Vol. 22, No.

5 May 2000

CE

Refereed Peer Review

FOCAL POINT #Therapy for diabetes mellitus is
aimed toward the underlying abnormality; insulin is administered when an absolute insulin deficiency exists, and oral hypoglycemic agents can be used if the metabolic abnormalities of type 2 diabetes are present.

Treatment of Feline Diabetes Mellitus: Overview and Therapy*
Auburn University

Ellen N. Behrend, VMD, MS
Colorado State University

Deborah S. Greco, DVM, PhD
ABSTRACT: Diabetes mellitus can be particularly frustrating for veterinarians and clients. Weight management plays a large role in diabetes control, but the recommended high-fiber foods can be unpalatable and are associated with other adverse effects. Rotation of diets and other solutions may help to avoid these problems. Deciding whether to use insulin or hypoglycemic agents can be difficult. Glipizide, vanadium, chromium, and acarbose are oral hypoglycemic agents that may be tried as therapy.

KEY FACTS
I Classification of cats as type 1 or type 2 diabetics is difficult; type 2 diabetes may be the more common form. I The importance of dietary therapy cannot be overemphasized. I Recombinant human insulin may be the preferred type of insulin for cats. I Glipizide, a sulfonylurea, has been shown to have relatively few adverse effects in cats, but long-term efficacy is only approximately 35% to 40%. I Oral administration of vanadium has been shown to decrease clinical signs in diabetic cats.

D

iabetes mellitus (DM) is a common endocrinopathy in older cats; an estimated 1 of 400 cats is affected.1 Aside from the debilitating consequences of DM, management of the disorder may present a significant problem to owners and diagnosis can be a challenge for veterinarians. Owners may need to change their animals’ diet and give daily insulin injections or oral hypoglycemic agents. The requirement for timely insulin injections and frequent rechecks dictates an owner’s schedule; some owners are unable to adhere to a rigid treatment plan or master injection technique. Although oral hypoglycemic agents may avert the necessity of insulin injections in some diabetic cats, these medications must still be administered twice daily.2,3 The need for regular monitoring and the occurrence of secondary problems can lead to frequent veterinary visits and substantial expense. For veterinarians, features peculiar to cats can present certain difficulties. Because of the finicky nature of some cats, compliance with prescribed dietary regimens can be poor. Serial blood glucose measurement to determine diabetic control can be complicated by the presence of stress hyperglycemia. In addition, the need for exogenous insulin in cats waxes and wanes; this phenomenon is understandable but can be a source of frustration for both owners and veterinarians.

DISEASE CLASSIFICATION IN HUMANS Because the study of DM in cats is based on that in humans, comprehension
*Copyright 1998 by the Western Veterinary Conference from the booklet “Clinical Pharmacology, Principles and Practice.” Modified with permission.

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of the human classification scheme is important. Human DM is classified as type 1 and type 2 and was previously known as insulin-dependent DM and non–insulin-dependent DM, respectively. The two types now denote specific pathophysiologies. Type 1 DM, commonly referred to as juvenile onset, is defined by an absence of insulin secondary to immune-mediated destruction of pancreatic islet beta cells4; overt DM results when beta-cell function decreases to less than 20% to 25% of normal.5 Human type 2 DM occurs in older people. Its pathophysiology is more complex and is associated with three major metabolic abnormalities that coexist to varying degrees: impaired insulin secretion, peripheral insulin resistance, and increased basal hepatic glucose production. Type 1 diabetes is still typically insulin dependent, but type 2 may be insulin dependent or independent.4,6 The abnormal insulin secretion in type 2 DM may be caused by altered ability of beta cells to sense blood glucose concentrations.7 Normally, the insulin response to a glucose or glucagon challenge occurs in two phases—immediate and delayed. In the early stages of type 2 DM, after the capacity of beta cells to release insulin has diminished by 80% to 90%, fasting hyperglycemia is present, the immediate insulin phase is markedly reduced or absent, and the delayed phase occurs later than normal and is often exaggerated.7 Because hyperglycemia and hyperinsulinemia coexist, the insulin response must be considered inadequate because the functional mission of beta cells is to secrete sufficient insulin to maintain normoglycemia.4 Disappearance of the delayed phase occurs later in the disease when fasting hyperglycemia supersedes the renal threshold, resulting in glycosuria.8 Insulin resistance is manifested by the need for higher-than-normal concentrations of insulin in the blood to promote peripheral glucose uptake and suppress hepatic gluconeogenesis for maintenance of normoglycemia. Basal hyperinsulinemia and an exaggerated insulin response early in the course of disease in type 2 DM are believed to be a compensatory response to insulin resistance.5 Therapy of DM is generally aimed toward the underlying abnormality. In type 1 DM, the primary problem is lack of insulin. Consequently, treatment provides an exogenous source of the hormone. In type 2 DM, oral agents can be used that attempt to diminish the underlying abnormalities by decreasing insulin resistance, increasing insulin secretion, and/or inhibiting hepatic glucose production. However, as type 2 DM progresses, insulin deficiency occurs and exogenous insulin injections will be required. Because the metabolic abnormalities treated by most oral hypoglycemic agents do not occur in type 1 diabetics, administration of these medi-

cations is inappropriate. An exception is acarbose, which has a role in management of both type 1 and type 2 diabetes.

DISEASE CLASSIFICATION IN CATS Although knowing the type of DM can direct the choice of therapy, distinguishing between the two types in cats tends to be difficult. As in humans, intravenous administration of glucose or glucagon in cats produces immediate and delayed phases of insulin secretion, and an abnormality in this response has been reported to differentiate the types of primary feline DM. In a study by O’Brien and colleagues,8 9 of 16 nondiabetic cats were judged to be glucose intolerant on the basis of abnormal glucose clearance after administration of a large dose of glucose, and the insulin response seen in three of these cats mimicked the pattern seen in early human type 2 DM. Insulin secretion of seven diabetic cats in the same study8 resembled that which occurs in advanced type 2 DM in humans. However, in a study by Kirk and colleagues,9 which used intravenous glucagon, 7 of 30 (23%) diabetic cats had insulin responses consistent with type 2 DM and the remaining 23 cats (77%) were classified with type 1 DM. The results of Kirk and coworkers’ study9 imply that oral hypoglycemic agents would not be helpful in most cats, whereas the results of O’Brien and coworkers’ study8 suggest that they would. This paradox demonstrates the difficulty in distinguishing between the two types of DM in cats. Variation of results in intravenous glucose tolerance tests among individual cats suggests that glucose or glucagon tolerance test results in a single cat must be interpreted with caution.10 Furthermore, classifying cats on the basis of these results may be inaccurate because of the tendency to overestimate the true incidence of type 1 DM. Prolonged hyperglycemia in itself diminishes the secretory capacity of pancreatic islet beta cells, thereby mimicking type 1 DM—an effect referred to as glucose toxicity.11 In other words, the inability to secrete insulin, which is the basis for classifying these cats as having type 1 DM, may actually be caused by type 2 DM. Histologic findings consistent with type 1 DM have been observed in diabetic cats, suggesting that this form of disease does exist.7,12,13 Although some authors believe that type 2 DM is by far the more common,6 the true incidence remains unknown. Type 2 DM is vastly more common than is type 1 DM in humans, and oral hypoglycemic agents with or without insulin are used for treatment. Accordingly, owners expect the same for their cats. Although type 2 diabetes is probably also the more common form in cats, glucose toxicity may be a more significant problem in cats because the diabetic state may be undetected for a longer period.14 Pa-

TYPE 1 VS. TYPE 2 DIABETES I GLUCOSE INTOLERANCE I GLUCOSE TOXICITY

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tients with advanced type 2 DM and glucose toxicity, a situation that is probable for most diabetic cats, have lost the ability to secrete insulin and are likely to require insulin therapy. Conversely, reversal of glucose toxicity may eliminate the diabetic state in some cats.2,3,15 Control of blood glucose may allow beta cells to regain insulin secretory capacity, and therapy with insulin or oral hypoglycemics can be discontinued, at least temporarily. Type 3 (secondary) DM is an uncommon form that results from insulin resistance or beta-cell loss from an unrelated disease process, such as hyperadrenocorticism or acromegaly.6 Resolution of the primary disease process also eliminates type 3 DM unless it has advanced beyond the early stages.

THERAPY Diet Appropriate dietary therapy is essential for diabetic control and should be directed at correcting obesity, maintaining consistency in the timing and caloric content of meals, coordinating with the physiologic effects of administered insulin, minimizing postprandial fluctuations in blood glucose, and preventing or managing concurrent diseases or diabetic complications.16,17 Dry and/or canned foods can be used. Soft, moist foods should be avoided because they contain simple carbohydrates that are rapidly absorbed from the gastrointestinal tract, resulting in a rapid postprandial rise in blood glucose.18 Calories Obesity and malnutrition can lead to insulin resistance, and malnutrition can lead to diminished insulin secretion.19,20 Because these effects can be reversed after body weight abnormalities have been corrected, achieving and maintaining ideal body weight are crucial. For maintenance, cats need 60 to 70 kcal/kg/day.17 If a patient is overweight, caloric intake should be restricted to 70% to 75% of calculated energy needs. Underweight patients should be fed at the maintenance level for ideal body weight. A high-calorie food may also be fed on a short-term basis. Weight change should occur gradually, and blood glucose concentrations must be monitored throughout periods of weight gain or loss because insulin requirements may change. Once ideal body weight has been achieved, maintenance is initiated by feeding the amount calculated to provide maintenance energy requirements. An animal’s weight should be monitored periodically to ensure that it is stable and caloric requirements are being met. The amount fed can be changed accordingly.17 Fiber The role of dietary fiber in diabetic cats is controver-

sial. Through unknown mechanisms, dietary fiber can delay gastrointestinal glucose absorption, reducing postprandial fluctuations in blood glucose and enhancing glycemic control.17,21 In humans, dietary fiber can also decrease serum cholesterol, triglyceride concentrations, and systemic blood pressure.17 One study22 showed that insoluble fiber (i.e., the type present in commercial high-fiber cat food) improves glycemic control in diabetic cats.22 Recent theories, however, suggest that highcarbohydrate diets may lead to DM in cats and that high protein may be beneficial.23 Certainly, high-fiber diets are good options for weight control. The diets that are likely to be most effective for weight loss are those that contain the most fiber and digestible complex carbohydrates on a dry-matter basis. Complications associated with high-fiber diets are poor palatability, increased frequency of defecation, constipation and obstipation (insoluble fiber), soft stools and diarrhea (soluble fiber), weight loss, and hypoglycemia.21 Flatulence and abdominal discomfort are noted in humans on high-fiber diets but are usually transient.17 If firm stools, constipation, or obstipation becomes a problem, soluble fiber, such as sugar-free Metamucil® (Proctor & Gamble, Cincinnati, OH), can be added to the food.24 One teaspoon should be added once or twice daily and then titrated as needed to keep stools soft. Lack of palatability can be problematic, and gradually switching to a high-fiber diet can preclude refusal on the part of the patient and thus may be a useful strategy. Rotating the type of high-fiber diet may avoid development of boredom with a particular food. If highfiber diets are refused, soluble fiber can be added as needed.21

Protein How dietary protein affects glycemic control is unknown. In human diabetics, low dietary protein is used to minimize progression of diabetic nephropathy. Whether this is necessary in cats or whether it would be beneficial to feed high dietary protein to mimic the natural diet is unknown.23 Current recommendations for cats are to feed a diet that is approximately 28% to 40% protein on a dry-matter basis. If concurrent renal disease exists, however, lower protein content is indicated.21 Fat In human diabetics, low dietary fat has been shown to both exacerbate and improve hyperlipemia, and high dietary fat may cause insulin resistance.17,21 In canine diabetics, alterations in synthesis of enzymes used in lipid metabolism or in liver function usually result in hypertriglyceridemia with less severe hypercholesterolemia.25 In light of these derangements and until the

TYPE 3 DIABETES I POSTPRANDIAL BLOOD GLUCOSE I MAINTENANCE ENERGY REQUIREMENTS

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results of dietary fat manipulation in cats are evaluated, restriction of dietary fat (i.e., 17% or less of dry matter) seems prudent.21

such a schedule can be fed free choice as long as daily caloric intake stays within prescribed limits.17,21

Concurrent Disease Because most diabetic cats are middle aged or older, a variety of other age-related diseases may be present, and the diet should be modified accordingly. Pancreatic diseases, such as pancreatitis and exocrine pancreatic insufficiency (EPI), may also occur in diabetic patients; and high dietary fiber may be detrimental in these cases.12,17 If the amount of fiber being fed seems to exacerbate concurrent pancreatitis, it should be decreased.17 Although fiber is considered to be deleterious in cases of EPI because of its ability to inactivate digestive enzymes,17,26 cellulose (the fiber most commonly found in commercial high-fiber cat foods) did not affect purified solutions of pancreatic enzymes in vitro.27 Successful use of high-fiber diets in diabetic cats with EPI has been reported.21 Human patients with EPI on highfiber diets experience increased flatulence.27 Feeding Schedule In human medicine, insulin is administered with each meal to mimic the normal physiologic response and blood glucose is checked at the time of insulin administration as a guide to dosing. Because this approach is not practical in veterinary medicine, at least calories should be ingested when insulin is still present in the circulation to avoid large increases in blood glucose.21 This schedule can be accomplished by feeding several small meals per day instead of one large meal. Accordingly, for animals that receive insulin once a day, three equal-sized meals at 6-hour intervals has been suggested. Animals receiving twice-daily insulin can be fed immediately before each insulin injection as well as in the mid-afternoon and late evening.28 Many owners are unable to comply with these feeding schedules. In these cases, animals receiving twicedaily insulin should be fed immediately before each injection.17,21,29 Animals receiving once-daily injection can be fed one meal before treatment and a second in the late afternoon or early evening.17 If an animal does not eat, the insulin dose can be reduced (usually by 50%) or skipped entirely; if anorexia persists, the animal should be evaluated by a veterinarian to determine the cause.29 Animals that eat small amounts throughout the day may most closely approximate the ideal situation because postprandial hyperglycemia is unlikely to be profound. Although feeding discrete meals is preferred because it is easier to determine whether the patient is eating normally and to administer insulin accordingly, cats that are refractory to

Insulin Mammalian insulin comprises 51 amino acids that are arranged in two polypeptide chains, but small interspecies differences in amino acid sequences exist. Feline insulin is most similar to beef insulin—varying by only one amino acid—but differs from pork and human insulin by three and four amino acids, respectively.21 Historically, beef, pork, and human recombinant insulins have been commercially prepared, but the availability of animal-source insulin is decreasing. Human recombinant insulin is preferred for humans, especially those who are prone to develop allergies or immune resistance to animal-source insulin.30 In contrast, although use of insulin derived from another species can lead to insulin resistance in cats, formation of a low titer of antibodies against a foreign insulin may actually help to prolong the duration of action, which is a desirable effect.21 Insulin Types and Syringes There are five main forms of insulin available to veterinarians: Lente® (Eli Lilly, Indianapolis, IN), Ultralente® (Eli Lilly), neutral protamine Hagedorn (NPH; also known as isophane suspension), protamine zinc insulin (PZI), and regular insulins. These insulins are derived from humans, cattle, and pigs and are marketed by different companies (Table I). Regardless of the source, these insulins can be further classified as short, intermediate, or long acting, depending on the formulation. In general, the longer acting the insulin is, the less potent it is.21 Regular insulin is not complexed to any other molecules that retard absorption and, as a result, is short acting (Table II). The insulin molecule in NPH and PZI is bound to the protein protamine to slow absorption. Although PZI was discontinued as a human preparation in 1991, it is now available on an investigational basis for veterinary use (Blue Ridge Pharmaceuticals, Greensboro, NC). NPH insulin is considered to be intermediate acting, and PZI is long acting. Lente® insulins rely on alterations in zinc content and the size of zinc–insulin crystals to alter the subcutaneous absorption rate.21 Lente® insulin is intermediate acting and consists of 30% regular and 70% Ultralente® insulin.21 Ultralente® insulin is microcrystalline and long acting. Insulin preparations that consist of NPH and regular insulin are also available. Although there is a system for naming insulin, the nomenclature can be confusing because manufacturers use different brand names even though the preparations may be from the same species and have the same dura-

PANCREATITIS I EXOCRINE PANCREATIC INSUFFICIENCY I ANOREXIA

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tion of action. In general, the name of an insulin identifies both its source and type; the source of the insulin is identified by a letter (R for regular, L for Lente®, N for NPH, and U for Ultralente®) or is spelled out. For example, Humulin ® L (Eli Lilly) and Novolin ® L (Novo Nordisk, Princeton, NJ) are both recombinant human Lente® insulins.29 Lente® Iletin® I (Eli Lilly) is beef/pork insulin, and Lente® Iletin® II (Eli Lilly) is pork insulin. Lente® Iletin® II and Humulin® L are both Lente® insulins but are derived from different species. One exception is Velosulin® (Novo Nordisk), which is a regular human insulin. Insulin is available in 40-, 100-, and 500-U/ml concentrations, designated U40, U100, and U500, respectively. In the United States, U100 is the primary concentration available, and 1 U of insulin is approximately equivalent to 36 µg.31 Insulin syringes are specifically manufactured to be used with one concentration of insulin and are designated U40 or U100 accordingly. Matching
TABLE I Insulin Preparations29,a Product (Manufacturer) Short acting Humulin® R (Eli Lilly, Indianapolis, IN) Novolin® R (Novo Nordisk, Princeton, NJ) Velosulin® BR (Novo Nordisk) Intermediate acting Humulin® L (Eli Lilly) Humulin® N (Eli Lilly) Novolin® L (Novo Nordisk) Novolin® N (Novo Nordisk) Type Regular Regular Regular Lente® NPH Lente® NPH

the insulin concentration with the correct syringe is essential to ensure accurate dosing. Insulin syringes are packaged with a fine 26- or 27gauge needle to minimize discomfort on injection. The U40 and U100 syringes are available in 1-ml sizes. U100 syringes are also manufactured in low-dose sizes (0.3 and 0.5 ml) designed to accurately draw a small dose of insulin without the need for dilution. These syringes help achieve accurate dosing when small quantities are required and are especially recommended in cats. They may also be particularly helpful for elderly pet owners because the unit marks are easier to read.29 Insulin can be diluted when extremely small doses or fractional increments (0.5 or 0.25 U) are needed. Because of the difficulty involved in giving small doses, administration of less than 2.0 U of undiluted U100 insulin results in marked overdose in diabetic children in up to 95% of cases.32 A diluent specifically designed by the manufacturer for a given insulin preparation should be used, and special care must be taken to ensure that the correct dose of diluted insulin is administered with an insulin Species of syringe. For example, if a 1:10 Origin Concentration dilution of insulin is prepared, the new concentration is 10 Human U100 U/ml and a full 1-ml U100 syringe contains only 10 U. Human U100 Similarly, a full 0.5-ml syringe contains 5 U and a full 0.3-ml Human U100 syringe contains 3 U.31
Human Human Human Human U100 U100 U100 U100

Dose Regimens The dose of insulin administered depends on whether Lente®, NPH, Ultralente®, or PZI insulin is used (Table III). Long acting Dosing should be conservaProtamine zinc insulin Protamine Beef, pork U40 tive, with increments increased (Blue Ridge Pharmaceuticals, zinc based on resolution of clinical Greensboro, NC) signs, urine glucose monitorHumulin® U (Eli Lilly) Ultralente® Human U100 ing, and serial measurement of blood glucose.29 IntermediateMixtures acting insulins (e.g., NPH), tend Humulin® 50/50 (Eli Lilly) 50% NPH, Human U100 to be more bioavailable than 50% regular are longer-acting insulins; thus Humulin® 70/30 (Eli Lilly) 70% NPH, Human U100 an injection of NPH achieves 30% regular a higher serum insulin conNovolin® 70/30 70% NPH, Human U100 (Novo Nordisk) 30% regular centration more rapidly and the starting dose is lower. BeaModified from Greco DS, Broussard JD, Peterson ME: Insulin therapy. Vet Clin North Am Small cause absorption of long-actAnim Pract 25:675, 1995; with permission. ing insulins varies greatly among BR = buffered regular; NPH = neutral protamine Hagedorn. cats,33,34 these dose recommenSYRINGE TYPES I INSULIN CONCENTRATION I DILUENTS

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TABLE II Characteristics of the Insulin Types3 Route of Administration Subcutaneous Subcutaneous Subcutaneous Subcutaneous Subcutaneous Duration of Action Short Intermediate Intermediate Long Long Time to Maximum Effect (hr) 1–5 2–8 2–8 3–12 4–16 Duration of Effect (hr) 4–10 6–14 4–12 6–24 8–24

Insulin Type Regular Lente® (Eli Lilly, Indianapolis, IN) Neutral protamine Hagedorn Protamine zinc insulin Ultralente (Eli Lilly)
®

Onset 10–30 min <1 hr 0.5–3 hr 1–4 hr 1–8 hr

TABLE III Initial Insulin Regimens for Diabetic Cats29,a Insulin Type Lente® (Eli Lilly, Indianapolis, IN) Neutral protamine Hagedorn Protamine zinc Ultralente® (Eli Lilly)
aModified

Initial Dose (U) 2–3 1 1–3 1–3

Dosing Frequency Twice daily Twice daily Once or twice dailyc Once or twice dailyc

Feeding Schedule Twice dailyb or free choice Twice dailyb or free choice Twice dailyb or free choice Twice dailyb or free choice

Insulin Adjustment (U/dose) 0.5–1 0.5–1 0.5–1 0.5–1

from Greco DS, Broussard JD, Peterson ME: Insulin therapy. Vet Clin North Am Small Anim Pract 25:684, 1995; with permission. b Preferred. c Therapy can be instituted once daily; twice-daily therapy may ultimately be required.

dations are offered only as guidelines. The correct dose needs to be determined individually. Ultralente® insulin, which is available as a human recombinant product, may be used initially.35 If Ultralente® insulin is used, treatment should begin with once-daily administration but can be increased to twice daily if blood glucose testing suggests an inadequate duration of action. However, in approximately 20% of diabetic cats, Ultralente® insulin does not adequately control blood glucose levels, which tend to remain above 300 mg/dl for most of the day with resultant polyuria and polydipsia.21,35 For these cats, Lente® insulin is often a better choice for glycemic control.36,37 When diabetic patients are in transition from complicated diabetes and ketoacidosis to maintenance therapy, the decision to change from short-acting (i.e., regular) to intermediate- or long-acting insulin should be made on the basis of resolution of ketosis and clinical signs. The transition from hospital to home maintenance therapy can be made by using a low dose (1 to 2 U) of regular insulin combined with intermediate- or

long-acting insulin at the recommended maintenance doses.29

Mixtures In human diabetics, insulins can be combined to fine-tune glucose regulation.38–40 Lente® insulin is already a combined form, and stable premixed 70% NPH–30% regular and 50% NPH–50% regular insulins are also available (Table I). Intermediate- or longacting insulins supply a basal insulin serum concentration for an extended period, whereas regular insulin mimics the increased insulin concentrations during and immediately after consumption of a meal and thus minimizes postprandial hyperglycemia. In veterinary medicine, meticulous glucose control is seldom necessary. Furthermore, the typically short duration of action (less than 8 hours) of premixed NPH and regular insulin causes a rapid decrease in blood glucose and is often associated with hypoglycemic episodes; thus they are seldom indicated. Despite their shortcomings, insulin combinations

INITIAL INSULIN DOSING I TRANSITION DOSES

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may be useful in three situations: to manage patients with insulin resistance, manage those with a tendency toward ketoacidosis,41,42 and facilitate administration of insulin to an animal for which once-daily insulin is inadequate and whose owner is unwilling or unable to administer insulin twice daily.29 For patients in the last category, a combination of intermediate- and long-acting insulins may be given in the morning after a meal that accounts for two thirds of the daily caloric requirement. The long-acting insulin dose should be 0.5 to 0.7 U/kg, and the intermediate-acting insulin should be one third of the long-acting insulin dose. The animal should be given a meal that meets the remainder of the daily caloric requirements 8 to 10 hours later. Good success has been achieved in regulating dogs with this regimen.29 The best combination may be Lente® and Ultralente® insulins because they can be mixed in one syringe and given as a single injection. Some other types of insulin should not be combined in a single syringe. In such cases, two separate injections can be given.

fold, the needle may penetrate the other side of the skin and deposit the insulin on the hair. Clipping or shaving a 2 × 2–inch square on the lateral thorax or abdomen can assist owners in accurate needle placement.29 At least 30 minutes should be set aside to instruct owners on proper technique. It often helps to reinforce a verbal discussion with written instructions to which owners can refer. Many commercially available pamphlets provide information on injection techniques, feeding, and management of hypoglycemic episodes along with formatted log sheets for owners to record food intake, clinical signs, urine glucose measurements, and insulin doses.

Injection Location and Technique and Client Education The site and method of insulin injection are important aspects of client education. An appropriate location for an injection site must be chosen because absorption of insulin from various sites in the body differs. For example, in humans, insulin absorption is more rapid from the abdomen than from the thigh, and injection into an extremity may result in inconsistent insulin absorption, depending on exercise and limb movement.39 In cats, the dorsal neck or scruff has commonly been used but may not be ideal because of low blood flow and increased fibrosis caused by repeated injections. A better option may be to administer insulin at sites along the lateral abdomen and thorax. The chosen area should be rotated daily to prevent injection-site fibrosis.29 Owners should be instructed to begin the injection process by removing the insulin bottle from the refrigerator and mixing the contents by gentle rolling or agitation. The insulin bottle should then be turned upside down and the correct amount of insulin drawn into an appropriate insulin syringe. The client should be given precise directions on technique. One common mistake is measuring the dose of insulin from the bottom, rather than the top, of the plunger. To detect and avoid all errors, owners should practice by using saline under the observation of a veterinarian or veterinary technician. Clients should be instructed to inject insulin in their pets by lifting the loose skin over the lateral abdomen or thorax and inserting the needle at a 45˚ angle to the skin along the long axis of the skinfold. If it is inserted perpendicular to the skin-

Oral Hypoglycemic Agents Oral hypoglycemic agents include the sulfonylureas (glipizide, glyburide, glimepiride), biguanides (metformin), thiazolidinediones (troglitazone), α-glucosidase inhibitors (acarbose), and transition metals (vanadium, chromium). These medications are the mainstay of therapy for humans with type 2 diabetes because they improve insulin sensitivity, increase insulin secretory response to glucose, and/or decrease hepatic glucose production. In other words, these agents correct the major metabolic derangements of type 2 DM.43 Although type 2 DM is likely the more common form of the disorder in cats, sulfonylureas have had limited success for several possible reasons. First, although both humans and cats with type 2 diabetes have deposition of amyloid in pancreatic islet beta cells, the extent of deposition is greater in cats and involves approximately 80% of the pancreatic islet beta cells compared with approximately 30% in humans.14 Consequently, cats reserve less insulin, and such agents as glipizide, which act to increase insulin release, are less effective. Second, glucose toxicity may be more profound in cats. Thus ketosis is more common in feline diabetics than in humans, and this is probably a reflection of the greater suppression of insulin secretion by glucose toxicity and/or loss of beta cells through amyloid deposition.14 Third, limited success may simply result from lack of experience. Glipizide is the only oral hypoglycemic agent that has undergone clinical trials in cats. Perhaps other agents that have different mechanisms of action (e.g., targeting hepatic glucose synthesis or insulin resistance) may be more effective. Agents That Promote Insulin Release from the Pancreas The primary action of sulfonylureas is to increase beta-cell insulin release and augment beta-cell responsiveness to glucose.44 Secondary effects include suppression of hepatic glucose production and increased in-

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sulin sensitivity. These effects may occur as a direct result of sulfonylurea action or as an indirect result of the better glycemic control and reduction of glucose toxicity induced by the sulfonylurea.45 Nelson and colleagues2 conducted a preliminary study of 20 diabetic cats treated for 12 weeks with oral glipizide (5 mg twice daily), a second-generation sulfonylurea. Thirteen cats (65%) initially had a complete or partial response, whereas the other seven (35%) did not respond. In one cat that responded completely and another that responded partially, glipizide became ineffective over time (6 and 9 months, respectively), suggesting a long-term response rate of 55%.2 A more recent intensive study3 of 50 cats treated similarly showed less success. Of the 50 cats, 7 (14%) responded completely, 6 (12%) were judged to be transient diabetics, and 28 (56%) did not respond. Treatment in six cats (12%) was considered to have failed on the basis of serial blood glucose measurement, but owner opinion and other laboratory evidence supported the belief that the cats’ condition had improved. (These cats would have been considered partial responders in the study by Nelson and colleagues.2) The remaining three cats (6%) responded initially to glipizide, but glycemic control deteriorated over time. Thus the long-term success rate was 38% if the cats with transient diabetes are counted as successes.3 Likewise, a recent retrospective study of 104 cats reported successful glipizide therapy in approximately 35%.12 Which cats will respond to glipizide cannot be predicted. Because glipizide acts by increasing insulin release, insulin must be present within the beta cells for the agent to be effective. The ability to secrete insulin, however, cannot be consistently demonstrated because of glucose toxicity. In the study by Nelson and coworkers,2 19 of 20 cats had little or no increase in serum insulin after intravenous glucagon administration; furthermore, no difference existed between cats that responded completely, partially, or not at all in terms of baseline serum insulin concentration, insulin peak response, and total insulin secretion. Adverse effects related to glipizide administration seem to be minimal and, in most cases, transient. Vomiting, the most common effect, was noted in approximately 15% of cats.2,3 In the study by Nelson and coworkers,2 vomiting occurred within 30 minutes of drug administration during the first week of treatment and ceased after 3 to 5 days in two cats despite ongoing treatment. In another study,3 the medication was discontinued and vomiting resolved within 5 days; therapy was restarted (using a gradually increasing regimen) without recurrence of vomiting in most cats. Two cats had persistent vomiting that necessitated discontinuation of the medication.2,3

In the study by Nelson and coworkers,2 two cats had mild increase in serum alanine aminotransferase activity, one had mild increase in serum alkaline phosphatase activity, and one had mild increase in serum cholesterol concentration. In two of three cats, glipizide was continued despite the biochemical changes,2 and whether these alterations resolved was not clear. Approximately 10% of cats developed increased liver enzymes and clinical icterus within 4 weeks after therapy was initiated.3,12 Icterus resolved within 5 days of cessation of drug administration; although hepatic abnormalities typically did not recur after therapy was restarted with gradually increasing doses,3 they have been shown to do so.46 Hypoglycemia has been noted in approximately 12% to 15% of cats that respond to glipizide.2,3 In these cats, DM had resolved, at least temporarily, and glipizide was discontinued. Most cats that respond without continued adverse effects can be treated with glipizide for life; some cats have been treated for longer than 7 years.21 However, glipizide loses its effectiveness in 5% to 10% of patients.2,3 This estimate may be conservative; studies conducted with longer follow-up periods may show a higher failure rate over time. The period from initiation of glipizide therapy to the need for insulin therapy is unpredictable and quite variable, ranging from a few weeks to more than 3 years. Presumably, development of insulin dependence is related to progressive loss of beta cells and insulin secretory capacity.21 The ideal patient for treatment with glipizide and dietary therapy is stable, nonketotic, and of optimum body weight to obese and has mild clinical signs and no complicating diseases. Conversely, patients that are emaciated, dehydrated, or debilitated; have recently lost 10% or more of their body weight; or have abnormalities that cannot be attributed to uncomplicated, untreated diabetes are not good candidates.46 Although ketoacidosis is usually considered a contraindication,12,21,46 two ketonuric cats treated with glipizide did respond.2 Glipizide should certainly be tried in cats whose owners refuse to give injections. In the study on glipizide using 50 cats,3 25 of 27 owners who initially refused to administer insulin agreed to do so later when glipizide therapy failed; the process of developing a better understanding of DM may have allowed these owners to reconsider their decision. Glipizide treatment should be instituted at 2.5 mg orally twice a day with food, and cats should be examined after 1 and 2 weeks. A history; complete physical examination; and measurement of body weight, preprandial blood glucose concentration, and glucose and ketones in urine should be done. If no problems occur during the first 2 weeks but the diabetes is not con-

ORAL GLIPIZIDE I ADVERSE EFFECTS I HEPATIC ABNORMALITIES

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trolled, the glipizide dose should be increased to 5.0 mg twice daily. If ketonuria is found, the medication should be discontinued and insulin therapy initiated.21 If vomiting or icterus is present, the drug should be discontinued for at least 5 days or until the problem resolves. Most cats tolerate the medication if it is started at a lower dose and gradually increased. A dose of 1.25 mg/day should be administered for 7 days, then increased, if indicated, to 2.5 mg/day for 7 days, then 2.5 mg twice daily for 14 days, and then 5.0 mg twice daily.3 If hepatic enzyme elevation or icterus occurred during the first administration, liver enzymes and serum bilirubin concentration should be checked periodically after reinitiating therapy. If vomiting, hepatic enzyme elevation, or icterus recurs, drug administration should be stopped and the cat treated with insulin.21 After the full dose of 5 mg twice daily has been administered for 2 weeks, the previously mentioned clinical parameters and, ideally, measurement of serum glucose concentrations every 1 to 2 hours from 8 AM to 6 PM should be checked every 4 weeks to monitor for therapeutic response and adverse effects.21 Response to therapy is evidenced by resolution of clinical signs, blood glucose concentrations of 200 mg/dl or less, and lack of glycosuria.46 Some evidence suggests that a preprandial blood glucose concentration lower than 200 mg/dl may also indicate control.3 Use of a single sample can be tried, but serial measurement should be done if there is suspicion about the level of control. Because the time until response is noted varies, the full dose regimen should be administered for 12 weeks unless a contraindication (e.g., ketonuria, deterioration of health) arises21 (Figure 1). If no response occurs after 12 weeks (i.e., if blood glucose concentrations are consistently above 300 mg/dl, weight loss occurs, and clinical signs continue), glipizide administration should be stopped and insulin therapy instituted. Conversely, if clinical signs and glycosuria resolve and blood glucose concentrations are 200 mg/dl or less, glipizide therapy may be tapered or stopped; the serum glucose concentration should be reevaluated in 1 week.21,46 If hyperglycemia is present at the recheck, glipizide therapy should be reinitiated at 50% of the previous dose.46 If normoglycemia is present, appropriate dietary therapy for diabetic patients should be continued. Glipizide can be used when hyperglycemia recurs, but normoglycemia may be maintained for 12 to 14 months or longer.2 The patient should be rechecked with a preprandial glucose concentration or serial blood glucose measurements, as necessary, every 3 months to document ongoing control. Cats that have resolution of clinical signs, stable body weight, and normal physical examinations but whose

preprandial or serial blood glucose measurements are 200 mg/dl or higher present a clinical dilemma about whether glipizide should be continued. This situation is often caused by a partial response to glipizide; cats with more advanced loss of pancreatic beta cells may not be able to produce sufficient insulin to become normoglycemic but may have enough to reduce the mean serum glucose concentration and partially control clinical signs.2 Alternatively, the hyperglycemia noted during serial glucose measurement may simply be a stress response. In one study,3 physical examination findings and glycosylated hemoglobin (GHb) measurement showed that cats fitting this description had adequate glycemic control at home. These cats should ideally be monitored by serum GHb or fructosamine concentrations to determine overall glycemic control. If these tests are not available, urine glucose can be monitored at home when the cat is not stressed. If glycosuria is absent or GHb or fructosamine concentrations are normal, glipizide therapy can proceed. If glycosuria is present or glycated protein levels are elevated, insulin therapy should be used instead.3,21 Glyburide is also a second-generation sulfonylurea. Experience with this drug in veterinary medicine is limited. Although reportedly similar to glipizide in terms of net glycemic control, a few qualitative differences may exist, and glyburide has a longer duration of action.21 Glyburide may be used at an initial dose of 0.625 mg (one half of a 1.25-mg tablet) once daily if glipizide is not available. Response to therapy and adverse reactions to glyburide are likely to be similar to those described for glipizide.21

Agents That Inhibit Intestinal Glucose Absorption α-Glucosidase inhibitors impair intestinal glucose absorption by decreasing fiber digestion and hence glucose production from food sources. In humans, acarbose is used as initial therapy in obese prediabetic patients with insulin resistance or as adjunct therapy to enhance the hypoglycemic effects of sulfonylureas or biguanides in patients with type 2 diabetes. Acarbose is not indicated in humans with low or normal body weight because of its effects on nutrition. In cats, acarbose may be administered at a dose of 12.5 to 25 mg with meals. Side effects are more common with higher doses and include flatulence, semiformed stools, and in some cases overt diarrhea. The glucose-lowering effect of acarbose alone is mild, with blood glucose concentrations decreasing only to the 250 to 300 mg/dl range. However, one of the authors (DSG) has noted that acarbose is an excellent adjunct to insulin for improving glycemic control.

KETONURIA I MONITORING I GLYCOSYLATED HEMOGLOBIN I ACARBOSE

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Start glipizide therapy at 2.5 mg twice daily administered with food

At end of weeks 1 and 2, perform a physical examination, conduct a urinalysis, and measure blood glucose concentration

If the cat is ketonuric, switch to insulin

If the cat is doing well, increase glipizide to 5 mg twice daily; after 2 weeks, monitor as before and measure blood glucose

If the cat is vomiting or icteric, discontinue glipizide for 5 days or until problem resolves

If no response after 12 weeks, switch to insulin If partial response occurs, reasons may vary (see text)

Restart glipizide therapy at a lower dose, and increase gradually (see text) Achieve a dose of 5 mg twice daily If clinical response is good, discontinue glipizide to determine if therapy can be stopped (see text)

If vomiting or icterus recurs, switch to insulin

Figure 1—Treatment protocol for glipizide.

Agents That Improve Peripheral Insulin Sensitivity Transition Metals. The transition metal vanadium is the only other oral hypoglycemic agent for which published studies in cats are available. Indeed, transition metals were used to treat DM in humans before the discovery of insulin, and their use has received renewed interest. Compounds containing vanadium have been shown to have insulin-mimetic properties in numerous rodent models of types 1 and 2 DM.47–49 In type 2 DM, vanadium, by working at a postreceptor site independent of insulin, leads to constant suppression of blood glucose compared with the fluctuating serum glucose levels that characterize insulin injections.47,48 One study50 assessed the toxicity of three forms of vanadium—orthovanadate, bis(maltolato)oxovanadium, and glycine-glycine vanadate—in six healthy cats. Each form was added to drinking water for a 4-week course with a 2-week wash-out period in between. All six cats received all three forms of vanadium during the course of the study. Occasional vomiting and/or diarrhea was noted in two of the cats, and water consumption decreased substantially. No biochemical or hematologic evidence of toxicity was observed. One diabetic

cat was also given orthovanadate in drinking water for 4 weeks; during this period, blood glucose decreased and clinical signs resolved without occurrence of hypoglycemia.50 One author (DSG)53 has noted that low doses (0.2 mg/kg/day) of oral vanadium decrease blood glucose and alleviate the clinical signs of DM in cats with early type 2 DM, similar to previous findings in rodent models.47,49,51,52 Compared with the placebo group, cats fed vanadium in water or food gained weight, showed a significant decrease in serum fructosamine, and had amelioration of clinical signs.53 The placebo group lost weight (1 kg) and had progression of clinical signs and significantly higher serum fructosamine concentrations at the end of the study.53 Vanadium-treated cats had posttreatment serum fructosamine concentrations of 484 µmol/L compared with 564 µmol/L in the placebo group (normal, below 360 µmol/L).53 These results are similar to those of another study54 in which the median serum fructosamine concentration in well-regulated diabetic cats treated with insulin alone was 450 µmol/L and the median serum fructosamine in nontreated diabetic cats was 624 µmol/L. Vanadium is available commercially (SuperVanadyl Fuel, Twin Labo-

VANADIUM I TOXICITY I SERUM FRUCTOSAMINE

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Compendium May 2000

ratories, Inc., Ronkonkoma, NY) and can be given as a half capsule once daily with food. Alternatively, chromium may be administered at a dose of 200 µg once daily as a tablet or capsule. Thiazolidinediones. A new class of oral hypoglycemic agents in human medicine are the thiazolidinedione compounds.55 The mechanism of action of these drugs may relate to interaction with a member of a family of nuclear receptors called peroxisome proliferator-activated receptors (PPARs), most likely PPARγ.43,55 Thiazolidinediones facilitate insulin-dependent glucose disposal and inhibit hepatic glucose output by attenuation of gluconeogenesis and glycogenolysis. Some authors have suggested that use of troglitazone, a first-generation thiazolidinedione, early in the course of type 2 DM may slow its progression.55,56 Side effects of troglitazone in humans are usually minor, and no hypoglycemic reactions have been described. However, idiosyncratic hepatic toxicity has been observed.a Improvement in fasting blood glucose, glycosylated hemoglobin, and diabetic complications were noted in all human diabetics and were significant when compared with the placebo.56,57 One author (DSG) has used 200 mg of troglitazone once daily in cats without observing significant changes in blood glucose regulation or side effects.

must be done cautiously because such combinations may induce hypoglycemic reactions. Changes from insulin to oral hypoglycemic agents or vice versa may be necessary in some diabetic cats. If a cat is particularly sensitive to insulin, changing to an oral hypoglycemic agent should be considered. On the other hand, if the cat is being managed with oral hypoglycemic agents and ketosis develops, oral medication should be discontinued and the cat should be treated with insulin.

Agents That Suppress Hepatic Glucose Output Although the exact mechanism is unknown, biguanides (metformin) work mainly by inhibiting hepatic glucose release and improving peripheral insulin sensitivity. Other actions may include increased peripheral glucose uptake and delayed gastrointestinal glucose absorption.43,59 No published information on their use in diabetic cats exists. Combining Oral Hypoglycemics with Insulin Agents that impair glucose absorption from the intestine (acarbose) or increase insulin sensitivity (vanadium, metformin, troglitazone) may be combined with insulin to improve glucose control in patients with type 2 diabetes. For cases of “brittle” diabetes, in which small incremental changes in the dose of insulin may precipitate hypoglycemia, addition of a drug that enhances the action of insulin may lead to a reduced insulin requirement for attainment of normoglycemia. In humans with type 2 diabetes, acarbose and metformin are commonly used in conjunction with insulin and other oral hypoglycemic agents that cause insulin release (sulfonylureas). Combining any oral hypoglycemic agent, particularly sulfonylureas, with insulin
a Editor’s note: In March 2000, the FDA withdrew troglitazone from the market after reports of its association with rare cases of fatal liver failure and liver failure requiring transplantation.

PROGNOSIS The prognosis for cats with DM is relatively good. Not all cats respond to all types of insulin, but fair to good control can be achieved in most feline DM patients.12 Interestingly, assessment of control by blood glucose measurement versus owner observation did not correlate in 54 cats in a study by Goossens and colleagues.12 The investigators considered mean blood glucose levels of 200 to 300 mg/dl to indicate average glycemic control, but owner-assessed clinical status was good in most cats that had a mean blood glucose level of less than 300 mg/dl.12 Studies by Goossens12 and Krauss59 and their coworkers showed that cats survived a median of approximately 17 months from the time of diagnosis; median follow-up time was 2012 and 3559 months, respectively. The difference between the two may be caused by the timing of data assessment rather than a true difference in the populations. Death may be highest during the first year—62% in one study—and may result from diabetes or unrelated diseases.59 The level of glycemic control may affect survival because the difference in survival times between cats with good or average glycemic control and cats with poor glycemic control approached statistical significance (P = .06).12 Similarly, cats that are not insulin dependent (i.e., their disease is controlled with oral hypoglycemic agents) and cats that are transiently diabetic also tend to have a better prognosis.59 REFERENCES
1. Panciera DL, Thomas CB, Eicker SW, et al: Epizootiologic patterns of diabetes mellitus in cats: 333 cases (1980–1986). JAVMA 197:1504–1508, 1990. 2. Nelson RW, Feldman EC, Ford SL, et al: Effect of an orally administered sulfonylurea, glipizide, for treatment of diabetes mellitus in cats. JAVMA 203:821–827, 1993. 3. Feldman EC, Nelson RW, Feldman MS: Intensive 50-week evaluation of glipizide administration in 50 cats with previously untreated diabetes mellitus. JAVMA 210:772–777, 1997. 4. Unger RH, Foster DW: Diabetes mellitus, in Wilson JD, Foster DW (eds): Williams Textbook of Endocrinology, ed 3. Philadelphia, WB Saunders Co, 1992, pp 1255–1334. 5. Porte Jr D: β cells in type II diabetes mellitus. Diabetes 40: 166–180, 1991.

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6. Lutz TA, Rand JS: Pathogenesis of feline diabetes mellitus. Vet Clin North Am Small Anim Pract 25:527–552, 1995. 7. Lutz TA, Rand JS: A review of new developments in type 2 diabetes in human beings and cats. Br Vet J 149:527–536, 1993. 8. O’Brien TD, Hayden DW, Johnson KH, et al: High dose intravenous glucose tolerance test and serum insulin and glucagon levels in diabetic and non-diabetic cats: Relationships to insular amyloidosis. Vet Pathol 22:250–261, 1985. 9. Kirk CA, Feldman EC, Nelson RW: Diagnosis of naturally acquired type-I and type-II diabetes mellitus in cats. Am J Vet Res 54:463–467, 1993. 10. Sparkes AH, Adams DT, Cripps PJ: Inter- and intraindividual variability of the response to intravenous glucose tolerance testing in cats. Am J Vet Res 57:1294–1298, 1996. 11. Link KR, Rand JS: Glucose toxicity in cats (Abstr). J Vet Intern Med 10:185, 1996. 12. Goossens M, Nelson RW, Feldman EC, et al: Response to insulin treatment and survival in 104 cats with diabetes mellitus (1985–1995). J Vet Intern Med 12:1–6, 1998. 13. Hall DG, Kelley LC, Gray ML, et al: Lymphocytic inflammation of pancreatic islets in a diabetic cat. J Vet Diagn Invest 9:98–100, 1997. 14. Rand JS: Understanding feline diabetes. Proc 14th ACVIM Forum:82–83,1996. 15. Nelson RW, Griffey FM, Feldman EC, Ford SL: Transient clinical diabetes mellitus in cats: 10 cases (1989–1991). J Vet Intern Med 13:28–35, 1999. 16. Nelson RW, Lewis LD: Nutritional management of diabetes mellitus. Semin Vet Med Surg 5:178–186, 1990. 17. Ihle SL: Nutritional therapy for diabetes mellitus. Vet Clin North Am Small Anim Pract 25:585–597, 1995. 18. Holste LC, Nelson RW, Feldman EC: Effect of dry, soft moist, and canned dog foods on postprandial blood glucose and insulin concentrations in healthy dogs. Am J Vet Res 50:984–989, 1989. 19. Nelson RW, Himsel CA, Feldman EC, et al: Glucose tolerance and insulin response in normal-weight and obese cats. Am J Vet Res 51:1357–1362, 1990. 20. Biourge V, Nelson RW, Feldman EC: Effect of weight gain and subsequent weight loss on glucose tolerance and insulin response in healthy cats. J Vet Intern Med 11:86–91, 1997. 21. Feldman EC, Nelson RW: Diabetes mellitus, in Canine and Feline Endocrinology and Reproduction. Philadelphia, WB Saunders Co, 1996, pp 339–391. 22. Nelson RW, Scott-Moncrieff C, DeVries S: Dietary insoluble fiber and glycemic control of diabetic cats (Abstr). J Vet Intern Med 8:165, 1994. 23. Rand JS: Pathogenesis of feline diabetes, in Reinhart GA, Carey DP (eds): Iams Nutr Symp Proc:83–95, 1998. 24. Nelson RW, Ihle SL, Lewis LD: Effects of dietary fiber supplementation on glycemic control in dogs with alloxan-induced diabetes mellitus. Am J Vet Res 52:2060–2066, 1991. 25. Zerbe CA: Canine hyperlipemias, in Kirk RW (ed): Current Veterinary Therapy IX. Philadelphia, WB Saunders Co, 1986, pp 1045–1053. 26. Remillard RL, Matz ME, Shell LG: Nutritional management of complicated cases of canine diabetes mellitus. Compend Contin Educ Pract Vet 14(2):176–183, 1992. 27. Dutta SK, Hlasko J: Dietary fiber in pancreatic disease: Effect of high fiber diet on fat malabsorption in pancreatic insufficiency and in vitro study of the interaction of dietary fibers with pancreatic enzymes. Am J Clin Nutr 41:517–525,

1985. 28. Nelson RW: Dietary therapy for diabetes mellitus. Compend Contin Educ Pract Vet 10(12):1387–1392, 1988. 29. Greco DS, Broussard JD, Peterson ME: Insulin therapy. Vet Clin North Am Small Anim Pract 25:677–689, 1995. 30. Scherthaner G: Immunogenicity and allergenic potential of animal and human insulins. Diabetes Care 16:155–165, 1983. 31. Peterson ME: Insulin and insulin syringes, in Kirk RW, Bonagura JD (eds): Kirk’s Current Veterinary Therapy XI. Small Anim Practice. Philadelphia, WB Saunders Co, 1992, pp 356–358. 32. Casella SJ, Mongilio MK, Plotnick LP: Accuracy and precision of low-dose insulin administration. Pediatrics 91:1155– 1157, 1993. 33. Wallace MS, Peterson ME, Nichols CE: Absorption kinetics of regular, isophane and protamine zinc insulin in normal cats. Domest Anim Endocrinol 7:509–516, 1990. 34. Broussard JD, Peterson ME: Comparison of two Ultralente insulin preparations with protamine zinc insulin in clinically normal cats. Am J Vet Res 55:127–131, 1994. 35. Nelson RW, Feldman EC, DeVries S: Use of Ultralente insulin in cats with diabetes mellitus. JAVMA 200:1828–1829, 1992. 36. Bertoy EH, Nelson RW, Feldman EC: Effect of Lente insulin for treatment of diabetes mellitus in 12 cats. JAVMA 206:1729–1731, 1995. 37. Nelson RW: Diabetes mellitus, in Ettinger SJ, Feldman EC (eds): Textbook of Veterinary Internal Medicine, ed 4. Philadelphia, WB Saunders, 1995, pp 1510–1537. 38. Turner RC, Mairead A, Ward EA: Ultralente based insulin regimens—Clinical applications, advantages and disadvantages. Acta Med Scand 671:75–86, 1983. 39. Turner RC, Holman RR: Optimizing conventional insulin regimens to improve control, in Pickup JC (ed): Brittle Diabetes. Oxford, Blackwell Scientific Publications, 1985, pp 200–213. 40. Service RJ, Rizza RA, Hall LD: Prandial insulin requirements in insulin-dependent diabetics: Effects of size, time of day, and sequence of meals. J Clin Endocrinol Metab 57:931–935, 1995. 41. Wallace MS, Kirk CA: The diagnosis and treatment of insulin dependent and non-insulin dependent diabetes mellitus in the dog and the cat. Probl Vet Med 2:573–590, 1990. 42. Peterson ME: Endocrine diseases, in Sherding RG (ed): The Cat: Diseases and Clinical Management, ed 2. New York, Churchill Livingstone, 1994, pp 1465–1470. 43. Larkins RG: New concepts for treatment of non-insulin-dependent diabetes mellitus. Trends Endocrinol Metab 8:187– 191, 1997. 44. Gerich JE: Oral hypoglycemic agents. N Engl J Med 321: 1231–1245, 1989. 45. Melander A, Bitzen PO, Faber O: Sulfonylurea antidiabetic drugs: An update of their clinical pharmacology and rational therapeutic use. Drugs 37:58–72, 1989. 46. Ford SL: NIDDM in the cat: Treatment with the oral hypoglycemic medication, glipizide. Vet Clin North Am Small Anim Pract 25:599–615, 1995. 47. Meyerovitch J, Rotenberg P, Shechter Y: Vanadate normalizes hyperglycemia in two mouse models of non-insulin-dependent diabetes mellitus. J Clin Invest 87:1286–1294, 1991. 48. Brichard SM, Pottier AM, Henquin JC: Long term improvement of glucose homeostasis by vanadate in obese hyperinsulinemic fa/fa rats. Endocrinology 125:2510–2516, 1989.

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49. Cam MC, Pederson RA, Brownsey RW, et al: Long-term effectiveness of oral vanadyl sulphate in streptozotocin-diabetic rats. Diabetologia 36:218–224, 1993. 50. Plotnick AN, Greco DS, Crans DC: Oral vanadium compounds: Preliminary studies on toxicity in normal cats and hypoglycemic potential in diabetic cats (Abstr). J Vet Intern Med 9:181, 1995. 51. Brichard SM, Bailey CJ, Henquin JC: Marked improvement of glucose homeostasis in diabetic ob/ob mice given oral vanadate. Diabetes 39:326–332, 1990. 52. Yuen VG, Pederson RA, Dai S, et al: Effects of low and high dose administration of bis(maltolato)oxovandium (IV) on fa/fa Zucker rats. Can J Physiol Pharmacol 74:1001–1009, 1996. 53. Greco DS: Treatment of type II diabetes mellitus in cats with oral vanadium (Abstr). Diabetes 46:1289, 1997. 54. Crenshaw KL, Peterson ME, Heeb LA: Serum fructosamine concentration as an index of glycemia in cats with diabetes mellitus and stress hyperglycemia. J Vet Intern Med 10:360– 364, 1996. 55. Saltiel AR, Olefsky JM: Thiazolidinediones in the treatment of insulin resistance and type II diabetes. Diabetes 45:1661– 1669, 1996.

56. Suter SL, Nolan JJ, Wallace P, et al: Metabolic effects of new oral hypoglycemic agent CS–045 in NIDDM subjects. Diabetes Care 15:193–203, 1992. 57. Kumar S, Boulton AJM, Beck-Nielsen H, et al: Troglitazone, an insulin action enhancer, improves metabolic control in NIDDM patients. Diabetologia 39:701–709, 1996. 58. Bailey CJ, Turner RC: Metformin. N Engl J Med 334: 574–579, 1996. 59. Kraus MS, Calvert AC, Jacobs GJ, et al: Feline diabetes mellitus: A retrospective mortality study of 55 cats (1982–1994). JAAHA 33:107–111, 1997.

About the Authors
Dr. Behrend is affiliated with the Department of Small Animal Surgery and Medicine, Auburn University, Alabama. Dr. Greco is affiliated with the Department of Clinical Sciences, Colorado State University, Fort Collins, Colorado. Drs. Behrend and Greco are Diplomates of the American College of Veterinary Internal Medicine.

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