrease in the blood glucose occurs with the evening insulin injection, hypoglycemia and the Somogyi response would occur at night and would explain the high blood glucose concentration in the morning and the poor control of the diabetic state.

FIG 52-9 Schematic of the change in the results of blood glucose curves obtained on sequential days after induction of the Somogyi response to hypoglycemia induced by an overdose of insulin. Hypoglycemia and the Somogyi response occur on day 1. The secretion of diabetogenic hormones in response to the hypoglycemia causes insulin resistance and increased blood glucose concentrations on day 2. Insulin resistance gradually wanes over the ensuing couple of days (days 3 and 4), eventually resulting in hypoglycemia and the Somogyi response (day 5) as sensitivity to insulin returns to normal. The same dose of insulin is administered each day (arrow).

Establishing the diagnosis may require several days of hospitalization and serial blood glucose curves, an approach that eventually leads to problems with stress-induced hyperglycemia. An alternative, preferable approach is to arbitrarily reduce the insulin dose 1 to 5 units and have the client evaluate the dog’s clinical response over the ensuing 2 to 5 days. If clinical signs of diabetes worsen after a reduction in the insulin dose, another cause for the insulin ineffectiveness should be pursued. However, if the client reports no change or improvement in clinical signs, continued gradual reduction of the insulin dose should be pursued. Alternatively, glycemic regulation of the diabetic dog could be started over using an insulin dose of 0.25 U/kg given twice daily.

Short duration of insulin effect.

For most dogs, the duration of effect of lente and NPH insulin is 10 to 14 hours and twice-daily insulin administration is effective in controlling blood glucose concentrations. However, in some diabetic dogs the duration of effect of lente and NPH insulin is less than 10 hours, a duration that is too short to prevent periods of hyperglycemia and persistence of clinical signs (Fig. 52-10). A diagnosis of short duration of insulin effect is made by demonstrating an initial blood glucose concentration greater than 300 mg/dl combined with a glucose nadir above 80 mg/dl that occurs less than 8 hours after insulin administration and recurrence of hyperglycemia (greater than 250 mg/dl) within 10 hours of the insulin injection (see Fig. 52-7). Treatment involves changing to a longer-acting insulin (e.g., switching to insulin glargine; Fig. 52-11) or increasing the frequency of insulin administration (e.g., initiating therapy q8h). PZI insulin of beef/pork source should not be used in dogs because of potential problems with insulin antibodies (discussed later).

FIG 52-10 Mean blood glucose (blue line) and serum insulin (red line) concentrations in eight dogs with diabetes mellitus treated with a beef-pork source NPH insulin subcutaneously once daily. The duration of NPH effect is too short, resulting in prolonged periods of hyperglycemia beginning shortly after the evening meal. ↑, Insulin injection; *, equal-sized meals consumed.

FIG 52-11 Categorization of types of commercial insulin based on the potency and duration of effect. An inverse relationship exists between the potency and duration of effect.

Cataracts

Cataract formation is the most common and one of the most important long-term complications of diabetes mellitus in the dog. A retrospective-cohort study on the development of cataracts in 132 diabetic dogs referred to a university referral hospital found cataract formation in 14% of dogs at the time diabetes was diagnosed and a time interval for 25%, 50%, 75%, and 80% of the study population to develop cataracts at 60, 170, 370, and 470 days, respectively (Beam et al., 1999). The pathogenesis of diabetic cataract formation is thought to be related to altered osmotic relationships in the lens induced by the accumulation of sorbitol and fructose, sugars that are potent hydrophilic agents and cause an influx of water into the lens, leading to swelling and rupture of the lens fibers and the development of cataracts. Cataract formation is an irreversible process once it begins, and it can occur quite rapidly. Diabetic dogs that are poorly controlled and have problems with wide fluctuations in the blood glucose concentration seem especially at risk for rapid development of cataracts. Blindness may be eliminated by removing the abnormal lens. Vision is restored in approximately 75% to 80% of diabetic dogs that undergo cataract removal. Factors that affect the success of surgery include the degree of glycemic control preceding surgery, presence of retinal disease, and presence of lens-induced uveitis. Acquired retinal degeneration affecting vision is more of a concern in older diabetic dogs than is diabetic retinopathy. Fortunately, acquired retinal degeneration is unlikely in an older diabetic dog with vision immediately before cataract formation. If available, electroretinography should be performed before surgery to evaluate retinal function.

Lens-Induced Uveitis

During embryogenesis the lens is formed within its own capsule, and its structural proteins are not exposed to the immune system. Therefore immune tolerance to the crystalline proteins does not develop. During cataract formation and reabsorption lens proteins are exposed to the local immune system, resulting in inflammation and uveitis. Uveitis that occurs in association with a reabsorbing, hypermature cataract may decrease the success of cataract surgery and must be controlled before surgery. The treatment of lens-induced uveitis focuses on decreasing the inflammation and preventing further intraocular damage. Topical ophthalmic corticosteroids are the most commonly used drug for the control of ocular inflammation. However, systemic absorption of topically applied corticosteroids may cause insulin resistance and interfere with glycemic control of the diabetic state, especially in toy and miniature breeds. An alternative is the topical administration of nonsteroidal antiinflammatory agents (e.g., 0.03% flurbiprofen) or cyclosporine.

Diabetic Neuropathy

Although a common complication in the diabetic cat (see p. 795), diabetic neuropathy is infrequently recognized in the diabetic dog. Subclinical neuropathy is probably more common than is severe neuropathy resulting in clinical signs. Clinical signs consistent with diabetic neuropathy are most commonly recognized in dogs that have been diabetic for a long time (i.e., 5 years or longer). Clinical signs and physical examination findings include weakness, knuckling, abnormal gait, muscle atrophy, depressed limb reflexes, and deficits in postural reaction testing. Diabetic neuropathy in the dog is primarily a distal polyneuropathy, characterized by segmental demyelination and remyelination and axonal degeneration and regeneration. There is no specific treatment for diabetic neuropathy besides meticulous metabolic control of the diabetic state.

Diabetic Nephropathy

Although diabetic nephropathy has occasionally been reported in the dog, its clinical recognition appears to be low. Histopathologic findings include membranous glomerulonephropathy, glomerular and tubular basement membrane thickening, an increase in the mesangial matrix material, the presence of subendothelial deposits, glomerular fibrosis, and glomerulosclerosis. The pathogenic mechanism of diabetic nephropathy is unknown. Clinical signs depend on the severity of glomerulosclerosis and the functional ability of the kidney to excrete metabolic wastes. Initially, diabetic nephropathy is manifested as proteinuria, primarily albuminuria. As glomerular changes progress, glomerular filtration becomes progressively impaired, resulting in the development of azotemia and eventually uremia. With severe fibrosis of the glomeruli, oliguric and then anuric renal failure develops. There is no specific treatment for diabetic nephropathy apart from meticulous metabolic control of the diabetic state, conservative medical management of the renal insufficiency, and control of systemic hypertension.

Systemic Hypertension

Diabetes mellitus and hypertension commonly co-exist in dogs. Struble et al. (1998) found the prevalence of hyperten sion to be 46% in 50 insulin-treated diabetic dogs, in which hypertension was defined as systolic, diastolic, or mean blood pressure greater than 160, 100, and 120 mm Hg, respectively. The development of hypertension was associated with the duration of diabetes and an increased albumin : creatinine ratio in the urine. Diastolic and mean blood pressure were higher in dogs with longer duration of disease. A correlation between control of glycemia and blood pressure was not identified. Treatment for hypertension should be initiated if the systolic blood pressure is consistently greater than 160 mm Hg.

Prognosis

The prognosis is dependent on the presence and reversibility of concurrent diseases, ease of regulation of the diabetic state with insulin, and client commitment toward treating the disease. The mean survival time in diabetic dogs is approximately 3 years from the time of diagnosis. This survival time is somewhat skewed because dogs are often 8 to 12 years old at the time of diagnosis and a relatively high mortality rate exists during the initial 6 months because of concurrent life-threatening or uncontrollable disease (e.g., ketoacidosis, acute pancreatitis, renal failure). Diabetic dogs that survive the initial 6 months can easily maintain a good quality of life for longer than 5 years with proper care by the clients, timely evaluations by the veterinarian, and good client-veterinarian communication.

Etiology

Common histologic abnormalities in cats with diabetes mellitus include islet-specific amyloidosis, β-cell vacuolation and degeneration, and chronic pancreatitis. The cause of β-cell degeneration is not known. Other diabetic cats have a reduction in the number of pancreatic islets and/or insulin-containing β cells on immunohistochemical evaluation, suggesting additional mechanisms may be involved in the physiopathology of diabetes mellitus in cats. Although lymphocytic infiltration of islets, in conjunction with islet amyloidosis and vacuolation, has been described in diabetic cats, this histologic finding is very uncommon, and β cell and insulin autoantibodies have not been identified in newly diagnosed diabetic cats. The role of genetics remains to be determined.

Noninsulin-dependent type 2 diabetes may be identified in as many as 50% to 70% of newly diagnosed diabetic cats. Islet amyloidosis and insulin resistance are important factors in the development of noninsulin-dependent type 2 diabetes in cats. Islet-amyloid polypeptide (IAPP), or amylin, is the principal constituent of amyloid in adult cats with diabetes, is stored in β-cell secretory granules, and is co-secreted with insulin by the β cell. Stimulants of insulin secretion also stimulate the secretion of amylin. Chronic increased secretion of insulin and amylin, as occurs with obesity and other insulin-resistant states, results in aggregation and deposition of amylin in the islets as amyloid (Fig. 52-12). IAPP-derived amyloid fibrils are cytotoxic and associated with apoptotic cell death of islet cells. If deposition of amyloid is progressive, as occurs with a sustained demand for insulin secretion in response to persistent insulin resistance, islet cell destruction progresses and eventually leads to diabetes mellitus. The severity of islet amyloidosis and β cell destruction determines, in part, whether the diabetic cat has IDDM or NIDDM. Total destruction of the islets results in IDDM and the need for insulin treatment for the rest of the cat’s life. Partial destruction of the islets may or may not result in clinically evident diabetes, insulin treatment may or may not be required to control glycemia, and diabetes may or may not revert to a noninsulin-requiring state once treatment is initiated. If amyloid deposition is progressive, the cat will progress from subclinical diabetes to NIDDM and ultimately to IDDM. Current research regarding the etiopathogenesis of diabetes in the cat suggests that the difference between IDDM and NIDDM is primarily a difference in severity of loss of β cells and severity and reversibility of concurrent insulin resistance. Cats may have IDDM or NIDDM at the time diabetes is diagnosed, cats with NIDDM may progress to IDDM with time, cats with apparent IDDM may revert to a noninsulin requiring state after initiation of treatment, and cats may flip back and forth between IDDM and NIDDM as severity of insulin resistance and impairment of β cell function waxes and wanes.

FIG 52-12 A, Severe islet amyloidosis (straight arrow) in a cat with initial noninsulin-dependent diabetes mellitus (NIDDM) that progressed to insulin-dependent diabetes mellitus (IDDM). A pancreatic biopsy specimen was obtained while the animal was in the IDDM state. Residual β cells containing insulin (red arrows) are also present. (Immunoperoxidase stain, ×100.) B, Severe vacuolar degeneration of islet cells. Pancreatic tissue was evaluated at necropsy 28 months after diabetes was diagnosed and 20 months after cat progressed from NIDDM to IDDM, requiring insulin to control blood glucose concentrations. The cat died from metastatic exocrine pancreatic adenocarcinoma. (H&E, ×500.) C, Severe chronic pancreatitis with fibrosis in a diabetic cat with IDDM. The cat was euthanized because of persistent problems with lethargy, inappetence, and poorly controlled diabetes mellitus. (H&E, ×100.)

(A from Feldman EC, Nelson RW: Canine and feline endocrinology and reproduction, ed 3, St Louis, 2004, WB Saunders.)

Approximately 20% of diabetic cats become transiently diabetic, usually within 4 to 6 weeks after the diagnosis of diabetes has been established and treatment has been initiated. In these cats hyperglycemia, glycosuria, and clinical signs of diabetes resolve, and insulin treatment can be discontinued. Some diabetic cats may never require insulin treatment once the initial bout of clinical diabetes mellitus has dissipated, whereas others become permanently insulin dependent weeks to months after the resolution of a prior diabetic state. Studies suggest that cats with transient diabetes mellitus are in a subclinical diabetic state that becomes clinical when the pancreas is stressed by exposure to a concurrent insulin-antagonistic drug or disease, most notably glucocorticoids, megestrol acetate, and chronic pancreatitis (Fig. 52-13). Unlike healthy cats, those with transient diabetes mellitus have a reduced population of β cells, dysfunctional β cells, or both, which impairs the ability of the pancreas to compensate for concurrent insulin resistance. An inadequate insulin response results in hyperglycemia. Persistent hyperglycemia can, in turn, cause hypoinsulinemia by suppressing function of remaining β cells and can induce insulin resistance by promoting downregulation of glucose transport systems and causing a defect in posttransport insulin action. This phenomenon is referred to as glucose toxicity. β cells have an impaired response to stimulation by insulin secretagogues, thereby mimicking IDDM. The effects of glucose toxicity are potentially reversible upon correction of the hyperglycemic state. The clinician makes a correct diagnosis of diabetes mellitus, insulin and treatment of insulin-antagonistic disorders improve hyperglycemia and insulin resistance, glucose toxicity and β cell function improve, insulin secretion returns, and an apparent IDDM state resolves. The future requirement for insulin treatment depends on the underlying abnormality in the islets. If the abnormality is progressive (e.g., amyloidosis), eventually enough β cells will be destroyed and IDDM will develop.

FIG 52-13 Sequence of events in the development and resolution of an insulin-requiring diabetic episode in cats with transient diabetes.

(From Feldman EC, Nelson RW: Canine and feline endocrinology and reproduction, ed 3, St Louis, 2004, WB Saunders.)

Clinical Features

Diagnosis

Establishing the diagnosis of diabetes mellitus is similar for cats and dogs and is based on identification of appropriate clinical signs, persistent hyperglycemia, and glycosuria (see p. 769). Transient, stress-induced hyperglycemia is a common problem in cats and can cause the blood glucose concentration to increase above 300 mg/dl. Unfortunately, stress is a subjective state that cannot be accurately measured, is not always easily recognized, and may evoke inconsistent responses among individual cats. Glycosuria usually does not develop in cats with transient stress–induced hyperglycemia but can be present if stress is prolonged (i.e., hours). For this reason, presence of appropriate clinical signs, persistent hyperglycemia, and glycosuria should always be documented when establishing a diagnosis of diabetes mellitus in cats. If the clinician is in doubt, the stressed cat can be sent home with instructions for the client to monitor the urine glucose concentration with the cat in the nonstressed home environment. Alternatively, a serum fructosamine concentration can be measured (see p. 774). Documenting an increase in the serum fructosamine concentration supports the presence of sustained hyperglycemia; however, a serum fructosamine concentration in the upper range of normal can occur in symptomatic diabetic cats if the diabetes developed shortly before presentation of the cat to the veterinarian.

Clinical signs develop when hyperglycemia causes glycosuria and are the same regardless of the functional status of pancreatic islets. Information used to establish the diagnosis of diabetes mellitus does not provide information on the status of pancreatic islet health, presence of glucose toxicity, ability of the cat to secrete insulin, or the severity and reversibility of concurrent insulin resistance. Unfortunately, measurements of baseline serum insulin concentration or serum insulin concentrations after administration of an insulin secretagogue have not been consistent aids in differentiating IDDM and NIDDM in the cat. Identification of a baseline serum insulin concentration greater than 15 μU/ml (reference range, 5 to 20 μU/ml) in a newly diagnosed, untreated diabetic cat supports the presence of functional β cells and partial destruction of the islets; however, low or undetectable serum insulin concentrations do not rule out partial β cell loss because of the suppressive effects of glucose toxicity on circulating insulin concentrations.

A thorough evaluation of the cat’s overall health is recommended once the diagnosis of diabetes mellitus has been established, for reasons discussed on p. 769. The minimal laboratory evaluation in any diabetic cat should include a CBC, serum biochemical panel, serum thyroxine concentration, and urinalysis with bacterial culture. If available, abdominal ultrasound should also be a routine part of the diagnostic evaluation because of the high prevalence of chronic pancreatitis in diabetic cats. Measurement of baseline serum insulin concentration or performance of an insulin secretory response test is not routinely done in cats because of problems encountered with glucose toxicity. Additional tests may be warranted after obtaining the history, performing the physical examination, or identifying ketoacidosis. See Box 52-4 for a list of potential clinical pathologic abnormalities.

Treatment

The significant incidence of NIDDM in cats raises interesting questions regarding the need for insulin treatment. Glycemic control can be maintained in some diabetic cats with dietary changes, oral hypoglycemic drugs, control of current diseases, discontinuation of insulin-antagonistic drugs, or a combination of these. The ultimate differentiation between IDDM and NIDDM is usually made retrospectively, after the clinician has had several weeks to assess the response of the cat to therapy and to determine the cat’s need for insulin. The initial treatment strategy is based on the severity of clinical signs and physical abnormalities, presence or absence of ketoacidosis, general health of the cat, and client wishes. For most newly diagnosed diabetic cats, treatment includes insulin, adjustments in diet, and correction or control of concurrent insulin resistance.

Sulfonylureas

Sulfonylurea drugs (e.g., glipizide, glyburide) are the most commonly used oral hypoglycemic drugs for the treatment of diabetes mellitus in cats. Sulfonylureas stimulate insulin secretion by pancreatic β cells. Some endogenous pancreatic insulin secretory capacity must exist for sulfonylureas to be effective. Clinical response to glipizide and glyburide treatment in diabetic cats has been variable, ranging from excellent (i.e., blood glucose concentrations decreasing to less than 200 mg/dl) to partial response (i.e., clinical improvement but failure to resolve hyperglycemia) to no response. Presumably, the population of functioning β cells varies from none (severe IDDM) to near normal (mild NIDDM) in treated cats, resulting in a response range from none to excellent. Cats with a partial response to glipizide have some functioning β cells but not enough to decrease the blood glucose concentration to less than 200 mg/dl. These cats may have severe NIDDM or the early stages of IDDM. Glipizide treatment has been found effective in improving clinical signs and severity of hyperglycemia in approximately 20% of diabetic cats.

No consistent parameters have been identified that allow the clinician to prospectively determine which cats will respond to glipizide or glyburide therapy. Identifying a high preprandial serum insulin concentration or an increase in serum insulin concentration during an insulin secretagogue test supports the diagnosis of NIDDM, but failure to identify these changes does not rule out the potential for a beneficial response to glipizide or glyburide. Selection of diabetic cats for treatment with glipizide must rely heavily on the veterinarian’s assessment of the cat’s health, severity of clinical signs, presence or absence of ketoacidosis, other diabetic complications (e.g., peripheral neuropathy), and the client’s desires.

Glipizide (Glucotrol, Pfizer; 2.5 mg/cat administered q12h) and glyburide (Micronase, Pharmacia and Upjohn Company; 0.625 mg/cat q12h) are initially administered in conjunction with a meal to diabetic cats that are nonketotic and relatively healthy on physical examination (Fig. 52-15). Each cat is examined weekly during the first month of therapy. A history, complete physical examination, body weight, urine glucose/ ketone measurement, and blood glucose concentration are evaluated at each examination. If adverse reactions (Table 52-4) have not occurred after 2 weeks of treatment, the glipizide and glyburide dose is increased to 5.0 mg and 1.25 mg, respectively, q12h. Therapy is continued as long as the cat is stable. If euglycemia or hypoglycemia develops, the dose may be tapered down or discontinued and blood glucose concentrations reevaluated 1 week later to assess the need for the drug. If hyperglycemia recurs, the dose is increased or the sulfonylurea is reinitiated, with a reduction in dose in those cats previously developing hypoglycemia. Sulfonylurea treatment is discontinued and insulin therapy initiated if clinical signs continue to worsen, the cat becomes ill or develops ketoacidosis or peripheral neuropathy, blood glucose concentrations remain greater than 300 mg/dl after 1 to 2 months of therapy, or the client becomes dissatisfied with the treatment. In some cats sulfonylureas become ineffective weeks to months later, and exogenous insulin is ultimately required to control the diabetic state. Presumably, the progression to IDDM coincides with progressive loss of β cells, a loss that may be exacerbated by sulfonylurea treatment. Regardless, the primary value of sulfonylureas is an alternative palatable option (pills versus injections) for clients initially unwilling to consider insulin injections and contemplating euthanasia of their cat. During the ensuing weeks many of these clients become willing to try insulin injections if sulfonylurea therapy fails.

FIG 52-15 Algorithm for treating diabetic cats with the oral sulfonylurea drug, glipizide.

(From Feldman EC, Nelson RW: Canine and feline endocrinology and reproduction, ed 3, St Louis, 2004, WB Saunders.)

TABLE 52-4 Adverse Reactions to Glipizide Treatment in Diabetic Cats

Acarbose

Although the α-glucosidase inhibitor acarbose has been effective in improving glycemic control in diabetic dogs and cats, the drug is not commonly used because of cost and adverse effects. Diarrhea and weight loss as a result of carbohydrate malassimilation occur in approximately 35% of treated dogs. Feeding carbohydrate-restricted diets is recommended in lieu of acarbose treatment in diabetic cats.

Techniques for Monitoring Diabetic Control

The techniques for monitoring diabetic control are discussed on p. 774. One important factor that affects monitoring of diabetic cats is the propensity to develop stress-induced hyperglycemia caused by frequent visits to the veterinary hospital for blood samplings. Once stress-induced hyperglycemia develops, it is a perpetual problem and blood glucose measurements can no longer be considered accurate. Veterinarians must remain wary of stress hyperglycemia in diabetic cats and should take steps to prevent its development. Micromanaging diabetic cats is not recommended, and serial blood glucose curves should be done only when the clinician perceives a need to change insulin therapy. The determination of good versus poor control of glycemia should be based on the client’s subjective opinion of the presence and severity of clinical signs and the overall health of the pet, ability of the cat to jump, grooming behavior, findings on physical examination, and stability of body weight. Generation of a serial blood glucose curve should be reserved for newly diagnosed and poorly controlled diabetic cats.

Protocol for Generating the Serial Blood Glucose Curve at Home

An alternative to hospital-generated blood glucose curves is to have the client generate the blood glucose curve at home using the marginal ear vein prick technique in cats (the ear or lip prick technique in dogs) and a portable home blood glucose monitoring device that allows the client to touch the drop of blood on the ear with the end of the glucose test strip (Fig. 52-16). The marginal ear vein prick technique decreases the need for physical restraint during sample collection, thereby minimizing the cat’s discomfort and stress. Accuracy of blood glucose results are similar when blood for glucose determination is obtained by ear prick and venipuncture. However, blood glucose results obtained by portable blood glucose monitoring devices may overestimate or, more commonly, underestimate the actual blood glucose values obtained with reference methods. This inherent error must be considered when interpreting blood glucose results obtained by a portable home blood glucose monitoring device. Several Web sites explain in detail the marginal ear vein prick technique in layman’s terms and provide information on client experiences with the technique and with different portable home blood glucose meters. After diagnosing diabetes, the clinician should recommend a particular Web site and find out whether the client would be interested in monitoring blood glucose concentrations at home. The clinician should allow for ample time to teach the technique to clients who are willing to give it a try and provide advice regarding the proper way to perform a blood glucose curve (ideally, no more frequently than 1 day every 4 weeks) and how often to measure the blood glucose concentration on the day of the curve (typically, at the time of insulin administration and 3, 6, 9, and 12 hours later). Use of the ear prick technique in cats has produced excellent results. Stress is often significantly reduced, and accuracy of the blood glucose measurements improved. Problems with the marginal ear vein prick technique include overzealous clients who start monitoring blood glucose concentrations too frequently, insulin overdosing and the Somogyi response caused by clients who interpret blood glucose results and adjust the insulin dose independent of input from the veterinarian, difficulty obtaining blood from the ear vein, and cats who do not tolerate manipulation and pricking of the ear.

FIG 52-16 Ear prick technique for measuring blood glucose concentration. A, A hot washcloth is applied to the pinna for 2 to 3 minutes to increase circulation to the ear. B, A spot is identified on the periphery of the outer side of the pinna, a small coating of petrolatum jelly is applied, and the spot is pricked with the lancet device supplied with the portable blood glucose meter. Gauze should be placed between the pinna and the digit holding the pinna to prevent pricking the finger if the blade of the lancet accidentally passes through the pinna. Petrolatum jelly is applied to help the blood form into a ball on the pinna as it seeps from the site that is lanced. C, Digital pressure is applied in the area of the lanced skin to promote bleeding. The glucose test strip is touched to the drop of capillary blood that forms and is removed once enough blood has been drawn into the test strip to activate the meter.

Role of Serum Fructosamine in Stressed Diabetic Cats

The use of serum fructosamine concentrations for assessing control of glycemia is discussed on p. 777. Serum fructosamine concentrations are not affected by acute transient increases in blood glucose concentration. Unlike blood glucose measurements, evaluation of serum fructosamine concentration in fractious or stressed diabetic cats provides reliable objective information on the status of glycemic control during the previous 2 to 3 weeks. In fractious or stressed cats the clinician must make an educated guess as to where the problem lies (e.g., wrong type of insulin, low insulin dose), make an adjustment in therapy, and rely on changes in serum fructosamine to assess the benefit of the change in treatment. Serum fructosamine concentrations can be measured before and 2 to 3 weeks after changing insulin therapy to assess the effectiveness of the change. If changes in insulin therapy are appropriate, a decrease in serum fructosamine concentration should occur. If the serum fructosamine concentration is the same or has increased, the change was ineffective in improving glycemic control, another change in therapy based on an educated guess should be done, and the serum fructosamine measured again 2 to 3 weeks later.

Stress Hyperglycemia

Transient hyperglycemia is a well-recognized problem in fractious, scared, or otherwise stressed cats. Hyperglycemia develops as a result of increased catecholamines and, in struggling cats, lactate concentrations. Blood glucose concentrations typically exceed 200 mg/dl in affected cats, and values in excess of 300 mg/dl are common. Stress hyperglycemia can significantly increase blood glucose concentrations in diabetic cats despite the administration of insulin, an effect that seriously compromises the clinician’s ability to accurately judge the effectiveness of the insulin injection. Frequent hospitalizations and venipunctures for monitoring blood glucose concentrations are the most common cause of stress hyperglycemia. Blood glucose concentrations can remain greater than 400 mg/dl throughout the day despite administration of insulin. Failure to recognize the effect of stress on blood glucose results may lead to the erroneous perception that the diabetic cat is poorly controlled. Insulin therapy is invariably adjusted, often by increasing the insulin dose, and another blood glucose curve recommended 1 to 2 weeks later. A vicious cycle ensues, which eventually culminates in the Somogyi response, clinically apparent hypoglycemia, or referral for evaluation of insulin resistance.

Failure to identify the presence of stress hyperglycemia and its impact on the interpretation of blood glucose measurements is one of the most important reasons that the status of glycemic control in diabetic cats is misinterpreted. Stress hyperglycemia should be suspected if the cat is visibly upset or aggressive or struggles during restraint and the venipuncture process. However, stress hyperglycemia can also be present in diabetic cats that are easily removed from the cage and do not resist the blood-sampling procedure. These cats are scared, but rather than become aggressive, they remain crouched in the back of the cage, often have dilated pupils, and usually are flaccid when handled. Stress hyperglycemia should also be suspected if a disparity exists between assessment of glycemic control based on results of the history, physical examination, and stability of body weight; assessment of glycemic control based on results of blood glucose measurements; or when the initial blood glucose concentration measured in the morning is in an acceptable range (i.e., 150 to 250 mg/dl) but subsequent blood glucose concentrations increase steadily throughout the day (Fig. 52-17). Once stress hyperglycemia develops, it is a perpetual problem and blood glucose measurements can no longer be considered accurate. If stress hyperglycemia is suspected, reliance on home monitoring of blood glucose or evaluation of sequential serum fructosamine concentrations (see p. 792) should be done, in addition to the history and physical examination findings.

FIG 52-17 Blood glucose concentration curves in a 5.3-kg male cat receiving 2 U of recombinant human ultralente insulin (pink line) 2 weeks after the initiation of insulin therapy, 2 U of recombinant human ultralente insulin (blue line) 2 months later, and 6 U of recombinant human ultralente insulin (red line) 4 months later. The insulin dose had been gradually increased on the basis of the blood glucose concentration curves. The client reported minimal clinical signs regardless of the insulin dose; at the 4-month recheck the cat had maintained its body weight and results of the physical exanination were normal. The cat became progressively more fractious during each hospitalization, supporting the existence of stress-induced hyperglycemia as the reason for the discrepancy between the blood glucose values and other parameters used to evaluate glycemic control. ↑, Subcutaneous insulin injection and food.

(From Feldman EC, Nelson RW: Canine and feline endocrinology and reproduction, ed 3, St Louis, 2004, WB Saunders.)

Hypoglycemia

Hypoglycemia, a common complication of insulin therapy, is discussed on p. 779. In diabetic cats symptomatic hypoglycemia is most apt to occur after sudden large increases in the insulin dose, after sudden improvement in concurrent insulin resistance, with excessive duration of insulin action in cats receiving insulin twice a day, after prolonged inappetence, and in insulin-treated cats that have reverted to a non–insulin-dependent state. In these situations severe hypoglycemia may occur before glucose counterregulation (i.e., secretion of glucagon, cortisol, epinephrine, growth hormone) is able to compensate for and reverse low blood glucose concentrations. The initial treatment approach for hypoglycemia is to discontinue insulin until hyperglycemia recurs and then reduce the ensuing insulin dose 25% to 50%. If hypoglycemia remains a reoccurring problem despite reductions in the insulin dose, excessive duration of insulin effect (see p. 781) or reversion to a noninsulin-dependent diabetic state should be considered. Reversion to a non–insulin-dependent diabetic state should be suspected if hypoglycemia remains a persistent problem despite administration of small doses of insulin (i.e., 1 U or less per injection) and administration of insulin once a day, if blood glucose concentrations are consistently below 150 mg/dl before insulin administration, if serum fructosamine concentration is less than 350 μmol/L, or if urine glucose test strips are consistently negative. Insulin therapy should be discontinued and periodic urine glucose testing should be performed in the home environment to identify recurrence of glycosuria.

Insulin Overdosing and the Somogyi Response

Insulin overdosing and the Somogyi response is discussed on p. 780. A similar phenomenon, characterized by wide fluctuations in blood glucose concentration after which there are several days of persistent hyperglycemia, is recognized clinically in diabetic cats. However, the exact role of the counterregulatory hormones remains to be clarified. Insulin overdose that induces the Somogyi response is one of the most common causes of poor glycemic control in diabetic cats. It can be induced with insulin doses of 1 to 2 U per injection and can result in cats receiving 10 to 15 U of insulin per injection as veterinarians react to the persistence of clinical signs and increased blood glucose and serum fructosamine concentrations. A cyclic history of 1 or 2 days of good glycemic control after which there are several days of poor control should raise suspicion for insulin overdosing and the Somogyi response. Arbitrarily decreasing the insulin dose and evaluating the clinical response over the ensuing 2 to 5 days is perhaps the best way to establish the diagnosis.

Insulin Underdosing

Insulin underdosing is discussed on p. 780. Control of glycemia can be established in most diabetic cats using 1 U or less of insulin/kg of body weight administered twice each day. In general, insulin underdosing should be considered if the insulin dose is less than 1 U/kg/injection and the cat is receiving insulin twice a day. If insulin underdosing is suspected, the dose of insulin should be gradually increased by 0.5 to 1 U/injection per week. The effectiveness of the change in therapy should be evaluated by client perception of clinical response and measurement of serum fructosamine or serial blood glucose concentrations. Other causes for poor glycemic control should be ruled out before an increase in the insulin dose above 1 U/kg/injection is considered.

Short Duration of Insulin Effect

Short duration of insulin effect is discussed on p. 781. Short duration of insulin effect is a common problem in diabetic cats despite twice-daily insulin administration. Short duration of effect is most common with NPH and lente insulin (see Table 52-2). A diagnosis of short duration of insulin effect is made by demonstrating an initial blood glucose concentration greater than 300 mg/dl combined with a glucose nadir above 80 mg/dl that occurs less than 8 hours after insulin administration and recurrence of hyperglycemia (greater than 250 mg/dl) within 10 hours of the insulin injection (see Fig. 52-7). Treatment involves changing to a longer-acting insulin preparation (i.e., PZI or glargine insulin).

Prolonged Duration of Insulin Effect

Prolonged duration of insulin effect is discussed on p. 781. In diabetic cats problems with prolonged duration of insulin effect are most common with twice-daily administration of PZI and glargine insulin.

Inadequate Insulin Absorption

Slow or inadequate absorption of subcutaneously deposited insulin was most commonly observed in diabetic cats receiving ultralente insulin, a long-acting basal insulin that had a slow onset and prolonged duration of effect. In affected cats the blood glucose concentration would decrease minimally, if at all, despite insulin doses of 8 to 12 U/cat. Ultralente insulin is no longer commercially available. A similar problem has not been reported for PZI or glargine insulin. Impaired and erratic absorption of insulin may occur as a result of thickening of the skin and inflammation of the subcutaneous tissues caused by chronic injection of insulin in the same area of the body. Rotation of the injection site helps prevent this problem.

Circulating Insulin-Binding Antibodies

Insulin-binding antibodies are discussed on p. 782. Feline and beef insulin are similar, and feline, human, and porcine insulin differ. Fortunately, insulin antibody formation is not common in diabetic cats treated with exogenous human insulin, despite differences between human and feline insulin. Studies identified an approximately equal frequency of positive serum insulin antibody titers in diabetic cats treated with beef insulin and recombinant human insulin. In my experience, antiinsulin antibody titers are weakly positive in most cats that develop insulin antibodies, prevalence of persistent titers is low, and presence of serum insulin antibodies do not appear to affect control of glycemia. Insulin resistance caused by insulin antibody formation appears to be uncommon. Switching from recombinant human or porcine source insulin to beef-/pork-source PZI may improve control of glycemia if insulin antibodies are the suspected cause for insulin ineffectiveness.

Concurrent Disorders Causing Insulin Resistance

Concurrent disorders causing insulin resistance is discussed on p. 783. The most common concurrent disorders interfering with insulin effectiveness in cats include severe obesity, chronic inflammation such as chronic pancreatitis and gingivitis, renal insufficiency, hyperthyroidism, acromegaly, and hyperadrenocorticism (see Box 52-7). Obtaining a complete history and performing a thorough physical examination are the most important steps in identifying these concurrent disorders. If the history and physical examination are unremarkable, a CBC, serum biochemical analysis, serum thyroxine concentration, urinalysis with bacterial culture, and (if available) abdominal ultrasound should be obtained to further screen for concurrent illness. Additional tests will depend on the results of the initial screening tests (see Box 52-8).

Diabetic Neuropathy

Diabetic neuropathy is one of the most common chronic complications of diabetes in cats, with a prevalence of approximately 10%. Clinical signs of a co-existent neuropathy in the diabetic cat include weakness, impaired ability to jump, knuckling, a plantigrade posture with the cat’s hocks touching the ground when it walks (see Fig. 52-14), muscle atrophy, depressed limb reflexes, and deficits in postural reaction testing. Clinical signs may progress to include the thoracic limbs (palmigrade posture; see Fig 52-14). Abnormalities on electrophysiologic testing are consistent with demyelination at all levels of the motor and sensory peripheral nerves and include decreased motor and sensory nerve conduction velocities in pelvic and thoracic limbs and decreased muscle action potential amplitudes. Electromyographic abnormalities are usually absent and, when identified, are consistent with denervation. The most striking abnormality detected on histologic examination of nerve biopsies from affected cats is Schwann cell injury; axonal degeneration is identified in severely affected cats. The cause of diabetic neuropathy is not known. Currently, there is no specific therapy. Aggressive glucoregulation with insulin may improve nerve conduction and reverse the posterior weakness and plantigrade posture (see Fig. 52-14). However, the response to therapy is variable, and the risks of hypoglycemia increase with aggressive insulin treatment. Generally, the longer the neuropathy has been present and the more severe the neuropathy, the less likely it is that improving glycemic control will reverse the clinical signs of neuropathy.

Prognosis

Diabetic cats and dogs have a similar prognosis (see p. 785). The mean survival time in diabetic cats is approximately 3 years from time of diagnosis. However, this survival time is skewed because cats are usually 8 to 12 years old at the time of diagnosis, and a high mortality rate exists during the first 6 months because of concurrent life-threatening or uncontrollable disease (e.g., ketoacidosis, pancreatitis, renal failure). Diabetic cats that survive the first 6 months can easily live longer than 5 years with the disease.

Etiology

The etiopathogenesis of DKA is complex and usually affected by concurrent clinical disorders. Virtually all dogs and cats with DKA have a relative or absolute deficiency of insulin. DKA develops in some diabetic dogs and cats even though they receive daily injections of insulin, and their circulating insulin concentrations may even be increased. The “relative” insulin deficiency in these animals is created by concurrent insulin resistance, which in turn is created by concurrent disorders such as pancreatitis, infection, or renal insufficiency. Increased circulating concentrations of diabetogenic hormones, most notably glucagon, accentuate insulin deficiency by promoting insulin resistance; stimulate lipolysis, leading to ketogenesis; and stimulate hepatic gluconeogenesis, which worsens hyperglycemia.

Insulin deficiency and insulin resistance, together with increased circulating concentrations of diabetogenic hormones, play a critical role in the stimulation of ketogenesis. For the synthesis of ketone bodies (i.e., acetoacetic acid, β-hydroxybutyric acid, acetone) to be enhanced, there must be two major alterations in intermediary metabolism: (1) enhanced mobilization of free fatty acids (FFAs) from triglycerides stored in adipose tissue and (2) a shift in hepatic metabolism from fat synthesis to fat oxidation and ketogenesis. Insulin is a powerful inhibitor of lipolysis and FFA oxidation. A relative or absolute deficiency of insulin allows lipolysis to increase, thus increasing the availability of FFAs to the liver and in turn promoting ketogenesis. As ketones continue to accumulate in the blood, the body’s buffering system becomes overwhelmed and metabolic acidosis develops. As ketones accumulate in the extracellular space, the amount eventually surpasses the renal tubular threshold for complete resorption and they spill into the urine, contributing to the osmotic diuresis caused by glycosuria and enhancing the excretion of solutes (e.g., sodium, potassium, magnesium). Insulin deficiency per se also contributes to the excessive renal losses of water and electrolytes. The result is an excessive loss of electrolytes and water, leading to volume contraction, an underperfusion of tissues, and the development of prerenal azotemia. The rise in the blood glucose concentration raises plasma osmolality, and the resulting osmotic diuresis further aggravates the rise in plasma osmolality by causing water losses in excess of salt loss. The increase in plasma osmolality causes water to shift out of cells, leading to cellular dehydration. The metabolic consequences of DKA, which include severe acidosis, hyperosmolality, obligatory osmotic diuresis, dehydration, and electrolyte derangements, eventually become life threatening.

Clinical Features

DKA is a serious complication of diabetes mellitus that occurs most commonly in dogs and cats with diabetes that has gone undiagnosed. Less commonly, DKA develops in an insulin-treated diabetic dog or cat that is receiving an inadequate dose of insulin, often occurring in conjunction with an infectious, inflammatory, or insulin-resistant hormonal disorder. Because of the close association between DKA and newly diagnosed diabetes mellitus, the signalment of DKA in dogs and cats is similar to that of nonketotic diabetics.

The history and physical examination findings are variable, in part because of the progressive nature of the disorder and the variable time between the onset of DKA and client recognition of a problem. Polyuria, polydipsia, polyphagia, and weight loss develop initially but are either unnoticed or considered insignificant by the client. Systemic signs of illness (e.g., lethargy, anorexia, vomiting) ensue as ketonemia and metabolic acidosis develop and worsen, with the severity of these signs directly related to the severity of the metabolic acidosis and the nature of concurrent disorders that are often present. The time interval from the onset of the initial clinical signs of diabetes to the development of systemic signs of DKA is unpredictable and ranges from a few days to longer than 6 months. Once ketoacidosis begins to develop, however, severe illness usually becomes evident within 7 days.

Common physical examination findings include dehydration, lethargy, weakness, tachypnea, vomiting, and sometimes a strong odor of acetone on the breath. Slow, deep breathing may be observed in animals with severe metabolic acidosis. Gastrointestinal tract signs such as vomiting and abdominal pain are common in animals with DKA, in part because of the common concurrent occurrence of pancreatitis. Other intraabdominal disorders should also be con sidered and diagnostic tests (e.g., abdominal ultrasound) performed to help identify the cause of the gastrointestinal signs.

Diagnosis

The diagnosis of diabetes mellitus is based on appropriate clinical signs, persistent fasting hyperglycemia, and glycosuria. Documenting ketonuria with reagent test strips that measure acetoacetic acid (KetoDiastix; Ames Division, Miles Laboratories) establishes the diagnosis of diabetic ketosis (DK), and documenting metabolic acidosis establishes the diagnosis of DKA. If ketonuria is not present but DKA is suspected, serum or urine can be tested for acetone using Acetest tablets (Ames Division, Miles Laboratories), serum can be tested for the presence of β-hydroxybutyrate using a benchtop chemistry analyzer, and plasma from heparinized hematocrit tubes can be used to test for the presence of acetoacetic acid using urine reagent strips used to document ketonuria. β-hydroxybutyrate and acetone are derived from acetoacetic acid, and commonly used urine reagent strips do not detect β-hydroxybutyrate and acetone. However, it is extremely uncommon for DKA to develop without an excess of acetoacetic acid.

Treatment of “Healthy” Dogs or Cats with Diabetic Ketosis or Diabetic Ketoacidosis

If systemic signs of illness are absent or mild, serious abnormalities are not readily identifiable on physical examination, and metabolic acidosis is mild (i.e., total venous CO₂ or arterial bicarbonate concentration greater than 16 mEq/L), short-acting regular crystalline insulin can be administered subcutaneously three times daily until the ketonuria resolves. Fluid therapy and intensive care are usually not needed. The insulin dose should be adjusted on the basis of blood glucose concentrations. To minimize hypoglycemia, the dog or cat should be fed one third of its daily caloric intake at the time of each insulin injection. The blood glucose and urine ketone concentrations, as well as the animal’s clinical status, should be monitored. A decrease in the blood glucose concentration implies a decrease in ketone production. This, in combination with metabolism of ketones and loss of ketones in urine, will usually correct ketosis within 48 to 96 hours of initiating insulin therapy. Prolonged ketonuria is suggestive of a significant concurrent illness or inadequate blood insulin concentrations to suppress lipolysis and ketogenesis. Once the ketosis has resolved and the dog or cat is stable, eating, and drinking, insulin therapy may be initiated using longer-acting insulin preparations (see pp. 765 and 788).

Treatment of Sick Dogs or Cats with Diabetic Ketoacidosis

Aggressive therapy is called for if the dog or cat has systemic signs of illness (e.g., lethargy, anorexia, vomiting); physical examination reveals dehydration, depression, weakness, or a combination of these; or metabolic acidosis is severe (i.e., total venous CO₂ or arterial bicarbonate concentration less than 12 mEq/L). The five goals of treatment of a severely ill ketoacidotic, diabetic pet are (1) to provide adequate amounts of insulin to suppress lipolysis, ketogenesis, and hepatic gluconeogenesis; (2) to restore water and electrolyte losses; (3) to correct acidosis; (4) to identify the factors precipitating the present illness; and (5) to provide a carbohydrate substrate (i.e., dextrose) when necessary to allow continued administration of insulin without causing hypoglycemia (Box 52-9). Proper therapy does not mean forcing a return to a normal state as rapidly as possible. Because osmotic and biochemical problems can arise as a result of overly aggressive therapy as well as from the disease itself, rapid changes in various vital parameters can be as harmful as, or more harmful than, no change. If all abnormal parameters can be slowly returned toward normal over a period of 24 to 48 hours, therapy is more likely to be successful.

Critically important information for formulating the initial treatment protocol include hematocrit and total plasma protein concentration; serum glucose, albumin, creatinine, and urea nitrogen concentrations; serum electrolytes; venous total CO₂ or arterial acid-base evaluation; and urine specific gravity. Abnormalities frequently associated with DKA are listed in Box 52-10. Once treatment for DKA is initiated, additional studies, such as a CBC, serum biochemistry panel, urinalysis, thoracic radiographs, and abdominal ultrasound, or diagnostic tests for pancreatitis, diestrus in the female dog, hyperthyroidism, and hyperadrenocorticism are usually warranted to identify underlying concurrent disorders (see Box 52-8).

Potassium Supplementation

Most dogs and cats with DKA initially have either normal or decreased serum potassium concentrations. During therapy for DKA the serum potassium concentration decreases because of rehydration (dilution), insulin-mediated cellular uptake of potassium (with glucose), continued urinary losses, and correction of acidemia (translocation of potassium into the intracellular fluid compartment; Fig. 52-18). Severe hypokalemia is the most common complication that devel ops during the initial 24 to 36 hours of treatment of DKA. Dogs and cats with hypokalemia require aggressive potassium replacement therapy to replace deficits and to prevent worsening, life-threatening hypokalemia after initiation of insulin therapy. The exception to potassium supplementation of fluids is hyperkalemia associated with oliguric renal failure. Potassium supplementation should initially be withheld in these dogs and cats until glomerular filtration is restored, urine production increases, and hyperkalemia is resolving.

FIG 52-18 Redistribution of extracellular fluid (ECF) and intracellular fluid (ICF) hydrogen, potassium, and phosphate ions in response to a decrease in ECF pH (i.e., acidosis), an increase in ECF glucose and osmolality, and the translocation of water from the ICF to the ECF compartment and subsequent correction of acidosis and the intracellular shift of glucose and electrolytes with insulin treatment. A, Normal ECF pH. B, ECF H⁺ concentration increases during acidosis, causing H⁺ to move into cells and down its concentration gradient. Increase in ECF glucose and osmolality causes extracellular shift of water, K⁺, and PO₄⁺². C, ECF H⁺ concentration decreases during correction of acidosis, causing H⁺ to move out of cells. Insulin administration and correction of acidemia cause an intracellular shift of glucose, K⁺ and PO₄⁺², decreasing ECF K⁺ and PO₄⁺² concentration.

(Feldman EC, Nelson RW: Canine and feline endocrinology and reproduction, ed 3, St Louis, 2004, WB Saunders.)

Ideally, the amount of potassium required should be based on actual measurement of the serum potassium concentration. If an accurate measurement of serum potassium is not available, 40 mEq of potassium should initially be added to each liter of intravenous fluids. Normal saline solution does not contain potassium, and Ringer’s solution contains 4 mEq of potassium per liter; thus these fluids should be supplemented with 40 mEq and 36 mEq of potassium, respectively. Subsequent adjustments in potassium supplementation should be based on measurement of serum potassium, preferably every 6 to 8 hours until the dog or cat is stable and serum electrolytes are in the normal range.

Phosphate Supplementation

Most dogs and cats with DKA have either normal or decreased serum phosphorus concentrations on pretreatment testing. Within 24 hours of initiating treatment for DKA, serum phosphorus concentration can decline to severe levels (i.e., <1 mg/dl) as a result of the dilutional effects of fluid therapy, the intracellular shift of phosphorus following the initiation of insulin therapy, and continuing renal and gastrointestinal loss (see Fig. 52-18). Hypophosphatemia affects primarily the hematologic and neuromuscular systems in dogs and cats. Hemolytic anemia is the most common problem and can be life threatening if not recognized and treated. Weakness, ataxia, and seizures may also be observed. Severe hypophosphatemia may be clinically silent in many animals.

Phosphate therapy is indicated if clinical signs or hemolysis are identified or if the serum phosphorus concentration decreases to less than 1.5 mg/dl. Phosphate is supplemented by IV infusion. Potassium and sodium phosphate solutions contain 3 mmol of phosphate and either 4.4 mEq of potassium or 4 mEq of sodium per milliliter. The recommended dosage for phosphate supplementation is 0.01 to 0.03 mmol of phosphate per kilogram of body weight per hour, preferably administered in calcium-free IV fluids (e.g., 0.9% sodium chloride). In dogs and cats with severe hypophosphatemia it may be necessary to increase the dosage to 0.03 to 0.12 mmol/kg/hour. Because the dose of phosphate necessary to replete an animal and the animal’s response to therapy cannot be predicted, it is important to initially monitor the serum phosphorus concentration every 8 to 12 hours and adjust the phosphate infusion accordingly. Adverse effects from overzealous phosphate administration include iatrogenic hypocalcemia and its associated neuromuscular signs, hypernatremia, hypotension, and metastatic calcification. Serum total or (preferably) ionized calcium concentration should be measured at the same time as serum phosphorus concentration and the rate of phosphate infusion decreased if hypocalcemia is identified. Phosphorus supplementation is not indicated in dogs and cats with hypercalcemia, hyperphosphatemia, oliguria, or suspected tissue necrosis. If renal function is in question, phosphorus supplementation should not be done until the status of renal function and serum phosphorus concentration are known.

Magnesium Supplementation

Plasma total and ionized magnesium concentrations may be within or below the reference range at the time DKA is diagnosed in the dog or cat, often decrease during the initial treatment of DKA, and typically normalize without treatment as the DKA resolves. Clinical signs of hypomagnesemia do not usually occur until the serum total and ionized magnesium concentration is less than 1.0 and 0.5 mg/dl, respectively, and even at these low levels many dogs and cats remain asymptomatic. I do not routinely treat hypomagnesemia in dogs or cats with DKA unless problems with persistent lethargy, anorexia, weakness, or refractory hypokalemia or hypocalcemia are encountered after 24 to 48 hours of fluid and insulin therapy and another cause for the problem cannot be identified (see p. 780).

Bicarbonate Therapy

The clinical presentation of the dog or cat, in conjunction with the plasma bicarbonate or total venous CO₂ concentration, should be used to determine the need for bicarbonate therapy. Bicarbonate supplementation is not recommended when plasma bicarbonate (or total venous CO₂) is 12 mEq/L or greater, especially if the animal is alert. An alert dog or cat probably has a normal or near-normal pH in the cerebrospinal fluid (CSF). The acidosis in these animals is corrected through insulin and fluid therapy. Improvement in renal perfusion enhances urinary loss of ketoacids, and insulin therapy markedly diminishes the production of ketoacids. Acetoacetate and β-hydroxybutyrate are also metabolically usable anions, and 1 mEq of bicarbonate is generated from each 1 mEq of ketoacid metabolized.

When the plasma bicarbonate concentration is 11 mEq/L or less (total venous CO₂ is below 12), bicarbonate therapy should be initiated. Many of these animals have severe depression that may be a result of concurrent severe central nervous system acidosis. Metabolic acidosis should be corrected slowly, thereby avoiding major alterations in the pH of the CSF. Only a portion of the bicarbonate deficit is given initially over a 6-hour period. The bicarbonate deficit (i.e., the milliequivalents of bicarbonate initially needed to correct acidosis to the critical level of 12 mEq/L over a period of 6 hours) is calculated by the following formula:

If the serum bicarbonate concentration is not known, the following formula should be used:

The difference between the animal’s serum bicarbonate concentration and the critical value of 12 mEq/L represents the treatable base deficit in DKA. If the animal’s serum bicarbonate concentration is not known, the number 10 should be used for the treatable base deficit. The factor 0.4 corrects for the ECF space in which bicarbonate is distributed (40% of body weight). The factor 0.5 provides one half of the required dose of bicarbonate in the IV infusion. This technique allows a conservative dose to be given over a 6-hour period. Bicarbonate should never be given by bolus infusion. After 6 hours of therapy the acid-base status should be reevaluated and a new dose calculated. Once the plasma bicarbonate level is greater than 12 mEq/L, further bicarbonate supplementation is not indicated.

Intermittent Intramuscular Regimen

Dogs and cats with severe DKA should receive an initial regular crystalline insulin loading dose of 0.2 U/kg followed by 0.1 U/kg every hour thereafter. The insulin dose can be reduced by 25% to 50% for the first 2 to 3 injections if hypokalemia is a concern. The insulin should be administered into the muscles of the rear legs to ensure that the injections are penetrating muscle rather than fat or subcutaneous tissue. Diluting regular insulin 1 : 10 with sterile saline and using 0.3 ml U100 insulin syringes are helpful when small doses of insulin are required. The blood glucose concentration should be measured every hour using a point-of-care chemistry analyzer or portable blood glucose monitoring device and the insulin dosage adjusted accordingly. The goal of initial insulin therapy is to slowly lower the blood glucose concentration to the range of 200 to 250 mg/dl, preferably over a 6- to 10-hour period. An hourly decline of 50 mg/dl in the blood glucose concentration is ideal. This provides a steady moderate decline, with no major shifts in osmolality. A declining blood glucose concentration also ensures that lipolysis and the supply of FFAs for ketone production have been effectively turned off. Glucose concentrations, however, decrease much more rapidly than do ketone levels. In general, hyperglycemia is corrected within 12 hours, but ketosis may take 48 to 72 hours to resolve.

Once the initial hourly insulin therapy brings the blood glucose concentration near 250 mg/dl, hourly administration of regular insulin should be discontinued and regular insulin given every 4 to 6 hours intramuscularly or, if hydration status is good, every 6 to 8 hours subcutaneously. The initial dose is usually 0.1 to 0.3 U/kg, with subsequent adjustments based on blood glucose concentrations. In addition, at this point the IV infusion solution should have enough 50% dextrose added to create a 5% dextrose solution (100 ml of 50% dextrose added to each liter of fluids). The blood glucose concentration should be maintained between 150 and 300 mg/dl until the animal is stable and eating. Usually, a 5% dextrose solution is adequate in maintaining the desired blood glucose concentration. If the blood glucose concentration dips below 150 mg/dl or rises above 300 mg/dl, the insulin dose can be lowered or raised accordingly. Dextrose helps minimize problems with hypoglycemia and allows insulin to be administered on schedule. Delaying the administration of insulin delays correction of the ketoacidotic state.

Constant Low-Dose Insulin Infusion Technique

Constant IV infusion of regular crystalline insulin is also effective in decreasing blood glucose concentrations. To prepare the infusion, regular crystalline insulin (2.2 U/kg for dogs; 1.1 U/kg for cats) is added to 250 ml of 0.9% saline and initially administered at a rate of 10 ml/hour in a line separate from that used for fluid therapy. This provides an insulin infusion of 0.05 (cat) and 0.1 (dog) U/kg/hour, an infusion rate that has been shown to produce plasma insulin concentrations between 100 and 200 μU/ml in dogs. Because insulin adheres to glass and plastic surfaces, approximately 50 ml of the insulin-containing fluid should be run through the drip set before it is administered to the animal. The rate of insulin infusion can be reduced for the initial 2 to 3 hours if hypokalemia is a concern. Two separate catheters are recommended for treatment: a peripheral catheter for insulin administration and a central catheter for fluid administration and blood sampling. An infusion or syringe pump should be used to ensure a constant rate of insulin infusion.

Adjustments in the infusion rate are based on hourly measurements of blood glucose concentration; an hourly decline of 50 mg/dl in the blood glucose concentration is ideal. Once the blood glucose concentration approaches 250 mg/dl, the insulin infusion can be discontinued and regular insulin given every 4 to 6 hours intramuscularly or every 6 to 8 hours subcutaneously, as discussed for the hourly intramuscular protocol. Alternatively, the insulin infusion can be continued (at a decreased rate to prevent hypoglycemia) until the insulin preparation is exchanged for a longer-acting product. Dextrose should be added to the IV fluids once the blood glucose concentration approaches 250 mg/dl, as discussed in the section on hourly intramuscular insulin technique.

Intermittent Intramuscular/ Subcutaneous Technique

The intermittent intramuscular followed by intermittent subcutaneous insulin technique is less labor intensive than the other techniques for insulin administration, but the decrease in blood glucose can be rapid and the risk of hypoglycemia is greater. The initial regular crystalline insulin dose is 0.25 U/kg, administered intramuscularly. Subsequent intramuscular injections are repeated every 4 hours. Usually, insulin is administered intramuscularly only once or twice. Once the animal is rehydrated, the insulin is administered subcutaneously rather than intramuscularly every 6 to 8 hours. Subcutaneous administration is not recommended initially because of problems with insulin absorption from subcutaneous sites of deposition in a dehydrated dog or cat. The dosage of intramuscular or subcutaneous insulin is adjusted according to blood glucose concentrations, which initially should be measured hourly beginning with the first intramuscular injection. An hourly decline of 50 mg/dl in the blood glucose concentration is ideal. Subsequent insulin dosages should be decreased by 25% to 50% if this goal is exceeded. Dextrose should be added to the IV fluids once the blood glucose concentration approaches 250 mg/dl, as discussed in the section on hourly intramuscular insulin technique.

Initiating Longer-Acting Insulin

Longer-acting insulin (e.g., NPH, lente, PZI) should not be administered until the dog or cat is stable; eating; maintaining fluid balance without any IV infusions; and no longer acidotic, azotemic, or electrolyte-deficient. The initial dose of the longer-acting insulin is similar to the regular insulin dose being used just before switching to the longer-acting insulin. Subsequent adjustments in the longer-acting insulin dose should be based on clinical response and measurement of blood glucose concentrations, as described on p. 775.

Prognosis

DKA remains one of the most difficult metabolic therapeutic challenges in veterinary medicine. Despite all precautions and diligent therapy, a fatal outcome is sometimes inevitable. Approximately 30% of cats and dogs with severe DKA die or are euthanized during the initial hospitalization. Death is usually the result of a severe underlying illness (e.g., oliguric renal failure, necrotizing pancreatitis), severe metabolic acidosis (i.e., arterial blood pH less than 7), or complications that develop during therapy (e.g., cerebral edema, hypokalemia). Nevertheless, if logical therapy is implemented and animals are monitored carefully, a positive outcome is attainable.

Etiology

Functional tumors arising from the β cells of the pancreatic islets are malignant tumors that secrete insulin independent of the typically suppressive effects of hypoglycemia. β cell tumors, however, are not completely autonomous and respond to provocative stimuli such as an increase in blood glucose by secreting insulin, often in excessive amounts. Immunohistochemical analysis of β cell tumors has revealed a high incidence of multihormonal production, including pancreatic polypeptide, somatostatin, glucagon, serotonin, and gastrin. However, insulin has been identified as the most common product demonstrated within the neoplastic cells, and clinical signs are primarily those that result from insulin-induced hypoglycemia.

Insulin-secreting β cell tumors are uncommon in dogs and rare in cats. Virtually all β cell tumors in dogs are malignant, and most dogs have microscopic or grossly visible metastatic lesions at the time of surgery. The most common metastatic sites are the regional lymphatics and lymph nodes, liver, and peripancreatic mesentery. Pulmonary metastasis is uncommon and occurs late in the disease. In most dogs hypoglycemia recurs weeks to months after surgical excision of the tumor. The high prevalence of metastatic lesions at the time afflicted dogs are initially examined results, in part, from the typically protracted time it takes for clinical signs to develop and the interval between the time a client initially observes signs and seeks assistance from a veterinarian. Most dogs are symptomatic for 1 to 6 months before being brought to a veterinarian.

Clinical Features

Peripheral Neuropathy

Peripheral neuropathies have been observed in dogs with β cell tumors and may cause paraparesis to tetraparesis; facial paresis to paralysis; hyporeflexia to areflexia; hypotonia; and muscle atrophy of the appendicular, masticatory, and/or facial muscles. Sensory nerves may also be affected. Onset of clinical signs may be acute (i.e., days) or insidious (i.e., weeks to months). The pathogenesis of the polyneuropathy is not known. Proposed theories include metabolic derangements of the nerves induced by chronic and severe hypoglycemia or some other tumor-induced metabolic deficiency, an immune-mediated paraneoplastic syndrome resulting from shared antigens between tumor and nerves, or toxic factors produced by the tumor that deleteriously affect the nerves. Treatment is aimed at surgical removal of the β cell tumor. Prednisone therapy (initially 1 mg/kg q24h) may also improve clinical signs.

Diagnosis

The diagnosis of a β cell tumor requires initial confirmation of hypoglycemia, followed by documentation of inappropriate insulin secretion and identification of a pancreatic mass using ultrasonography or laparotomy. Considering the potential differential diagnoses for hypoglycemia (see Box 52-2), a tentative diagnosis of a β cell tumor can often be made on the basis of the history, physical examination findings, and an absence of abnormalities other than hypoglycemia shown by routine blood tests. Abdominal ultrasonography can be used to identify a mass in the region of the pancreas and to look for evidence of potential metastatic disease in the liver and surrounding structures (Fig. 52-19). Because of the small size of most β cell tumors, abdominal ultrasonographic findings are often interpreted as normal, although a pancreatic mass or metastatic lesion can be found at surgery. A normal abdominal ultrasonographic finding does not rule out the diagnosis of a β cell tumor. Although computed tomographic imaging was better than ultrasonography or somatostatin receptor scintigraphy at identifying primary tumors, false-positive identification of metastatic sites was unacceptably high in one study (Robben et al., 2005). Thoracic radiographs are of minimal value in documenting metastatic disease, primarily because identifiable metastatic nodules in the lung occur late in the disease.

FIG 52-19 Ultrasonogram of the pancreas showing an islet β-cell tumor (arrow) (A) and an enlarged hepatic lymph node (arrows) (B) resulting from metastasis of the β-cell tumor to the liver in a 9-year-old Cocker Spaniel.

The diagnosis of a β cell tumor is established by evaluating the serum insulin concentration at a time when hypoglycemia is present. Hypoglycemia suppresses insulin secretion in normal animals, with the degree of suppression directly related to its severity. Hypoglycemia fails to have this same suppressive effect on insulin secretion if the insulin is synthesized and secreted from autonomous neoplastic cells because tumor cells that produce and secrete insulin are less responsive to hypoglycemia than are normal β cells. Invariably, the dog with a β cell tumor will have an inappropriate excess of insulin relative to that needed for a particular blood glucose concentration. Confidence in identifying an inappropriate excess of insulin depends on the severity of the hypoglycemia; the lower the blood glucose concentration, the more confident the clinician can be in identifying inappropriate hyperinsulinemia, especially when the serum insulin concentration falls in the normal range. If the blood glucose concentration is low and the insulin concentration is in the upper half of the normal range or increased, the animal has a relative or absolute excess of insulin that can best be explained by the presence of an insulin-secreting β cell tumor.

Most dogs with β cell neoplasia are persistently hypoglycemic. If the blood glucose concentration is less than 60 mg/dl (preferably less than 50 mg/dl), serum should be submitted to a commercial veterinary endocrine laboratory for determination of glucose and insulin concentrations. If the blood glucose concentration is greater than 60 mg/dl, fasting may be necessary to induce hypoglycemia. Blood glucose concentrations should be evaluated hourly during the fast and blood obtained for glucose and insulin determination when the blood glucose concentration decreases to less than 50 mg/dl. It is important to remember that blood glucose results obtained from portable home blood glucose– monitoring devices are often lower than results obtained using benchtop methodologies. A blood sample for submission to a commercial laboratory for glucose and insulin determinations should not be obtained until the blood glucose measured on these devices is less than 40 mg/dl. Once hypoglycemia has been induced, the dog can be fed several small meals over the next 1 to 3 hours to prevent a marked increase in the blood glucose concentration and a potential postprandial reactive hypoglycemia.

Serum insulin concentrations must be evaluated simultaneously in relation to the blood glucose concentration. The serum insulin and glucose concentrations in the healthy fasted dog are usually between 5 and 20 μU/ml and 70 and 110 mg/dl, respectively. Fnding a serum insulin concentration greater than 20 μU/ml in a dog with a corresponding blood glucose concentration less than 60 mg/dl (preferably less than 50 mg/dl) in combination with appropriate clinical signs and clinicopathologic findings strongly supports the diagnosis of a β cell tumor. A β cell tumor is also possible if the serum insulin concentration is in the high-normal range (10 to 20 μU/ml). Insulin values in the low-normal range (5 to 10 μU/ml) may be found in animals with other causes of hypoglycemia as well as a β cell tumor. Carefully reviewing the history, physical examination findings, and diagnostic tests results and, if necessary, repeating serum glucose and insulin measurements when hypoglycemia is more severe will usually identify the cause of the hypoglycemia. Any serum insulin concentration that is below the normal range (typically less than 5 μU/ml) is consistent with insulinopenia and does not indicate the presence of a β cell tumor. Similar guidelines are used for cats with a suspected β cell tumor.

Treatment

Frequent Feedings

Frequent feedings provide a constant source of calories as a substrate for the excess insulin secreted by β cell tumors. Diets that are high in fat, complex carbohydrates, and fiber will delay gastric emptying and slow intestinal glucose absorption, helping to minimize the postprandial increase in the portal blood glucose concentration and the stimulation of insulin secretion by the tumor. Simple sugars are rapidly absorbed, have a potent stimulatory effect on insulin secretion by neoplastic β cells, and should be avoided. A combination of canned and dry dog food, fed in three to six small meals daily, is recommended. Daily caloric intake should be controlled because hyperinsulinemia promotes obesity. Exercise should be limited to short walks on a leash.

Glucocorticoid Therapy

Glucocorticoid therapy should be initiated when dietary manipulations are no longer effective in preventing clinical signs of hypoglycemia. Glucocorticoids antagonize the effects of insulin at the cellular level, stimulate hepatic glycogenolysis, and indirectly provide the necessary substrates for hepatic gluconeogenesis. Prednisone is most often used at an initial dose of 0.25 mg/kg q12h. Adjustments in the dose are based on clinical response. The dose of prednisone required to control clinical signs increases with time in response to growth of the tumor and its metastatic sites. Eventually, the adverse effects of prednisone, specifically polyuria and poly dipsia, become unacceptable to clients. When this occurs, the dose of prednisone should be reduced but not stopped and additional therapy considered.

Diazoxide Therapy

Diazoxide (Proglycem; Baker Norton Pharmaceuticals) is a benzothiadiazide diuretic that inhibits insulin secretion, stimulates hepatic gluconeogenesis and glycogenolysis, and inhibits tissue use of glucose. The net effect is hyperglycemia. Unfortunately, diazoxide is difficult to procure and is expensive. The initial dose is 5 mg/kg q12h. The dose is adjusted according to clinical response but should not exceed 60 mg/kg/day. The most common adverse reactions to diazoxide are anorexia and vomiting. Administering the drug with a meal or decreasing the dose, at least temporarily, is usually effective in controlling adverse gastrointestinal signs.

Somatostatin Therapy

Octreotide (Sandostatin; Novartis Pharmaceuticals) is an analog of somatostatin that inhibits the synthesis and secretion of insulin by normal and neoplastic β cells. The responsiveness of β cell tumors to the suppressive effects of octreotide depends on the presence of membrane receptors for somatostatin on the tumor cells. Octreotide at a dose of 10 to 40 μg/dog, administered subcutaneously two to three times a day, has alleviated hypoglycemia in approximately 40% to 50% of treated dogs. Adverse reactions have not been seen at these doses. Octreotide is not a viable option for most clients because of cost.

Streptozotocin Therapy

Streptozotocin is a naturally occurring nitrosourea that selectively destroys pancreatic β cells. The treatment protocol for β cell tumors in dogs involves a 0.9% saline diuresis for 7 hours with streptozotocin (500 mg/m²) administered over a 2-hour period beginning 3 hours after initiating the diuresis. Antiemetics are administered immediately after streptozotocin administration to minimize vomiting. Streptozotocin treatment is repeated every 3 weeks. The effectiveness of streptozotocin in improving hypoglycemia, controlling clinical signs, and prolonging survival time has been variable. Adverse reactions of streptozotocin treatment include vomiting, pancreatitis, diabetes mellitus, and renal failure. Renal failure is less likely when the drug is administered during fluid diuresis as described previously. (See Moore et al. [2002] in Suggested Readings for more information on the use of streptozotocin in treating β cell neoplasia in dogs.)

Prognosis

The long-term prognosis for β cell neoplasia is guarded to poor. Survival time is dependent, in part, on the willingness of the client to treat the disease. Tobin et al. (1999) reported a median survival time after diagnosis of only 74 days (range 8 to 508 days) in dogs treated medically, compared with 381 days (range 20 to 1758 days) in dogs that initially underwent surgery at a tertiary care center. The short survival time for dogs treated medically was because many clients opted for euthanasia when seizures recurred or signs of iatrogenic hyperadrenocorticism developed. The extent to which surgery can alter the prognosis depends on the clinical stage of the disease, most notably the extent of metastatic lesions. Approximately 10% to 15% of dogs undergoing surgery for a β cell tumor die or are euthanized at the time of or within 1 month of surgery because of metastatic disease causing postoperative hypoglycemia that is refractory to medical management or because of complications related to pancreatitis. An additional 20% to 25% of dogs die or are euthanized within 6 months of surgery because of recurrence of clinical hypoglycemia that is refractory to medical management. The remaining 60% to 70% live beyond 6 months postoperatively, many beyond 1 year after surgery, before uncontrollable hypoglycemia develops, resulting in death or necessitating euthanasia. Additional surgery to debulk metastatic lesions may improve the animal’s responsiveness to medical therapy and prolong the survival time in some dogs that become nonresponsive to medical treatment after the initial surgery.

Clinical Features

The most consistent clinical signs are chronic vomiting, weight loss, anorexia, and diarrhea in an older animal (Box 52-13). Gastric and duodenal ulcers and esophagitis are common and may cause hematemesis, hematochezia, melena, and regurgitation. Acidification of intestinal contents may inactivate pancreatic digestive enzymes, precipitate bile salts, interfere with formation of chylomicrons, and damage intestinal mucosal cells. Diarrhea with malabsorption and steatorrhea may develop as a consequence. Findings on physical examination include lethargy, fever, dehydration, abdominal pain, and shock if blood loss is severe or ulcers have perforated. Potential abnormalities identified on a CBC include a regenerative anemia, hypoproteinemia, and neutrophilic leukocytosis. Abnormalities in the serum biochemistry panel include hypoproteinemia, hypoalbuminemia, hypocalcemia, and mild increases in serum alanine aminotransferase and alkaline phosphatase activities. Hyponatremia, hypochloremia, hypokalemia, and metabolic alkalosis may develop in dogs and cats that vomit frequently. Hyperglycemia and hypoglycemia have been noted in a few cases. The urinalysis is usually unremarkable.

Abdominal radiographs are usually normal. If an ulcer has perforated through the serosal surface, radiographic signs consistent with peritonitis may be present. Contrast-enhanced radiographic studies may show gastric or duodenal ulcers; thickening of the gastric rugal folds, pyloric antrum, or intestine; and the rapid intestinal transit of barium. In an animal with concurrent severe esophagitis, secondary megaesophagus or aberrant, nonperistaltic esophageal motility may be identified fluoroscopically. Ultrasonographic evaluation of the abdomen may identify a pancreatic mass or its metastasis. However, gastrinomas vary tremendously in size and may not be detected with ultrasound.

Gastroduodenoscopy may reveal severe esophagitis and ulceration, especially near the cardia. Gastric rugal folds may be thickened. Gastric and duodenal hyperemia, erosions, or ulcerations are often visible. Histologic evaluation of esophageal, gastric, and duodenal biopsy specimens may be normal or may reveal variable degrees of inflammation consisting of infiltrates of lymphocytes, plasma cells and neutrophils, gastric mucosal hypertrophy, fibrosis, and loss of the mucosal barrier.

Diagnosis

Gastrinoma should be included among the differential diagnoses for any dog or cat with melena or hematemesis or in which severe gastric and duodenal ulceration is identified. Unless a pancreatic mass is identified by ultrasonography, most dogs and cats with gastrinoma will inadvertently be diagnosed with severe inflammatory bowel disease, gastroduodenal erosions, and ulcers, and they will be treated with inhibitors of gastric acid secretion, mucosal protectants, antibiotics, and changes in diet. The probability of a gastrinoma increases if ultrasonography reveals a pancreatic mass, the dog or cat does not respond to medical therapy directed at nonspecific inflammation and ulceration of the gastrointestinal tract, or clinical signs and gastrointestinal tract ulceration recur after antiulcer therapy is discontinued. A definitive diagnosis of gastrinoma requires histologic and immunocytochemical evaluation of a pancreatic mass excised at surgery. Finding increased baseline serum gastrin concentrations from blood obtained after an overnight fast increases the suspicion of gastrinoma. Additional differential diagnoses for increased serum gastrin concentration include gastric outflow tract obstruction, renal failure, short-bowel syndrome, chronic gastritis, hepatic disease, and animals receiving antacid therapy (e.g., H₂-receptor antagonists, proton pump inhibitors). Baseline serum gastrin concentrations may vary, with occasional values in the reference range in animals with gastrinoma. Provocative testing (e.g., secretin stimulation test, calcium challenge test) may be considered in dogs strongly suspected of having gastrinoma but with normal baseline serum gastrin concentrations. Exploratory laparotomy should also be considered. (See Suggested Readings for more information on provocative testing).

Treatment

Treatment should be directed at surgical excision of the tumor and control of gastric acid hypersecretion. Gastrointestinal tract ulceration can usually be managed by reducing gastric hyperacidity through the administration of H₂-receptor antagonists (e.g., ranitidine, famotidine), proton pump inhibitors (e.g., omeprazole), gastrointestinal tract protectants (e.g., sucralfate), or prostaglandin E₁ analogs (e.g., misoprostol). (See Chapter 30 for more information on these gastrointestinal tract drugs.) Surgical resection of an ulcer may be required, especially if the ulcer has perforated the bowel. Surgical resection of the tumor is necessary to obtain a cure, although metastasis to the liver, regional lymph nodes, and mesentery is common. Even if metastatic disease is present, tumor debulking may enhance the success of medical therapy.

Prognosis

The long-term prognosis for gastrinoma is guarded to poor. Evidence of metastasis was present in 76% of reported dogs and cats at the time a gastrinoma was diagnosed. Reported survival time in dogs and cats treated surgically, medically, or both ranged from 1 week to 18 months (mean, 4.8 months). However, the short-term prognosis has improved with the advent of drugs that can reduce gastric hyperacidity (e.g., ranitidine, famotidine) and protect and promote healing of the ulcers (e.g., sucralfate, misoprostol).