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Diabetes Mellitus in Animals
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Diabetes Mellitus in Animals: Diagnosis and Treatment of Diabetes Mellitus in Dogs and Cats Deborah S. Greco Nestle Purina PetCare, St. Louis, MO, United States
O U T L I N E Clinical Pathology of Diabetes Mellitus in Animals511 Treatment of Diabetes Mellitus in Cats and Dogs 512
Introduction507 Diabetes in Dogs and Cats 508 Etiology: Feline Diabetes Mellitus 508 Pathogenesis of Clinical Signs: IDDM 509 Pathogenesis of Clinical Signs: NIDDM 509 Clinical Signs of Nonketotic Diabetes Mellitus510 Physical Examination Findings 510 Ketoacidotic, Hyperosmolar, or Complicated Diabetes Mellitus: Pathophysiology and Clinical Signs 510
INTRODUCTION The field of companion animal diabetology is in its infancy but new discoveries are being made every day. The overlap between human and companion animal medicine and research grows larger with each new discovery. This Nutritional and Therapeutic Interventions for Diabetes and Metabolic Syndrome https://doi.org/10.1016/B978-0-12-812019-4.00037-4
The Role of Diet Oral Hypoglycemic Therapy
512 512
Insulin Therapy 513 Treatment of Diabetic Ketoacidosis in Animals514 Monitoring Diabetic Animals 515 References516
chapter covers the diagnosis and treatment of diabetes mellitus (DM) in companion animals, such as the dog and cat. Dogs develop insulindependent diabetes mellitus (IDDM) and most dogs require insulin therapy; however, cats develop type 2 diabetes and can be managed with diet alone or diet combined with insulin or
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© 2018 Elsevier Inc. All rights reserved.
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oral hypoglycemic therapy. The etiology, clinical signs, clinical pathology, and diagnostic tests for diabetes in dogs and cats will be covered along with treatment modalities such as diet, oral hypoglycemics, and insulin. Finally, a discussion of monitoring options for small animal diabetics is included.
DIABETES IN DOGS AND CATS IDDM is a diabetic state in which endogenous insulin secretion is never sufficient to prevent ketone production. Dogs may suffer from type 1 diabetes, which is thought to have an autoimmune basis and genetic basis; however, reclassification of the types of DM would suggest that exocrine pancreatic diseases, such as pancreatitis, may cause type 3c diabetes in dogs as well.1 Dogs suffering from DM range in age from 4 to 14 years with a peak incidence at 7–9 years.1 In dogs, females are twice as likely to develop diabetes than are males. A genetic basis for DM is suspected in the Samoyed, Australian terrier, Keeshond, and Cairn terriers.1 Other commonly affected breeds include poodles, dachshunds, miniature schnauzers, beagles, puliks, and miniature pinschers; however, a genetic susceptibility has not been identified in these breeds.1
Etiology: Feline Diabetes Mellitus DM is a commonly occurring feline endocrinopathy and type 2 diabetes is most commonly identified. Diabetes can also develop as a result of acromegaly in the cat. Neutered males are 1.5 times more likely than females to develop DM. Risk factors for the development of DM in cats include increased body weight (>6.8 kg), older age (>10 years), and neutering.1,2 Historically, feline diabetics were suspected to be insulinopenic; however, research indicates that most cats develop diabetes similar to type 2 DM in humans.3,4 Obesity and amyloidosis
are involved in the pathogenesis of type 2 DM in cats. It is now recognized that the classic metabolic abnormalities found in type 2 DM, decreased insulin secretion and peripheral insulin resistance, are both consequences of abnormal amyloid production by pancreatic beta cells. In 1986, a previously unidentified protein called islet amyloid polypeptide (IAPP or amylin) was identified as the main component of amyloid deposits in a human insulinoma. This novel protein was also found to be the main component of islet amyloid isolated from pancreatic islets in cats with type 2 DM.3 Another major distinguishing feature of type 2 diabetes is peripheral insulin resistance. Obesity plays a significant role in the insulin resistance seen in feline diabetics. The resistance is due to internalization of the insulin receptors in membranes of muscle and fat cells. Obesity also decreases receptor affinity for the insulin molecule. Both the amount and distribution of adipose tissue play a role in insulin resistance and other obesity-related disorders.4 Obese cats have low insulin-sensitive glucose transporter 4 (GLUT-4) expression in both muscle and adipose tissue; however, the expression of GLUT-1 is the same in lean versus obese cats.5 The GLUT in pancreatic beta cells is actually GLUT-2 and a decreased expression of these receptors causes a loss of the first phase of insulin secretion but normal second phase of insulin secretion similar to what is seen in later stages of obesity in the cat. Insulin secretion is affected early on in the course of type 2 DM, particularly, glucosemediated insulin secretion. Insulin resistance in beta cells may lead to a decrease in insulin secretion. In some forms of diabetes in humans, a mutation of the glucokinase enzyme may lead to impaired insulin secretion. The feline liver exhibits normal hexokinase activity but glucokinase activity is virtually absent.6 Glucokinase converts glucose to glycogen for storage in the liver and is important in “mopping” up excess postprandial glucose. Normal cats are in fact similar to human beings with type 2 DM whose
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glucokinase levels drop precipitously with persistent hyperglycemia. To summarize the current hypothesis of the pathogenesis of type 2 DM, peripheral insulin resistance (due to obesity, elevated plasma IAPP, or both) causes chronic stimulation of insulin production in the pancreatic beta cells.3–7 Amylin is cosynthesized with insulin; therefore impaired insulin secretion causes insulin and IAPP to accumulate in the beta cells.3 The high local concentration of IAPP causes polymerization of IAPP to form insular amyloid. Deposition of insular amyloid further impairs glucorecognition and diffusion of nutritive substances into the beta cells. Eventually, insular amyloidosis leads to necrosis of the beta cells and release of amyloid into the extracellular space.3,4
Pathogenesis of Clinical Signs: IDDM Hyperglycemia, caused by insulin deficiency, results primarily from impaired glucose utilization; however, increased hepatic gluconeogenesis and glycogenolysis by the liver contributes to hyperglycemia. Decreased peripheral utilization of glucose leads to accumulation of glucose in the serum; as the renal threshold for glucose is exceeded, osmotic diuresis ensues. Progressive dehydration results in the classic clinical signs of diabetes such as polyuria with compensatory polydipsia. Impaired glucose utilization by the hypothalamic satiety center combined with loss of calories in the form of glycosuria causes polyphagia and weight loss, respectively. Insulin is anabolic; therefore insulin deficiency leads to protein catabolism and contributes to the clinical signs of weight loss and muscle atrophy. With insulin deficiency, the hormone-sensitive lipase system, which is normally suppressed by insulin, becomes activated. As a consequence of this increased lipase activity, adipose tissue is broken down at an accelerated rate into nonesterified fatty acids. The unrestrained lipolytic activity of hormone-sensitive lipase results in
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the clinical signs of weight loss in a previously obese or overweight animal.
Pathogenesis of Clinical Signs: NIDDM In cats with type 2 DM, the initial abnormality is insulin resistance. Cats, like human beings with type 2 diabetes, may show very few or no signs of “classic” diabetes until progressive amyloid deposition and glucose toxicity impair insulin secretion to the point that hyperglycemia exceeds the renal threshold (about 15 mmol/L in cats, which is higher than in dogs). At this point, the DM has become insulin dependent, at least temporarily. Lowering of blood glucose via exogenous insulin or oral hypoglycemic agents may be sufficient to reverse glucose toxicity and result in resolution of the clinical signs of polydipsia and polyuria. However, it should be emphasized that cats with resolved IDDM still have the underlying pathophysiology of type 2 DM, i.e., insulin resistance and impaired insulin secretory capacity. Clinical signs of type 2 DM are subtle and progressive over a period of months to years. In the author’s experience, obesity combined with fasting or postprandial hyperglycemia may be the only clinical “sign” of early type 2 DM. Prior to the onset of polydipsia and polyuria, a constellation of gastrointestinal abnormalities and signs of diabetic neuropathy may also be observed. In diabetic cats, the first signs of DM may be periodic vomiting, anorexia, and less frequently diarrhea. These gastrointestinal signs may originate as a result of autonomic diabetic neuropathy or possibly as a result of concurrent pancreatitis, cholangiohepatitis, or inflammatory bowel disease. Another observation, in the author’s experience, is that owners of diabetic cats will report gait abnormalities, weakness, and problems with jumping prior to the onset of polydipsia and polyuria. There is often a history of administration of diabetogenic medications, such as glucocorticoids or progestins, in cats presenting for type 2 DM.
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Clinical Signs of Nonketotic Diabetes Mellitus Most diabetic dogs and cats present with the classic clinical signs of polyuria and polydipsia. Polydipsia was the most common clinical sign of DM in dogs (93%).2 Polyuria, on the other hand, was observed in only 77% of dogs. In cats, polydipsia (77%) and polyuria (72%) occur with equal frequency.2 Dramatic and rapid weight loss in an animal with a good or even ravenous appetite will often alert the owner to seek veterinary advice. Weight loss is observed more commonly in dogs (62%) compared with cats (44%).2 Only 12% of cats and 19% of dogs exhibited polyphagia as a clinical sign of DM.2 In dogs, progressive polyuria, polydipsia, and weight loss develop relatively rapidly, usually over a period of several weeks. Another common presenting complaint of DM in dogs is acute onset of blindness caused by bilateral cataract formation. Cats will present with chronic complications of diabetes, such as gait abnormalities (13%) resulting from diabetic neuropathy, or with chronic gastrointestinal signs such as vomiting, diarrhea, and anorexia.2 There is often a history of inappropriate elimination or house soiling as a result of muscle weakness caused by neuropathy (inability to climb stairs or get into or out of the litter pan) and polyuria.
Physical Examination Findings Physical examination findings of nonketotic DM in cats and dogs are typically nonspecific. The most common physical examination findings in cats are lethargy and depression (70%), dehydration (63%), unkempt haircoat (35%), and muscle wasting (47%).2 Cats may present with “frosty paws” or accumulation of cat litter on the hind legs and paws as a result of diabetic neuropathy and sticky urine caused by glucosuria. Cats often have concurrent gastrointestinal disease such as pancreatitis, inflammatory bowel disease, and cholangiohepatitis.8
Plantigrade rear limb stance resulting from diabetic neuropathy has been observed in approximately 8% of diabetic cats in previous studies. However, recent evidence suggests that diabetic cats can have a variety of clinical signs suggestive of diabetic neuropathy, including pain on palpation of distal extremities, hypersensitivity, gait abnormalities, and palmagrade stance. Based on electromyography, nerve biopsy, and nerve conduction studies, all diabetic cats have some degree of diabetic neuropathy at the time of presentation.9 In dogs, the most common physical examination findings are dehydration (48%) and muscle wasting or thin body condition (44%). About 35% of cats and 20% of dogs are obese upon initial examination; obese diabetic animals are more likely to suffer from noninsulin-dependent diabetes mellitus (NIDDM). Hepatomegaly is observed in both diabetic cats (30%) and dogs (17%). Cataracts are observed in approximately 40% of diabetic dogs.
Ketoacidotic, Hyperosmolar, or Complicated Diabetes Mellitus: Pathophysiology and Clinical Signs Lipid metabolism in the liver becomes deranged with insulin deficiency and nonesterified fatty acids are converted to acetyl-CoA rather than being incorporated into triglycerides. Acetyl-CoA accumulates in the liver and is converted into acetoacetyl-CoA and then ultimately to acetoacetic acid. Finally, the liver starts to generate large amounts of ketones, including acetoacetic acid, beta-hydroxybutyrate, and acetone. As insulin deficiency culminates in diabetic ketoacidosis (DKA), accumulation of ketones and lactic acid in the blood and loss of electrolytes and water in the urine result in profound dehydration, hypovolemia, metabolic acidosis, and shock. Ketonuria and osmotic diuresis caused by glycosuria result in urinary sodium and potassium loss, which exacerbates hypovolemia and dehydration. Nausea, anorexia, and
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vomiting, caused by stimulation of the chemoreceptor trigger zone via ketonemia and hyperglycemia, contribute to the dehydration caused by osmotic diuresis. Dehydration and shock lead to prerenal azotemia and a decline in glomerular filtration rate (GFR). Declining GFR leads to further accumulation of glucose and ketones in the blood. Stress hormones such as cortisol and epinephrine contribute to the hyperglycemia in a vicious cycle. Eventually, severe dehydration may result in hyperviscosity, thromboembolism, severe metabolic acidosis, renal failure, and finally death. The most common historical findings in cats and dogs with DKA are anorexia (61%), weakness, depression, and vomiting.2 Physical examination findings may include shock, depression, tachypnea, dehydration, weakness, vomiting, and occasionally a strong acetone odor on the breath. Cats can present recumbent or comatose; this may be a manifestation of mixed ketotic hyperosmolar syndrome. In cats, 33% exhibited clinical icterus at presentation.2
Clinical Pathology of Diabetes Mellitus in Animals In dogs, a diagnosis of DM should be based on the presence of clinical signs compatible with DM and evidence of fasting hyperglycemia and glycosuria. Common clinicopathologic features of DM in dogs and cats include: fasting hyperglycemia, hypercholesterolemia, increased liver enzymes (ALP, ALT), neutrophilic leukocytosis, proteinuria, increased urine specific gravity, and glycosuria. Common clinicopathologic findings in DKA include all of the foregoing plus azotemia, hyponatremia, hyperkalemia, hyperlipasemia, hyperamylasemia, ketonemia, regenerative or degenerative left shifts, hyperosmolality, ketonuria, bacteriuria, hematuria, and pyuria. Many cats are susceptible to “stress-induced” hyperglycemia in which the serum glucose concentrations may approach 300–400 mg/dL. In addition, renal glycosuria may be found in
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animals with renal tubular disease and occasionally with stress-induced hyperglycemia. It may be difficult to differentiate early type 2 diabetes in cats from stress-induced hyperglycemia, because cats with early NIDDM are often asymptomatic. Glycosylated proteins, such as glycosylated hemoglobin and fructosamine, may aid in the diagnosis of early type 2 DM in cats.10 Glycosylated hemoglobin is formed by an irreversible, nonenzymatic binding of glucose to hemoglobin. As plasma glucose concentrations increase, hemoglobin glycosylation increases proportionately. Normal glycosylated hemoglobin (mean ± SD) values are 2.95 ± 0.15% in dogs and 1.6 ± 0.5% in cats.10 Serum fructosamine is formed by glycosylation of serum protein such as albumin. The concentration of fructosamine in serum is directly related to blood glucose concentration. However, due to the shorter lifespan of albumin compared with hemoglobin, fructosamine concentrations reflect more recent (1–3 weeks) changes in serum glucose concentrations. Serum fructosamine measurement may be beneficial in differentiating early or subclinical DM in the cat from stress-induced hyperglycemia.11–13 One study in 17 normal cats showed that transient glucose administration (1 g/kg 50% glucose solution, intravenously) did not cause increased serum fructosamine concentrations.13 Furthermore, hyperglycemic serum samples from sick cats were analyzed for serum fructosamine content; approximately 40% exhibited normal fructosamine concentrations consistent with transient hyperglycemia. In the same study, it was noted that 50% of sick cats showed mold increases in serum fructosamine concentrations consistent with subclinical or mildly clinical DM even when the serum glucose concentrations were in the normal or near normal range.13 This finding suggests that subclinical type 2 DM is probably much more common than previously believed and that obese cats with increased serum fructosamine should be followed carefully for evidence of developing DM. Normal fructosamine concentrations in dogs are
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254 ± 42 μmol/L and in cats normal fructosamine concentrations are 283 ± 32 μmol/L.11–13
Treatment of Diabetes Mellitus in Cats and Dogs The Role of Diet The goals of dietary therapy in DM for both cats and dogs are to provide sufficient calories to maintain ideal body weight and correct obesity or emaciation, to minimize postprandial hyperglycemia, and to facilitate ideal absorption of glucose by timing meals to coincide with insulin administration. Caloric intake should be 60–70 kcal/kg/day for small dogs and 50–60 kcal/kg/day for large dogs. Most cats will consume between 200 and 250 kcal/day. Obese animals should have their body weight reduced gradually over a period of 2–4 months by feeding 60%–70% of the calculated caloric requirements for ideal body weight. The feeding schedule should be adjusted to the insulin therapy and most animals are fed twice daily. One approach to managing DM in dogs uses nutritional components such as starch blends, carboxymethyl cellulose, and fermentable fiber blends. Barley and sorghum are used to blunt the postprandial rise in blood glucose, adjust postprandial insulin to appropriate levels, and to help blunt glucose surge. Fermentable fibers, such as fructooligosaccharide, beet pulp, and gum arabic, increase short chain fatty acids from the large intestine, which in turn increases glucagon-like peptide-1 (GLP-1) secretion and activity. GLP-1 is necessary for normal insulin secretion and for normal timing of insulin secretion after eating. Another approach is to limit carbohydrate in the diet to less than 30% of metabolizable energy. The cat is an obligate carnivore; therefore amino acids, rather than glucose, are the signal for insulin release in cats.14 Another unusual aspect of feline metabolism is the increase in hepatic gluconeogenesis seen after a normal meal. Normal cats maintain essential glucose
requirements from gluconeogenic precursors (i.e., amino acids) rather than from dietary carbohydrates. As a result, cats can maintain normal blood glucose concentrations even when deprived of food for over 72 h.15 When type 2 diabetes occurs in cats, the metabolic adaptations to a carnivorous diet become even more deleterious leading to severe protein catabolism; feeding a diet rich in carbohydrates may exacerbate hyperglycemia and protein wasting in these diabetic cats. A low-carbohydrate (<15% of dry matter) or ultralow (<10% of dry matter), high-protein diet, which is similar in fact to a cat’s natural diet (mice), may ameliorate some of the abnormalities associated with DM in the cat. Initial studies using a canned high-protein/low-carbohydrate diet and the starch blocker acarbose have shown that 58% of cats discontinue insulin injections and those with continued insulin requirements could be regulated on a much lower dosage (1 U BID).16 Comparison of canned high-fiber versus lowcarbohydrate diets showed that cats fed lowcarbohydrate diets were twice as likely to discontinue insulin injections.17 Oral Hypoglycemic Therapy Oral hypoglycemic agents are used in cats only to attenuate the physiologic abnormalities of type 2 diabetes by decreasing hepatic glucose output and glucose absorption from the intestine, increasing peripheral insulin sensitivity, and increasing insulin secretion from the pancreas. In cats, the clinician must rely on the response to oral hypoglycemic agents as a guide to whether the cat has sufficient beta-cell function to be managed with oral hypoglycemic agents. Oral hypoglycemic agents used in cats include the sulfonylureas (glipizide) and alpha- glucosidase inhibitors (acarbose).16,18 Indications for oral hypoglycemic therapy in cats include normal or increased body weight, lack of ketones, probable type 2 diabetics with no underlying disease (pancreatitis, pancreatic tumor), history of diabetogenic medications, and owners’ willingness to administer oral medication rather
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than an injection. Diet should consist of low- carbohydrate/high-protein foods only. The mechanism of action of the sulfonylureas is to increase insulin secretion and improve insulin resistance. Sulfonylureas, because of provocation of insulin release, may promote progression of pancreatic amyloidosis. In cats, glipizide has been used to successfully treat DM at a dosage of 2.5 mg BID when combined with a high-protein, low-carbohydrate diet. The patient is evaluated weekly or every 2 weeks for a period of 2–3 months. Cats with early type 2 diabetes are most likely to respond to any oral hypoglycemic agent. Gastrointestinal side effects, which occur in about 15% of cats treated with glipizide, resolve when the drug is administered with food.18 The alpha-glucosidase inhibitors impair glucose absorption from the intestine by decreasing fiber digestion and hence glucose production from food sources. Acarbose is used as initial therapy in obese prediabetic patients suffering from insulin resistance or as adjunct therapy with sulfonylureas to enhance the hypoglycemic effect in patients with DM. Side effects include flatulence, loose stools, and diarrhea at high dosages. One advantage of these medications is that they are not absorbed systemically and may be used in conjunction with other oral hypoglycemics or insulin. The author has had experience with acarbose at a dosage of 12.5 mg/cat BID with meals; side effects, although rare if diet is adjusted, include semiformed stools or in some cases overt diarrhea.16 The glucose- lowering effect of acarbose alone is mild with blood glucose concentrations decreasing only into the 250–300 mg/dL range. However, acarbose is an excellent agent when combined with insulin to improve glycemic control.
Insulin Therapy Recombinant human and synthetic insulin, including isophane (NPH), lente, glargine, protamine zinc (PZI), and detemir, have been used in animals.19–22 Preliminary studies on glargine
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have shown that it has some advantages over other types of insulin in cats. In fact, early studies showed that a combination of glargine with a low-carbohydrate, high-protein diet resulted in 100% remission of insulin dependence in cats. Detemir insulin is rapidly becoming the insulin of choice in dogs due to greater efficacy and longer half-life. Detemir is unusual in that it is “stored” on protein-binding sites on albumin in the blood and slowly dissociates throughout the day, which leads to a long half-life. Because of differences in albumin binding in dogs and cats versus humans, animals require one-quarter the dose of detemir compared with humans. The primary difference between insulin designed for use in animals (PZI, lente) and for humans (glargine, NPH, detemir) is the insulin concentration; U-40 insulin is available for PZI and lente insulin; however, NPH, glargine, and detemir are only available as U-100 insulin.20 Care should be taken when using insulin syringes: U-100 syringes for U-100 insulin and U-40 syringes for U-40 insulin to prevent accidental overdose. In dogs, with conventional insulin therapy (NPH, lente, PZI, glargine), a starting dose of 0.5 U/kg is recommended; however, detemir is dosed at 0.1–0.2 U/kg because of the aforementioned albumin binding. Most cats are readily managed on 2 units twice daily as a starting dose. If intermediate-acting insulin is used, it must be administered twice daily because of the short duration of action in cats. If PZI insulin is used, a dosage of 1–3 units per cat is often recommended as a once daily therapy. Glargine (Lantus insulin) should be used cautiously in the cat to avoid hypoglycemia. A dosage of 1–2 units twice daily is recommended along with careful blood or urine monitoring to avoid hypoglycemic episodes. The site of insulin injection should be discussed with the pet owner. Absorption of insulin from various injections sites in the body may differ. In animals, the back of the neck or scruff has commonly been used as a site for insulin injection. However, this site has several
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disadvantages because of lack of blood flow and increased fibrosis caused by repeated injections at this site. The author recommends administration of insulin at sites along the lateral abdomen and thorax. The owner should rotate the site of injection each day.
Treatment of Diabetic Ketoacidosis in Animals Treatment of DKA includes the following steps in order of importance: (1) fluid therapy initially using shock doses of 0.9% saline; (2) shortacting insulin therapy (low-dose intramuscular or intravenous); (3) electrolyte supplementation (potassium chloride and/or potassium phosphate); and (4) reversal of metabolic acidosis.23,24 Fluid therapy should consist of 0.9% NaCl supplemented with potassium when insulin therapy is initiated. Normal saline is the fluid of choice initially, and when the blood glucose decreases to below 250 mg/dL, fluid therapy is changed to 5% or 2.5% dextrose in water and 0.45% saline when the blood glucose falls below 250 mg/dL.25 A large central venous catheter should be used to administer fluid therapy as animals in DKA are severely dehydrated and require rapid fluid administration. Use of hypotonic solutions is controversial in that hyperosmolality often causes idiogenic osmoles in the brain, which are “trapped” when serum osmolality is decreased rapidly resulting in cerebral edema. Insulin therapy should be initiated as soon as possible and the author prefers intravenous insulin therapy as previously described.26 Regular insulin is mixed in a 250 mL saline bag at a dosage of 2.2 units of regular insulin/kg of body weight for dogs and 1.1 U/kg for cats. Approximately 50 mL of fluid and insulin are allowed to run through the intravenous drip set and is discarded because insulin binds to the plastic tubing. The species of regular insulin (beef, pork, or human) used does not affect response; however, the type of insulin given is
very important. Regular insulin must be used; lente, ultralente, and NPH should never be given intravenously. Diluted regular insulin is administered initially at a rate of 10 mL/h via an infusion pump and decreased according to the drop in serum glucose. As serum glucose decreases, the insulin fluid rate is decreased from 10 to 7 to 5 mL/h and finally shut off as blood glucose approaches the normal range (100 mg/dL). Concurrently with the decrease in serum glucose, fluid therapy is changed from normal saline to saline dextrose mixtures. When blood glucose decreases below 250 mg/dL, the fluid is changed to 2.5% dextrose and 0.45% NaCl. When the blood glucose falls below 150 mg/dL, the fluids are changed to 5% dextrose and 0.45% NaCl. Using this method, blood glucose decreases to below 250 mg/dL by approximately 10 h in dogs and in cats after about 16 h. Insulin is administered through a separate catheter to the fluids to allow for more flexible insulin administration. Once euglycemia has been achieved, the animal is maintained on subcutaneous regular insulin (0.1 U/kg, for the following 4–6 h) until it starts to eat and/or the ketosis has resolved. Another protocol is to use low-dose intramuscular insulin at an initial dosage of 0.2 U/kg followed by hourly intramuscular injections of 0.1 U/kg until the blood glucose concentration is <250 mg/dL. After the blood glucose drops to <250 mg/dL, regular insulin is administered subcutaneously every 6–8 h. The disadvantage of this protocol is that blood glucose levels may drop precipitously as depots of intramuscular insulin are absorbed from previously poorly perfused muscle tissue. Electrolyte, specifically potassium, balance may be difficult to manage during a ketoacidotic crisis. Potassium should be supplemented as soon as insulin therapy is initiated. While serum potassium may be normal or elevated in DKA, the animal actually suffers from total body depletion of potassium. Furthermore, correction of the metabolic acidosis tends to drive potassium intracellularly in exchange for hydrogen
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ions. Insulin facilitates this exchange and the net effect is a dramatic decrease in serum potassium, which must be attenuated with appropriate potassium supplementation in fluids. General guidelines list 40–80 meq/L as appropriate supplementation; however, as much as 100 meq/L may be required to maintain serum potassium within the normal range in some diabetic cats. Monitoring serum potassium frequently during the course of treatment of DKA is essential to avoid under- or oversupplementation of potassium and other electrolytes. Serum and tissue phosphorus may also be depleted during a ketoacidotic crisis and some of the potassium supplementation should consist of potassium phosphate (0.01–0.03 mmol phosphate/kg/h), particularly in small dogs and cats that are most susceptible to hemolysis caused by hypophosphatemia. Another cause of hemolysis in cats with DKA is Heinz body anemia. While Heinz body anemia usually does not result in overt hemolysis by itself, it probably shortens the lifespan of red blood cells, and when coupled with low phosphorus levels may precipitate a hemolytic crisis. Finally, serum pH should be addressed after administration of fluids, insulin, and potassium. Often, the first three steps will result in normalization of serum acid–base status; however, bicarbonate therapy may be necessary in some patients. Caution with bicarbonate therapy is recommended as metabolic alkalosis may be difficult to reverse.
Monitoring Diabetic Animals Although often overlooked, clinical signs, such as polydipsia or polyuria, are the best indicators of adequate diabetic regulation.27 Underregulation is often manifested as continued or worsening polydipsia, polyuria, weight loss, vomiting, diarrhea, anorexia, neuropathy in cats, and cataracts in dogs. Overregulation can be detected by weight gain (as a result of the anabolic effects of insulin), progression of
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diabetic neuropathy or nephropathy, progression of cataracts, and signs of hypoglycemia such as weakness or coma. Body weight should remain stable or normalize with underweight animals gaining and overweight animals losing weight. Irritability or changes in personality (aggressiveness, biting) should alert the clinician to a worsening diabetic situation in a cat. Signs of ketosis include vomiting, diarrhea, weakness, and acetone odor on the breath in both dogs and cats. Hyperosmolar or mixed ketotic– hyperosmolar syndrome in cats may manifest as weakness, severe dehydration, bradycardia, hypotension, and eventually coma. Urine glucose is a measure of trends in blood glucose, and should not be used alone to increase insulin dosage. Urine glucose monitoring may be performed at home by the owner, is not affected by stress, and may indicate insulin-induced hyperglycemia (Somogyi effect).28 Urine glucose should decrease to trace or one plus with appropriate therapy. Consistently high urine glucose indicates the need for blood glucose evaluation. Glucose monitors designed for home monitoring in human beings and animals are inexpensive, accurate, rapid, and require only a drop of blood.29,30 Although reasonably accurate in the blood glucose range of 60–120 mg/dL (4–12.5 mmol/L), these glucose monitors are designed to read lower than the actual value as glucose approaches the hypoglycemic range. Factors that affect accuracy of these monitors include altitude, oxygen therapy, patient hematocrit, shock, dehydration, severe infection, and out-of-date or improperly stored test strips. Whole blood glucose concentrations are lower than serum glucose and the manufacturer should be consulted about the suitability of these monitors for canine patients. A veterinary glucose monitor has been developed and marketed as the Abbott AlphaTRAK. AlphaTRAK has the highest correlation to clinical laboratory sample analysis of glucose. The Bayer Ascensia Contour and the Roche Accu-Chek Advantage are both
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excellent human monitors, but fall short of the accuracy of the Abbott product in cats. The ideal glucose curve has a glucose nadir (lowest blood glucose concentration on the curve) between 100 and 150 mg/dL (4–6 mmol/L). The time of the glucose nadir indicates peak insulin action. The nadir should occur approximately halfway through the dosing interval. For example, if insulin is being given every 12 h, the nadir should fall 5–6 h after the dose. The glucose differential is the difference between the glucose nadir and the blood glucose concentration prior to the next insulin dose. The glucose differential should be less than 100–150 mg/dL (5–7 mmol/L) in dogs to prevent cataract formation and between 150 and 200 mg/dL (7.5 mmol/L) in cats. The duration of insulin action is related to both the time of the glucose nadir and the absolute concentration of the glucose nadir. One cannot make a determination of insulin duration unless the target glucose nadir concentration (80–120 mg/dL) has been achieved. If the glucose nadir occurs approximately halfway through the dosing interval, the duration of action of insulin should be adequate. Unfortunately, blood glucose curves are highly variable in cats and dogs and since cats are susceptible to stress-induced hyperglycemia, the response to therapy may be masked.31 The best use of blood glucose curves in cats is to determine if insulin is being absorbed adequately and if the insulin is lasting throughout the day (short duration of action). Glycosylated blood proteins are indicative of mean glucose concentrations in serum over an extended period of time.32,33 Glycated blood proteins may be used to monitor long-term insulin therapy; these proteins are particularly useful in monitoring diabetic cats that may be stressed by hospitalization and serial blood glucose curves. As plasma glucose concentrations increase, hemoglobin glycosylation increases proportionately. Serum fructosamine is formed by glycosylation of serum protein such as albumin. The concentration of fructosamine in serum is directly related to blood glucose
concentration.33 However, due to the shorter lifespan of albumin compared with hemoglobin, fructosamine concentrations reflect more recent (1–3 weeks) changes in serum glucose concentrations. Fructosamine concentrations less than 350–450 μmol/L are associated with good-toexcellent diabetic control, whereas serum fructosamine concentrations of 450–500 μmol/L indicate fair-to-good control, and serum fructosamine concentrations greater than 500 μmol/L indicate poor glycemic control. Relative changes in serum fructosamine may be more helpful than absolute values in some cases.
References 1. Nelson RW. Diabetes mellitus. In: Ettinger SJ, Feldman EC, editors. Textbook of veterinary internal medicine. 4th ed. Philadelphia: WB Saunders; 1995. 2. Greco DS. Diagnosis of diabetes mellitus in dogs and cats. In: Behrend EN, Kemppainen RJ, editors. Vet Clin N Am, vol. 31. Philadelphia: WB Saunders; 2001. p. 845–53. 3. O’Brien TD, Butler PC, Westermark P, Johnson KH. Islet amyloid polypeptide: a review of its biology and potential roles in the pathogenesis of diabetes mellitus. Vet Pathol 1993;30:317–32. 4. Lutz TA, Rand JS. A review of new developments in type 2 diabetes mellitus in human beings and cats. Br Vet J 1993;149:527–36. 5. Brennan CL, Hoenig M, Ferguson DC. GLUT4 but not GLUT1 expression decreases early in the development of feline obesity. Domest Anim Endocrinol 2004;26(4):291–301. 6. Ballard FJ. Glucose utilization in mammalian liver. Comp Biochem Physiol 1965;14:437–43. 7. Rand JS. Canine and feline diabetes mellitus: nature or nurture? J Nutr 2004;134:2072S–80S. 8. Diehl KJ. Long-term complications of diabetes mellitus, part II: gastrointestinal and infectious. In: Greco DS, Peterson ME, editors. Vet Clin N Am, vol. 25. 1995. p. 731–40. 9. Munana KR. Long-term complications of diabetes mellitus, part I: retinopathy, nephropathy, neuropathy. In: Greco DS, Peterson ME, editors. Vet Clin N Am, vol. 25. 1995. p. 715–30. 10. Haberer B, Reusch CE. Glycated haemoglobin in various pathological conditions: investigations based on a new, fully automated method. J Small Anim Pract 1998;39:510–7.
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11. Reusch CE, Liehs MR, Hoyer M, Vochezer R. Fructosamine. A new parameter for diagnosis and metabolic control in diabetic dogs and cats. J Vet Intern Med 1993;7:177–82. 12. Thoresen SI, Bredal WP. Clinical usefulness of fructosamine measurements in diagnosing and monitoring feline diabetes mellitus. J Small Anim Pract 1996;37:64–8. 13. Lutz TA, Rand JS. Fructosamine concentrations in hyperglycemic cats. Can Vet J March 1995;36(3):155–9. 14. Kitamura T, Yasuda J, Hashimoto A. Acute insulin response to intravenous arginine in nonobese healthy cats. J Vet Intern Med 1999;13(6):549–56. 15. Kettlehut IC, Foss MC, Migliorini RH. Glucose homeostasis in a carnivorous animal (cat) and in rats fed a highprotein diet. Am J Physiol 1978;239:R115–21. 16. Mazzaferro EM, Greco DS, Turner AS, Fettman MJ. Treatment of feline diabetes mellitus with a high protein diet and acarbose. J Feline Med Surg 2003;5:183–9. 17. Bennett N, Greco DS, Peterson ME, Kirk CE, Mathes M, Fettman ME. Comparison of a low carbohydrate vs high fiber canned diet for the treatment of diabetes mellitus in cats. J Feline Med Surg April 2006;8(2):73–84. 18. Ford S. NIDDM in the cat: treatment with the oral hypoglycemic medication, glipizide. In: Greco DS, Peterson ME, editors. Vet Clin N Am, vol. 25. 1995. p. 599 (3). 19. Nelson RW, Lynn RC, Wagner-Mann CC, Michels GM. Efficacy of protamine zinc insulin for treatment of diabetes mellitus in cats. J Am Vet Med Assoc 2001;218:38–42. 20. Greco DS, Broussard JD, Peterson ME. Insulin therapy. Vet Clin N Am Small Anim Pract 1995;25(3):677. 21. Gilor C, Ridge TK, Attermeier KJ, Graves TK. Pharmacodynamics of insulin detemir and insulin glargine assessed by an isoglycemic clamp method in healthy cats. J Vet Intern Med 2010;24(4):870–4. 22. Graham PA, Nash AS, McKellar QA. Pharmacokinetics of a porcine insulin zinc suspension in diabetic dogs. J Small Anim Pract 1997;38:434–8. 23. Macintire DK. Treatment of diabetic ketoacidosis in dogs by continuous low-dose intravenous infusion of insulin. J Am Vet Med Assoc 1993;202:1266–72.
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24. MacIntyre DK. Emergency therapy of diabetic crises: insulin overdose, diabetic ketoacidosis and hyperosmolar coma. In: Greco DS, Peterson ME, editors. Vet Clin N Am, vol. 25. 1995. p. 639–50 (3). 25. Rand JS, Martin GJ. Management of feline diabetes mellitus. In: Behrend EN, Kemppainen RJ, editors. Vet Clin N Am, vol. 31. Philadelphia: WB Saunders Co; 2001. p. 881–913. 26. Fleeman LM, Rand JS. Management of canine diabetes. In: Behrend EN, Kemppainen RJ, editors. Vet Clin N Am, vol. 31. Philadelphia: WB Saunders Co; 2001. p. 855–80. 27. Briggs CE, Nelson RW, Feldman EC, Elliott DA, Neal LA. Reliability of history and physical examination findings for assessing control of glycemia in dogs with diabetes mellitus: 53 cases (1995–1998). J Am Vet Med Assoc 2000;217:48–53. 28. Schaer M. A justification for urine glucose monitoring in the diabetic dog and cat. J Am Anim Hosp Assoc 2001;37:311–2. 29. Wess G, Reusch C. Capillary blood sampling from the ear of dogs and cats and use of portable meters to measure glucose concentration. J Small Anim Pract 2000;41:60–6. 30. Reusch CE, Wess G, Casella M. Home monitoring of blood glucose concentration in the management of diabetes mellitus. Comp Cont Educ 2001;23:544–56. 31. Fleeman LM, Rand JS. Evaluation of day-to-day variability in serial blood glucose concentrations in diabetic dogs. J Am Vet Med Assoc 2003;222:317–21. 32. Elliott DA, Nelson RW, Feldman EC, Neal LA. Glycosylated hemoglobin concentration for assessment of glycemic control in diabetic cats. J Vet Intern Med 1997;11:161–5. 33. Elliott DA, Nelson RW, Reusch CE, Feldman EC, Neal LA. Comparison of serum fructosamine and blood glycosylated hemoglobin concentrations for assessment of glycemic control in cats with diabetes mellitus. J Vet Intern Med 1998;12:1794–8.
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Diabetes Mellitus in Animals: Diagnosis and Treatment of Diabetes Mellitus in Dogs and Cats Deborah S. Greco Nestle Purina PetCare, St. Louis, MO, United States
O U T L I N E Clinical Pathology of Diabetes Mellitus in Animals511 Treatment of Diabetes Mellitus in Cats and Dogs 512
Introduction507 Diabetes in Dogs and Cats 508 Etiology: Feline Diabetes Mellitus 508 Pathogenesis of Clinical Signs: IDDM 509 Pathogenesis of Clinical Signs: NIDDM 509 Clinical Signs of Nonketotic Diabetes Mellitus510 Physical Examination Findings 510 Ketoacidotic, Hyperosmolar, or Complicated Diabetes Mellitus: Pathophysiology and Clinical Signs 510
INTRODUCTION The field of companion animal diabetology is in its infancy but new discoveries are being made every day. The overlap between human and companion animal medicine and research grows larger with each new discovery. This Nutritional and Therapeutic Interventions for Diabetes and Metabolic Syndrome https://doi.org/10.1016/B978-0-12-812019-4.00037-4
The Role of Diet Oral Hypoglycemic Therapy
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Insulin Therapy 513 Treatment of Diabetic Ketoacidosis in Animals514 Monitoring Diabetic Animals 515 References516
chapter covers the diagnosis and treatment of diabetes mellitus (DM) in companion animals, such as the dog and cat. Dogs develop insulindependent diabetes mellitus (IDDM) and most dogs require insulin therapy; however, cats develop type 2 diabetes and can be managed with diet alone or diet combined with insulin or
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© 2018 Elsevier Inc. All rights reserved.
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oral hypoglycemic therapy. The etiology, clinical signs, clinical pathology, and diagnostic tests for diabetes in dogs and cats will be covered along with treatment modalities such as diet, oral hypoglycemics, and insulin. Finally, a discussion of monitoring options for small animal diabetics is included.
DIABETES IN DOGS AND CATS IDDM is a diabetic state in which endogenous insulin secretion is never sufficient to prevent ketone production. Dogs may suffer from type 1 diabetes, which is thought to have an autoimmune basis and genetic basis; however, reclassification of the types of DM would suggest that exocrine pancreatic diseases, such as pancreatitis, may cause type 3c diabetes in dogs as well.1 Dogs suffering from DM range in age from 4 to 14 years with a peak incidence at 7–9 years.1 In dogs, females are twice as likely to develop diabetes than are males. A genetic basis for DM is suspected in the Samoyed, Australian terrier, Keeshond, and Cairn terriers.1 Other commonly affected breeds include poodles, dachshunds, miniature schnauzers, beagles, puliks, and miniature pinschers; however, a genetic susceptibility has not been identified in these breeds.1
Etiology: Feline Diabetes Mellitus DM is a commonly occurring feline endocrinopathy and type 2 diabetes is most commonly identified. Diabetes can also develop as a result of acromegaly in the cat. Neutered males are 1.5 times more likely than females to develop DM. Risk factors for the development of DM in cats include increased body weight (>6.8 kg), older age (>10 years), and neutering.1,2 Historically, feline diabetics were suspected to be insulinopenic; however, research indicates that most cats develop diabetes similar to type 2 DM in humans.3,4 Obesity and amyloidosis
are involved in the pathogenesis of type 2 DM in cats. It is now recognized that the classic metabolic abnormalities found in type 2 DM, decreased insulin secretion and peripheral insulin resistance, are both consequences of abnormal amyloid production by pancreatic beta cells. In 1986, a previously unidentified protein called islet amyloid polypeptide (IAPP or amylin) was identified as the main component of amyloid deposits in a human insulinoma. This novel protein was also found to be the main component of islet amyloid isolated from pancreatic islets in cats with type 2 DM.3 Another major distinguishing feature of type 2 diabetes is peripheral insulin resistance. Obesity plays a significant role in the insulin resistance seen in feline diabetics. The resistance is due to internalization of the insulin receptors in membranes of muscle and fat cells. Obesity also decreases receptor affinity for the insulin molecule. Both the amount and distribution of adipose tissue play a role in insulin resistance and other obesity-related disorders.4 Obese cats have low insulin-sensitive glucose transporter 4 (GLUT-4) expression in both muscle and adipose tissue; however, the expression of GLUT-1 is the same in lean versus obese cats.5 The GLUT in pancreatic beta cells is actually GLUT-2 and a decreased expression of these receptors causes a loss of the first phase of insulin secretion but normal second phase of insulin secretion similar to what is seen in later stages of obesity in the cat. Insulin secretion is affected early on in the course of type 2 DM, particularly, glucosemediated insulin secretion. Insulin resistance in beta cells may lead to a decrease in insulin secretion. In some forms of diabetes in humans, a mutation of the glucokinase enzyme may lead to impaired insulin secretion. The feline liver exhibits normal hexokinase activity but glucokinase activity is virtually absent.6 Glucokinase converts glucose to glycogen for storage in the liver and is important in “mopping” up excess postprandial glucose. Normal cats are in fact similar to human beings with type 2 DM whose
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glucokinase levels drop precipitously with persistent hyperglycemia. To summarize the current hypothesis of the pathogenesis of type 2 DM, peripheral insulin resistance (due to obesity, elevated plasma IAPP, or both) causes chronic stimulation of insulin production in the pancreatic beta cells.3–7 Amylin is cosynthesized with insulin; therefore impaired insulin secretion causes insulin and IAPP to accumulate in the beta cells.3 The high local concentration of IAPP causes polymerization of IAPP to form insular amyloid. Deposition of insular amyloid further impairs glucorecognition and diffusion of nutritive substances into the beta cells. Eventually, insular amyloidosis leads to necrosis of the beta cells and release of amyloid into the extracellular space.3,4
Pathogenesis of Clinical Signs: IDDM Hyperglycemia, caused by insulin deficiency, results primarily from impaired glucose utilization; however, increased hepatic gluconeogenesis and glycogenolysis by the liver contributes to hyperglycemia. Decreased peripheral utilization of glucose leads to accumulation of glucose in the serum; as the renal threshold for glucose is exceeded, osmotic diuresis ensues. Progressive dehydration results in the classic clinical signs of diabetes such as polyuria with compensatory polydipsia. Impaired glucose utilization by the hypothalamic satiety center combined with loss of calories in the form of glycosuria causes polyphagia and weight loss, respectively. Insulin is anabolic; therefore insulin deficiency leads to protein catabolism and contributes to the clinical signs of weight loss and muscle atrophy. With insulin deficiency, the hormone-sensitive lipase system, which is normally suppressed by insulin, becomes activated. As a consequence of this increased lipase activity, adipose tissue is broken down at an accelerated rate into nonesterified fatty acids. The unrestrained lipolytic activity of hormone-sensitive lipase results in
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the clinical signs of weight loss in a previously obese or overweight animal.
Pathogenesis of Clinical Signs: NIDDM In cats with type 2 DM, the initial abnormality is insulin resistance. Cats, like human beings with type 2 diabetes, may show very few or no signs of “classic” diabetes until progressive amyloid deposition and glucose toxicity impair insulin secretion to the point that hyperglycemia exceeds the renal threshold (about 15 mmol/L in cats, which is higher than in dogs). At this point, the DM has become insulin dependent, at least temporarily. Lowering of blood glucose via exogenous insulin or oral hypoglycemic agents may be sufficient to reverse glucose toxicity and result in resolution of the clinical signs of polydipsia and polyuria. However, it should be emphasized that cats with resolved IDDM still have the underlying pathophysiology of type 2 DM, i.e., insulin resistance and impaired insulin secretory capacity. Clinical signs of type 2 DM are subtle and progressive over a period of months to years. In the author’s experience, obesity combined with fasting or postprandial hyperglycemia may be the only clinical “sign” of early type 2 DM. Prior to the onset of polydipsia and polyuria, a constellation of gastrointestinal abnormalities and signs of diabetic neuropathy may also be observed. In diabetic cats, the first signs of DM may be periodic vomiting, anorexia, and less frequently diarrhea. These gastrointestinal signs may originate as a result of autonomic diabetic neuropathy or possibly as a result of concurrent pancreatitis, cholangiohepatitis, or inflammatory bowel disease. Another observation, in the author’s experience, is that owners of diabetic cats will report gait abnormalities, weakness, and problems with jumping prior to the onset of polydipsia and polyuria. There is often a history of administration of diabetogenic medications, such as glucocorticoids or progestins, in cats presenting for type 2 DM.
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Clinical Signs of Nonketotic Diabetes Mellitus Most diabetic dogs and cats present with the classic clinical signs of polyuria and polydipsia. Polydipsia was the most common clinical sign of DM in dogs (93%).2 Polyuria, on the other hand, was observed in only 77% of dogs. In cats, polydipsia (77%) and polyuria (72%) occur with equal frequency.2 Dramatic and rapid weight loss in an animal with a good or even ravenous appetite will often alert the owner to seek veterinary advice. Weight loss is observed more commonly in dogs (62%) compared with cats (44%).2 Only 12% of cats and 19% of dogs exhibited polyphagia as a clinical sign of DM.2 In dogs, progressive polyuria, polydipsia, and weight loss develop relatively rapidly, usually over a period of several weeks. Another common presenting complaint of DM in dogs is acute onset of blindness caused by bilateral cataract formation. Cats will present with chronic complications of diabetes, such as gait abnormalities (13%) resulting from diabetic neuropathy, or with chronic gastrointestinal signs such as vomiting, diarrhea, and anorexia.2 There is often a history of inappropriate elimination or house soiling as a result of muscle weakness caused by neuropathy (inability to climb stairs or get into or out of the litter pan) and polyuria.
Physical Examination Findings Physical examination findings of nonketotic DM in cats and dogs are typically nonspecific. The most common physical examination findings in cats are lethargy and depression (70%), dehydration (63%), unkempt haircoat (35%), and muscle wasting (47%).2 Cats may present with “frosty paws” or accumulation of cat litter on the hind legs and paws as a result of diabetic neuropathy and sticky urine caused by glucosuria. Cats often have concurrent gastrointestinal disease such as pancreatitis, inflammatory bowel disease, and cholangiohepatitis.8
Plantigrade rear limb stance resulting from diabetic neuropathy has been observed in approximately 8% of diabetic cats in previous studies. However, recent evidence suggests that diabetic cats can have a variety of clinical signs suggestive of diabetic neuropathy, including pain on palpation of distal extremities, hypersensitivity, gait abnormalities, and palmagrade stance. Based on electromyography, nerve biopsy, and nerve conduction studies, all diabetic cats have some degree of diabetic neuropathy at the time of presentation.9 In dogs, the most common physical examination findings are dehydration (48%) and muscle wasting or thin body condition (44%). About 35% of cats and 20% of dogs are obese upon initial examination; obese diabetic animals are more likely to suffer from noninsulin-dependent diabetes mellitus (NIDDM). Hepatomegaly is observed in both diabetic cats (30%) and dogs (17%). Cataracts are observed in approximately 40% of diabetic dogs.
Ketoacidotic, Hyperosmolar, or Complicated Diabetes Mellitus: Pathophysiology and Clinical Signs Lipid metabolism in the liver becomes deranged with insulin deficiency and nonesterified fatty acids are converted to acetyl-CoA rather than being incorporated into triglycerides. Acetyl-CoA accumulates in the liver and is converted into acetoacetyl-CoA and then ultimately to acetoacetic acid. Finally, the liver starts to generate large amounts of ketones, including acetoacetic acid, beta-hydroxybutyrate, and acetone. As insulin deficiency culminates in diabetic ketoacidosis (DKA), accumulation of ketones and lactic acid in the blood and loss of electrolytes and water in the urine result in profound dehydration, hypovolemia, metabolic acidosis, and shock. Ketonuria and osmotic diuresis caused by glycosuria result in urinary sodium and potassium loss, which exacerbates hypovolemia and dehydration. Nausea, anorexia, and
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vomiting, caused by stimulation of the chemoreceptor trigger zone via ketonemia and hyperglycemia, contribute to the dehydration caused by osmotic diuresis. Dehydration and shock lead to prerenal azotemia and a decline in glomerular filtration rate (GFR). Declining GFR leads to further accumulation of glucose and ketones in the blood. Stress hormones such as cortisol and epinephrine contribute to the hyperglycemia in a vicious cycle. Eventually, severe dehydration may result in hyperviscosity, thromboembolism, severe metabolic acidosis, renal failure, and finally death. The most common historical findings in cats and dogs with DKA are anorexia (61%), weakness, depression, and vomiting.2 Physical examination findings may include shock, depression, tachypnea, dehydration, weakness, vomiting, and occasionally a strong acetone odor on the breath. Cats can present recumbent or comatose; this may be a manifestation of mixed ketotic hyperosmolar syndrome. In cats, 33% exhibited clinical icterus at presentation.2
Clinical Pathology of Diabetes Mellitus in Animals In dogs, a diagnosis of DM should be based on the presence of clinical signs compatible with DM and evidence of fasting hyperglycemia and glycosuria. Common clinicopathologic features of DM in dogs and cats include: fasting hyperglycemia, hypercholesterolemia, increased liver enzymes (ALP, ALT), neutrophilic leukocytosis, proteinuria, increased urine specific gravity, and glycosuria. Common clinicopathologic findings in DKA include all of the foregoing plus azotemia, hyponatremia, hyperkalemia, hyperlipasemia, hyperamylasemia, ketonemia, regenerative or degenerative left shifts, hyperosmolality, ketonuria, bacteriuria, hematuria, and pyuria. Many cats are susceptible to “stress-induced” hyperglycemia in which the serum glucose concentrations may approach 300–400 mg/dL. In addition, renal glycosuria may be found in
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animals with renal tubular disease and occasionally with stress-induced hyperglycemia. It may be difficult to differentiate early type 2 diabetes in cats from stress-induced hyperglycemia, because cats with early NIDDM are often asymptomatic. Glycosylated proteins, such as glycosylated hemoglobin and fructosamine, may aid in the diagnosis of early type 2 DM in cats.10 Glycosylated hemoglobin is formed by an irreversible, nonenzymatic binding of glucose to hemoglobin. As plasma glucose concentrations increase, hemoglobin glycosylation increases proportionately. Normal glycosylated hemoglobin (mean ± SD) values are 2.95 ± 0.15% in dogs and 1.6 ± 0.5% in cats.10 Serum fructosamine is formed by glycosylation of serum protein such as albumin. The concentration of fructosamine in serum is directly related to blood glucose concentration. However, due to the shorter lifespan of albumin compared with hemoglobin, fructosamine concentrations reflect more recent (1–3 weeks) changes in serum glucose concentrations. Serum fructosamine measurement may be beneficial in differentiating early or subclinical DM in the cat from stress-induced hyperglycemia.11–13 One study in 17 normal cats showed that transient glucose administration (1 g/kg 50% glucose solution, intravenously) did not cause increased serum fructosamine concentrations.13 Furthermore, hyperglycemic serum samples from sick cats were analyzed for serum fructosamine content; approximately 40% exhibited normal fructosamine concentrations consistent with transient hyperglycemia. In the same study, it was noted that 50% of sick cats showed mold increases in serum fructosamine concentrations consistent with subclinical or mildly clinical DM even when the serum glucose concentrations were in the normal or near normal range.13 This finding suggests that subclinical type 2 DM is probably much more common than previously believed and that obese cats with increased serum fructosamine should be followed carefully for evidence of developing DM. Normal fructosamine concentrations in dogs are
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254 ± 42 μmol/L and in cats normal fructosamine concentrations are 283 ± 32 μmol/L.11–13
Treatment of Diabetes Mellitus in Cats and Dogs The Role of Diet The goals of dietary therapy in DM for both cats and dogs are to provide sufficient calories to maintain ideal body weight and correct obesity or emaciation, to minimize postprandial hyperglycemia, and to facilitate ideal absorption of glucose by timing meals to coincide with insulin administration. Caloric intake should be 60–70 kcal/kg/day for small dogs and 50–60 kcal/kg/day for large dogs. Most cats will consume between 200 and 250 kcal/day. Obese animals should have their body weight reduced gradually over a period of 2–4 months by feeding 60%–70% of the calculated caloric requirements for ideal body weight. The feeding schedule should be adjusted to the insulin therapy and most animals are fed twice daily. One approach to managing DM in dogs uses nutritional components such as starch blends, carboxymethyl cellulose, and fermentable fiber blends. Barley and sorghum are used to blunt the postprandial rise in blood glucose, adjust postprandial insulin to appropriate levels, and to help blunt glucose surge. Fermentable fibers, such as fructooligosaccharide, beet pulp, and gum arabic, increase short chain fatty acids from the large intestine, which in turn increases glucagon-like peptide-1 (GLP-1) secretion and activity. GLP-1 is necessary for normal insulin secretion and for normal timing of insulin secretion after eating. Another approach is to limit carbohydrate in the diet to less than 30% of metabolizable energy. The cat is an obligate carnivore; therefore amino acids, rather than glucose, are the signal for insulin release in cats.14 Another unusual aspect of feline metabolism is the increase in hepatic gluconeogenesis seen after a normal meal. Normal cats maintain essential glucose
requirements from gluconeogenic precursors (i.e., amino acids) rather than from dietary carbohydrates. As a result, cats can maintain normal blood glucose concentrations even when deprived of food for over 72 h.15 When type 2 diabetes occurs in cats, the metabolic adaptations to a carnivorous diet become even more deleterious leading to severe protein catabolism; feeding a diet rich in carbohydrates may exacerbate hyperglycemia and protein wasting in these diabetic cats. A low-carbohydrate (<15% of dry matter) or ultralow (<10% of dry matter), high-protein diet, which is similar in fact to a cat’s natural diet (mice), may ameliorate some of the abnormalities associated with DM in the cat. Initial studies using a canned high-protein/low-carbohydrate diet and the starch blocker acarbose have shown that 58% of cats discontinue insulin injections and those with continued insulin requirements could be regulated on a much lower dosage (1 U BID).16 Comparison of canned high-fiber versus lowcarbohydrate diets showed that cats fed lowcarbohydrate diets were twice as likely to discontinue insulin injections.17 Oral Hypoglycemic Therapy Oral hypoglycemic agents are used in cats only to attenuate the physiologic abnormalities of type 2 diabetes by decreasing hepatic glucose output and glucose absorption from the intestine, increasing peripheral insulin sensitivity, and increasing insulin secretion from the pancreas. In cats, the clinician must rely on the response to oral hypoglycemic agents as a guide to whether the cat has sufficient beta-cell function to be managed with oral hypoglycemic agents. Oral hypoglycemic agents used in cats include the sulfonylureas (glipizide) and alpha- glucosidase inhibitors (acarbose).16,18 Indications for oral hypoglycemic therapy in cats include normal or increased body weight, lack of ketones, probable type 2 diabetics with no underlying disease (pancreatitis, pancreatic tumor), history of diabetogenic medications, and owners’ willingness to administer oral medication rather
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than an injection. Diet should consist of low- carbohydrate/high-protein foods only. The mechanism of action of the sulfonylureas is to increase insulin secretion and improve insulin resistance. Sulfonylureas, because of provocation of insulin release, may promote progression of pancreatic amyloidosis. In cats, glipizide has been used to successfully treat DM at a dosage of 2.5 mg BID when combined with a high-protein, low-carbohydrate diet. The patient is evaluated weekly or every 2 weeks for a period of 2–3 months. Cats with early type 2 diabetes are most likely to respond to any oral hypoglycemic agent. Gastrointestinal side effects, which occur in about 15% of cats treated with glipizide, resolve when the drug is administered with food.18 The alpha-glucosidase inhibitors impair glucose absorption from the intestine by decreasing fiber digestion and hence glucose production from food sources. Acarbose is used as initial therapy in obese prediabetic patients suffering from insulin resistance or as adjunct therapy with sulfonylureas to enhance the hypoglycemic effect in patients with DM. Side effects include flatulence, loose stools, and diarrhea at high dosages. One advantage of these medications is that they are not absorbed systemically and may be used in conjunction with other oral hypoglycemics or insulin. The author has had experience with acarbose at a dosage of 12.5 mg/cat BID with meals; side effects, although rare if diet is adjusted, include semiformed stools or in some cases overt diarrhea.16 The glucose- lowering effect of acarbose alone is mild with blood glucose concentrations decreasing only into the 250–300 mg/dL range. However, acarbose is an excellent agent when combined with insulin to improve glycemic control.
Insulin Therapy Recombinant human and synthetic insulin, including isophane (NPH), lente, glargine, protamine zinc (PZI), and detemir, have been used in animals.19–22 Preliminary studies on glargine
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have shown that it has some advantages over other types of insulin in cats. In fact, early studies showed that a combination of glargine with a low-carbohydrate, high-protein diet resulted in 100% remission of insulin dependence in cats. Detemir insulin is rapidly becoming the insulin of choice in dogs due to greater efficacy and longer half-life. Detemir is unusual in that it is “stored” on protein-binding sites on albumin in the blood and slowly dissociates throughout the day, which leads to a long half-life. Because of differences in albumin binding in dogs and cats versus humans, animals require one-quarter the dose of detemir compared with humans. The primary difference between insulin designed for use in animals (PZI, lente) and for humans (glargine, NPH, detemir) is the insulin concentration; U-40 insulin is available for PZI and lente insulin; however, NPH, glargine, and detemir are only available as U-100 insulin.20 Care should be taken when using insulin syringes: U-100 syringes for U-100 insulin and U-40 syringes for U-40 insulin to prevent accidental overdose. In dogs, with conventional insulin therapy (NPH, lente, PZI, glargine), a starting dose of 0.5 U/kg is recommended; however, detemir is dosed at 0.1–0.2 U/kg because of the aforementioned albumin binding. Most cats are readily managed on 2 units twice daily as a starting dose. If intermediate-acting insulin is used, it must be administered twice daily because of the short duration of action in cats. If PZI insulin is used, a dosage of 1–3 units per cat is often recommended as a once daily therapy. Glargine (Lantus insulin) should be used cautiously in the cat to avoid hypoglycemia. A dosage of 1–2 units twice daily is recommended along with careful blood or urine monitoring to avoid hypoglycemic episodes. The site of insulin injection should be discussed with the pet owner. Absorption of insulin from various injections sites in the body may differ. In animals, the back of the neck or scruff has commonly been used as a site for insulin injection. However, this site has several
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disadvantages because of lack of blood flow and increased fibrosis caused by repeated injections at this site. The author recommends administration of insulin at sites along the lateral abdomen and thorax. The owner should rotate the site of injection each day.
Treatment of Diabetic Ketoacidosis in Animals Treatment of DKA includes the following steps in order of importance: (1) fluid therapy initially using shock doses of 0.9% saline; (2) shortacting insulin therapy (low-dose intramuscular or intravenous); (3) electrolyte supplementation (potassium chloride and/or potassium phosphate); and (4) reversal of metabolic acidosis.23,24 Fluid therapy should consist of 0.9% NaCl supplemented with potassium when insulin therapy is initiated. Normal saline is the fluid of choice initially, and when the blood glucose decreases to below 250 mg/dL, fluid therapy is changed to 5% or 2.5% dextrose in water and 0.45% saline when the blood glucose falls below 250 mg/dL.25 A large central venous catheter should be used to administer fluid therapy as animals in DKA are severely dehydrated and require rapid fluid administration. Use of hypotonic solutions is controversial in that hyperosmolality often causes idiogenic osmoles in the brain, which are “trapped” when serum osmolality is decreased rapidly resulting in cerebral edema. Insulin therapy should be initiated as soon as possible and the author prefers intravenous insulin therapy as previously described.26 Regular insulin is mixed in a 250 mL saline bag at a dosage of 2.2 units of regular insulin/kg of body weight for dogs and 1.1 U/kg for cats. Approximately 50 mL of fluid and insulin are allowed to run through the intravenous drip set and is discarded because insulin binds to the plastic tubing. The species of regular insulin (beef, pork, or human) used does not affect response; however, the type of insulin given is
very important. Regular insulin must be used; lente, ultralente, and NPH should never be given intravenously. Diluted regular insulin is administered initially at a rate of 10 mL/h via an infusion pump and decreased according to the drop in serum glucose. As serum glucose decreases, the insulin fluid rate is decreased from 10 to 7 to 5 mL/h and finally shut off as blood glucose approaches the normal range (100 mg/dL). Concurrently with the decrease in serum glucose, fluid therapy is changed from normal saline to saline dextrose mixtures. When blood glucose decreases below 250 mg/dL, the fluid is changed to 2.5% dextrose and 0.45% NaCl. When the blood glucose falls below 150 mg/dL, the fluids are changed to 5% dextrose and 0.45% NaCl. Using this method, blood glucose decreases to below 250 mg/dL by approximately 10 h in dogs and in cats after about 16 h. Insulin is administered through a separate catheter to the fluids to allow for more flexible insulin administration. Once euglycemia has been achieved, the animal is maintained on subcutaneous regular insulin (0.1 U/kg, for the following 4–6 h) until it starts to eat and/or the ketosis has resolved. Another protocol is to use low-dose intramuscular insulin at an initial dosage of 0.2 U/kg followed by hourly intramuscular injections of 0.1 U/kg until the blood glucose concentration is <250 mg/dL. After the blood glucose drops to <250 mg/dL, regular insulin is administered subcutaneously every 6–8 h. The disadvantage of this protocol is that blood glucose levels may drop precipitously as depots of intramuscular insulin are absorbed from previously poorly perfused muscle tissue. Electrolyte, specifically potassium, balance may be difficult to manage during a ketoacidotic crisis. Potassium should be supplemented as soon as insulin therapy is initiated. While serum potassium may be normal or elevated in DKA, the animal actually suffers from total body depletion of potassium. Furthermore, correction of the metabolic acidosis tends to drive potassium intracellularly in exchange for hydrogen
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Diabetes in Dogs and Cats
ions. Insulin facilitates this exchange and the net effect is a dramatic decrease in serum potassium, which must be attenuated with appropriate potassium supplementation in fluids. General guidelines list 40–80 meq/L as appropriate supplementation; however, as much as 100 meq/L may be required to maintain serum potassium within the normal range in some diabetic cats. Monitoring serum potassium frequently during the course of treatment of DKA is essential to avoid under- or oversupplementation of potassium and other electrolytes. Serum and tissue phosphorus may also be depleted during a ketoacidotic crisis and some of the potassium supplementation should consist of potassium phosphate (0.01–0.03 mmol phosphate/kg/h), particularly in small dogs and cats that are most susceptible to hemolysis caused by hypophosphatemia. Another cause of hemolysis in cats with DKA is Heinz body anemia. While Heinz body anemia usually does not result in overt hemolysis by itself, it probably shortens the lifespan of red blood cells, and when coupled with low phosphorus levels may precipitate a hemolytic crisis. Finally, serum pH should be addressed after administration of fluids, insulin, and potassium. Often, the first three steps will result in normalization of serum acid–base status; however, bicarbonate therapy may be necessary in some patients. Caution with bicarbonate therapy is recommended as metabolic alkalosis may be difficult to reverse.
Monitoring Diabetic Animals Although often overlooked, clinical signs, such as polydipsia or polyuria, are the best indicators of adequate diabetic regulation.27 Underregulation is often manifested as continued or worsening polydipsia, polyuria, weight loss, vomiting, diarrhea, anorexia, neuropathy in cats, and cataracts in dogs. Overregulation can be detected by weight gain (as a result of the anabolic effects of insulin), progression of
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diabetic neuropathy or nephropathy, progression of cataracts, and signs of hypoglycemia such as weakness or coma. Body weight should remain stable or normalize with underweight animals gaining and overweight animals losing weight. Irritability or changes in personality (aggressiveness, biting) should alert the clinician to a worsening diabetic situation in a cat. Signs of ketosis include vomiting, diarrhea, weakness, and acetone odor on the breath in both dogs and cats. Hyperosmolar or mixed ketotic– hyperosmolar syndrome in cats may manifest as weakness, severe dehydration, bradycardia, hypotension, and eventually coma. Urine glucose is a measure of trends in blood glucose, and should not be used alone to increase insulin dosage. Urine glucose monitoring may be performed at home by the owner, is not affected by stress, and may indicate insulin-induced hyperglycemia (Somogyi effect).28 Urine glucose should decrease to trace or one plus with appropriate therapy. Consistently high urine glucose indicates the need for blood glucose evaluation. Glucose monitors designed for home monitoring in human beings and animals are inexpensive, accurate, rapid, and require only a drop of blood.29,30 Although reasonably accurate in the blood glucose range of 60–120 mg/dL (4–12.5 mmol/L), these glucose monitors are designed to read lower than the actual value as glucose approaches the hypoglycemic range. Factors that affect accuracy of these monitors include altitude, oxygen therapy, patient hematocrit, shock, dehydration, severe infection, and out-of-date or improperly stored test strips. Whole blood glucose concentrations are lower than serum glucose and the manufacturer should be consulted about the suitability of these monitors for canine patients. A veterinary glucose monitor has been developed and marketed as the Abbott AlphaTRAK. AlphaTRAK has the highest correlation to clinical laboratory sample analysis of glucose. The Bayer Ascensia Contour and the Roche Accu-Chek Advantage are both
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37. DIABETES IN ANIMALS
excellent human monitors, but fall short of the accuracy of the Abbott product in cats. The ideal glucose curve has a glucose nadir (lowest blood glucose concentration on the curve) between 100 and 150 mg/dL (4–6 mmol/L). The time of the glucose nadir indicates peak insulin action. The nadir should occur approximately halfway through the dosing interval. For example, if insulin is being given every 12 h, the nadir should fall 5–6 h after the dose. The glucose differential is the difference between the glucose nadir and the blood glucose concentration prior to the next insulin dose. The glucose differential should be less than 100–150 mg/dL (5–7 mmol/L) in dogs to prevent cataract formation and between 150 and 200 mg/dL (7.5 mmol/L) in cats. The duration of insulin action is related to both the time of the glucose nadir and the absolute concentration of the glucose nadir. One cannot make a determination of insulin duration unless the target glucose nadir concentration (80–120 mg/dL) has been achieved. If the glucose nadir occurs approximately halfway through the dosing interval, the duration of action of insulin should be adequate. Unfortunately, blood glucose curves are highly variable in cats and dogs and since cats are susceptible to stress-induced hyperglycemia, the response to therapy may be masked.31 The best use of blood glucose curves in cats is to determine if insulin is being absorbed adequately and if the insulin is lasting throughout the day (short duration of action). Glycosylated blood proteins are indicative of mean glucose concentrations in serum over an extended period of time.32,33 Glycated blood proteins may be used to monitor long-term insulin therapy; these proteins are particularly useful in monitoring diabetic cats that may be stressed by hospitalization and serial blood glucose curves. As plasma glucose concentrations increase, hemoglobin glycosylation increases proportionately. Serum fructosamine is formed by glycosylation of serum protein such as albumin. The concentration of fructosamine in serum is directly related to blood glucose
concentration.33 However, due to the shorter lifespan of albumin compared with hemoglobin, fructosamine concentrations reflect more recent (1–3 weeks) changes in serum glucose concentrations. Fructosamine concentrations less than 350–450 μmol/L are associated with good-toexcellent diabetic control, whereas serum fructosamine concentrations of 450–500 μmol/L indicate fair-to-good control, and serum fructosamine concentrations greater than 500 μmol/L indicate poor glycemic control. Relative changes in serum fructosamine may be more helpful than absolute values in some cases.
References 1. Nelson RW. Diabetes mellitus. In: Ettinger SJ, Feldman EC, editors. Textbook of veterinary internal medicine. 4th ed. Philadelphia: WB Saunders; 1995. 2. Greco DS. Diagnosis of diabetes mellitus in dogs and cats. In: Behrend EN, Kemppainen RJ, editors. Vet Clin N Am, vol. 31. Philadelphia: WB Saunders; 2001. p. 845–53. 3. O’Brien TD, Butler PC, Westermark P, Johnson KH. Islet amyloid polypeptide: a review of its biology and potential roles in the pathogenesis of diabetes mellitus. Vet Pathol 1993;30:317–32. 4. Lutz TA, Rand JS. A review of new developments in type 2 diabetes mellitus in human beings and cats. Br Vet J 1993;149:527–36. 5. Brennan CL, Hoenig M, Ferguson DC. GLUT4 but not GLUT1 expression decreases early in the development of feline obesity. Domest Anim Endocrinol 2004;26(4):291–301. 6. Ballard FJ. Glucose utilization in mammalian liver. Comp Biochem Physiol 1965;14:437–43. 7. Rand JS. Canine and feline diabetes mellitus: nature or nurture? J Nutr 2004;134:2072S–80S. 8. Diehl KJ. Long-term complications of diabetes mellitus, part II: gastrointestinal and infectious. In: Greco DS, Peterson ME, editors. Vet Clin N Am, vol. 25. 1995. p. 731–40. 9. Munana KR. Long-term complications of diabetes mellitus, part I: retinopathy, nephropathy, neuropathy. In: Greco DS, Peterson ME, editors. Vet Clin N Am, vol. 25. 1995. p. 715–30. 10. Haberer B, Reusch CE. Glycated haemoglobin in various pathological conditions: investigations based on a new, fully automated method. J Small Anim Pract 1998;39:510–7.
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11. Reusch CE, Liehs MR, Hoyer M, Vochezer R. Fructosamine. A new parameter for diagnosis and metabolic control in diabetic dogs and cats. J Vet Intern Med 1993;7:177–82. 12. Thoresen SI, Bredal WP. Clinical usefulness of fructosamine measurements in diagnosing and monitoring feline diabetes mellitus. J Small Anim Pract 1996;37:64–8. 13. Lutz TA, Rand JS. Fructosamine concentrations in hyperglycemic cats. Can Vet J March 1995;36(3):155–9. 14. Kitamura T, Yasuda J, Hashimoto A. Acute insulin response to intravenous arginine in nonobese healthy cats. J Vet Intern Med 1999;13(6):549–56. 15. Kettlehut IC, Foss MC, Migliorini RH. Glucose homeostasis in a carnivorous animal (cat) and in rats fed a highprotein diet. Am J Physiol 1978;239:R115–21. 16. Mazzaferro EM, Greco DS, Turner AS, Fettman MJ. Treatment of feline diabetes mellitus with a high protein diet and acarbose. J Feline Med Surg 2003;5:183–9. 17. Bennett N, Greco DS, Peterson ME, Kirk CE, Mathes M, Fettman ME. Comparison of a low carbohydrate vs high fiber canned diet for the treatment of diabetes mellitus in cats. J Feline Med Surg April 2006;8(2):73–84. 18. Ford S. NIDDM in the cat: treatment with the oral hypoglycemic medication, glipizide. In: Greco DS, Peterson ME, editors. Vet Clin N Am, vol. 25. 1995. p. 599 (3). 19. Nelson RW, Lynn RC, Wagner-Mann CC, Michels GM. Efficacy of protamine zinc insulin for treatment of diabetes mellitus in cats. J Am Vet Med Assoc 2001;218:38–42. 20. Greco DS, Broussard JD, Peterson ME. Insulin therapy. Vet Clin N Am Small Anim Pract 1995;25(3):677. 21. Gilor C, Ridge TK, Attermeier KJ, Graves TK. Pharmacodynamics of insulin detemir and insulin glargine assessed by an isoglycemic clamp method in healthy cats. J Vet Intern Med 2010;24(4):870–4. 22. Graham PA, Nash AS, McKellar QA. Pharmacokinetics of a porcine insulin zinc suspension in diabetic dogs. J Small Anim Pract 1997;38:434–8. 23. Macintire DK. Treatment of diabetic ketoacidosis in dogs by continuous low-dose intravenous infusion of insulin. J Am Vet Med Assoc 1993;202:1266–72.
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24. MacIntyre DK. Emergency therapy of diabetic crises: insulin overdose, diabetic ketoacidosis and hyperosmolar coma. In: Greco DS, Peterson ME, editors. Vet Clin N Am, vol. 25. 1995. p. 639–50 (3). 25. Rand JS, Martin GJ. Management of feline diabetes mellitus. In: Behrend EN, Kemppainen RJ, editors. Vet Clin N Am, vol. 31. Philadelphia: WB Saunders Co; 2001. p. 881–913. 26. Fleeman LM, Rand JS. Management of canine diabetes. In: Behrend EN, Kemppainen RJ, editors. Vet Clin N Am, vol. 31. Philadelphia: WB Saunders Co; 2001. p. 855–80. 27. Briggs CE, Nelson RW, Feldman EC, Elliott DA, Neal LA. Reliability of history and physical examination findings for assessing control of glycemia in dogs with diabetes mellitus: 53 cases (1995–1998). J Am Vet Med Assoc 2000;217:48–53. 28. Schaer M. A justification for urine glucose monitoring in the diabetic dog and cat. J Am Anim Hosp Assoc 2001;37:311–2. 29. Wess G, Reusch C. Capillary blood sampling from the ear of dogs and cats and use of portable meters to measure glucose concentration. J Small Anim Pract 2000;41:60–6. 30. Reusch CE, Wess G, Casella M. Home monitoring of blood glucose concentration in the management of diabetes mellitus. Comp Cont Educ 2001;23:544–56. 31. Fleeman LM, Rand JS. Evaluation of day-to-day variability in serial blood glucose concentrations in diabetic dogs. J Am Vet Med Assoc 2003;222:317–21. 32. Elliott DA, Nelson RW, Feldman EC, Neal LA. Glycosylated hemoglobin concentration for assessment of glycemic control in diabetic cats. J Vet Intern Med 1997;11:161–5. 33. Elliott DA, Nelson RW, Reusch CE, Feldman EC, Neal LA. Comparison of serum fructosamine and blood glycosylated hemoglobin concentrations for assessment of glycemic control in cats with diabetes mellitus. J Vet Intern Med 1998;12:1794–8.
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