Chapter 29. Diabetes Mellitus
Diabetes mellitus (DM) is an endocrine disorder that occurs in both dogs and cats. It is caused by the relative or absolute deficiency of the hormone insulin, which is produced by the beta cells of the pancreas. Insulin stimulates the transport of glucose and other nutrients across cell membranes for cellular use and is involved in a number of anabolic processes within the body. A lack of insulin activity leads to elevated blood glucose levels (hyperglycemia) and an inability of tissues to receive the glucose that they need (glucoprivation). Primary clinical signs include polyuria, polydipsia, polyphagia, and, in some cases, weight loss. Diagnosis is usually made using the initial signs of the disorder, which include the presence of a persistent hyperglycemia and a persistent or concurrent glucosuria. 1
INCIDENCE AND RISK FACTORS
DM is currently one of the most frequently diagnosed endocrine disorders in companion dogs and cats. Depending upon the group studied, DM has an incidence ranging between 0.13% and 2% of the population of dogs and cats living in homes. 1 A recent study of an insured population of Swedish dogs estimated that 1.2% of dogs would develop DM before 12 years of age. 2 This prevalence has increased dramatically over the last 30 years. 3 Similarly, there is evidence that the incidence of DM in cats has been steadily increasing. In 1970, DM incidence in cats was reported to be less than 0.1%; this increased by more than tenfold by 1999. 4 Although other factors may be involved, increases in both obesity and the frequency of sedentary lifestyles in pet cats have probably contributed to this change. More recently, a study of pet cats in the United Kingdom reported the incidence of DM in an insured population of adult cats to be 0.4%. 5
Risk factors for the development of DM in dogs include previous or concurrent hyperadrenocorticism, recurrent episodes of pancreatitis (estimated to cause 28% of cases), stress, and the presence of a genetic (breed) predisposition. 3.6. and 7. Intact females are more likely to be affected than males and may also develop an insulin-resistant type of DM during diestrus and pregnancy. 3 The increased incidence of DM in reproducing females may be explained by the insulin-antagonistic effects of progesterone and mammary tissue–derived growth hormone. 8 Increasing age is an important and consistently identified risk factor; most dogs with DM are older than 7 years at the time of diagnosis. 1. and 9. Many dogs diagnosed with DM are at normal body weight or even underweight at the time of diagnosis, and obesity has not been identified as a consistent risk factor for DM in dogs. Although there is some evidence from a small pilot study suggesting that dogs diagnosed with DM are more likely to have been chronically overweight when compared with healthy matched controls, other studies have not found this association. 10 Although it is well documented that obesity in dogs leads to insulin resistance and impaired glucose tolerance, these changes resolve with weight loss and do not typically lead to the development of overt diabetes. 11 This is an important way in which the pathogenesis of DM differs between dogs and cats.
Finally, recent studies suggest a strong genetic component for DM among certain dog breeds. 2. and 12. In the United States, breeds that experience significantly increased risk include Samoyeds, Siberian Huskies, Keeshonds, Finnish Spitz, Miniature Schnauzers, and Miniature Poodles. 3. and 12. A study of insured dogs in Sweden showed similar results and noted the prevalence of northern breeds in these groupings. 2 It was hypothesized that metabolic changes that favor adaptation to a cold environment may also increase susceptibility to DM. The Swedish study also reported a breed-sex interaction for susceptibility to DM. Female dogs were affected almost exclusively in some breeds, such as Border Collies, Norwegian Elkhounds, and Beagles. However, other breeds did not show a sex predilection. Dog breeds that have a low risk for developing DM include the Golden Retriever, Boxer, Papillion, and Tibetan Spaniel.
Although there are several important differences between DM in dogs and cats, cats experience many of the same risk factors as those reported in dogs. The chance of developing DM increases as cats age; between 70% and 90% of diabetic cats are 7 years or older, and more than 65% are 10 years or older at time of diagnosis. 13 Obesity is well documented as an important risk factor for DM in cats. Up to 80% of cats are overweight at the time of diagnosis, and overweight cats have an almost fivefold increased risk of developing DM compared with cats that are at their optimal weight. 14 One difference between dogs and cats is that neutered male cats have a higher risk of developing DM than do intact cats of either sex or spayed females. Other predisposing factors for cats include neutered status, indoor confinement and, related to living indoors, having a low level of physical inactivity. 1.4. and 15. Cats with complicating diseases such as pancreatitis, pancreatic neoplasia, acromegaly, hyperadrenocorticism, hyperthyroidism, and dental disease are also at increased risk. 16.17.18. and 19. The administration of medications such as progestagens and glucocorticoids has been associated with DM in cats. 20 Just as in dogs, there is evidence for a breed-specific predisposition in cats. Family lines of Burmese cats in Australia, New Zealand, and the United Kingdom show a higher frequency of DM when compared with other breeds and mixed-breed cats. 5. and 21. In some lines, more than 10% of the individuals are affected. 22
Finally, there is evidence of a genetic component to DM in cats that is not breed specific. Some cats appear to be predisposed to developing glucose intolerance because of naturally occurring low insulin sensitivity. While these cats show no signs of DM when they are maintained at optimal body condition, they are more likely than other cats to develop DM if they gain weight and become obese. 1. and 23. For example, fasting hyperinsulinemia prior to weight gain was found to be the strongest risk factor for development of impaired glucose tolerance in a group of cats that were fed to induce weight gain. 23 This effect is theorized to be similar to the genetic component of type II DM that has been reported in human subjects. Insulin resistance is largely determined by genetics in humans, but its phenotypic expression and the development of DM is influenced by environmental factors, most notably obesity. 24
Risk factors for the development of diabetes mellitus (DM) in dogs and cats include increasing age, sex (intact females in dogs; neutered males in cats); previous or concurrent hyperadrenocorticism, pancreatitis, or acromegaly; and the presence of a genetic (breed) predisposition. Although many dogs diagnosed with DM are at normal body weight, or even underweight at the time of diagnosis, obesity is an important risk factor for DM in cats.
CLASSIFICATION OF DIABETES MELLITUS
DM is considered a heterogeneous syndrome, with its primary characteristic being a persistent and detrimental hyperglycemia. In humans, diabetes is typically classified as either type I or type II. The classification of diabetes in dogs and cats is generally patterned after the human classification, with some modification.
Type I Diabetes Mellitus
Type I diabetes (formerly referred to as insulin-dependent diabetes mellitus [IDDM]) is identified by an absolute lack of endogenous insulin and a resultant dependence upon exogenous insulin for survival. This form of the disease is often caused by the immune-mediated destruction of the pancreatic beta cells by T cells and antibodies. It is estimated that at least 50% of diabetic dogs have immune-mediated type 1 diabetes as indicated by the presence of islet cell antibodies. 25 Evidence in human subjects with type I DM suggests that there may be an immune-mediated component involving the gut immune system, but this has not been studied yet in dogs. 26 The majority of diabetic dogs also have an absolute insulin deficiency, although the underlying cause is not always known. As discussed previously, there is a strong association between DM and pancreatitis in dogs. It is theorized that extensive pancreatic damage and the loss of beta cells in dogs with recurrent or chronic pancreatitis may lead to the development of DM. In human patients with type I DM, the rate of progression to absolute insulin deficiency is highly variable and can occur rapidly (childhood onset) or very gradually (latent autoimmune diabetes of adults [LADA]). Because DM is typically diagnosed in dogs that are 7 years of age or older, it is theorized that the form of DM observed in dogs may be similar to LADA in human subjects. Type I diabetes is not well documented in cats, and the prevalence of islet cell antibodies in this species has not been reported. 27. and 28. Although many cats with diabetes will require insulin therapy at some point during their disease, the proportion of cats that have type I diabetes (i.e., an absolute lack of endogenous insulin production) is very low.
Type II Diabetes Mellitus
Type II diabetes is characterized by impaired insulin secretion; insulin resistance; and the deposition of amyloid in the islets of the pancreas. (In humans, type II diabetes was previously referred to as non–insulin-dependent diabetes mellitus [NIDDM].) Human subjects with type II DM do not usually require exogenous insulin therapy for survival, although insulin or oral hypoglycemic agents may be administered to better manage blood glucose levels. With this form of DM, the total amount of insulin secreted after a meal may be increased, normal, or decreased, and the pattern of insulin secretion is usually abnormal. 29 Insulin resistance occurs when an elevated concentration of circulating hormone is needed to adequately maintain blood glucose levels. Based upon glucose tolerance tests and measured levels of serum insulin, it appears that insulin resistance is a common feature of both canine and feline diabetes. 30. and 31. The persistent hyperglycemia that results from insulin resistance and abnormal insulin secretion results in glucose toxicity. Glucose toxicity exacerbates the metabolic abnormalities of diabetes and leads to impaired insulin secretion and to the destruction and loss of beta cells.
More than 80% of cats with DM have type II DM; the remaining cases are usually secondary to other conditions such as acromegaly, pancreatitis, or neoplasia. Amyloid deposition in pancreatic islets is a consistent histological finding in cats with diabetes. Amyloid is a precipitation product of a pancreatic compound called amylin. Amylin is cosecreted with insulin and helps to maintain normal blood glucose levels by stimulating the breakdown of muscle glycogen. Amyloid deposition contributes to a loss of the insulin-secreting beta cells of the pancreas, eventually causing decreased or insufficient insulin secretion. Although most diabetic cats are identified as having type II diabetes, more of these cats require insulin therapy than do humans with type II diabetes, probably because of the deposition of amylin and the greater loss of beta cells in this species. 27.32. and 33. Because the effects of glucose toxicity are initially reversible, a substantial number of cats with type II diabetes that are promptly treated with diet and insulin therapy may revert to a state that does not require insulin weeks to months after hyperglycemia has been controlled. 34. and 35.
Peripheral insulin resistance primarily manifests itself after insulin binds to its cellular receptors, resulting in a decreased conversion of circulating glucose to glycogen or fat. In addition to being a characteristic of type II diabetes, insulin resistance also occurs as an adaptive response to low carbohydrate intake, allowing blood glucose levels to be conserved and maintained immediately after eating a low-carbohydrate meal. 36 It has been hypothesized that, as a species, the domestic cat is naturally insulin resistant when compared with other more omnivorous or herbivorous species. Insulin resistance would be expected to confer an adaptive advantage for a species that evolved as an obligate carnivore, consuming a diet that was high in protein but low in carbohydrate (see Section 2, pp. 76-77). A degree of peripheral resistance to insulin promotes the delivery of protein and fat to tissues while conserving blood glucose levels. If this theory is correct, it would follow that the consumption of a diet that is high in carbohydrate (such as some commercially available dry cat foods) would require cats to secrete much higher levels of insulin after eating than would be secreted after eating a high-protein, high-fat meal. Over time, the beta cells of the pancreas may no longer be able to meet this enhanced need, resulting in an abnormal or impaired insulin response. This hypothesis has been referred to as the “carnivore connection” and has been examined in humans and cats. 37
However, as discussed previously, the presence of innate insulin resistance alone does not appear to lead to DM. The development of obesity, plus a sedentary lifestyle, increasing age, and neuter status are factors that contribute to the exacerbation of insulin resistance in cats and may lead to development of type II DM. Although more study of this hypothesis is needed, a recent survey study of 96 diabetic cats and 192 matched control cats found no association between the amount of dry cat food that was fed to cats and DM, but did corroborate both a sedentary lifestyle and indoor confinement as risk factors for DM. 15Table 29-1 summarizes the classification of DM in dogs and cats.
| F orm | M ajor underlying cause | I ncidence (% of DM cases) | T reatment |
|---|---|---|---|
| Type I | Inability of beta cells to synthesize or secrete insulin | Dogs: >95% Cats: 20% or less | Exogenous insulin and dietary management |
| Type II | Insensitivity of peripheral tissues to insulin; impaired insulin secretion | Dogs: Rarely reported Cats: >80% | Weight loss, dietary management and/or hypoglycemic agents; insulin therapy (in some cases) |
Type I diabetes is characterized by an absolute lack of endogenous insulin and dependence upon exogenous insulin. This form of the disease is often immune-mediated and is responsible for the majority of cases of diabetes mellitus (DM) in dogs. Type II diabetes is characterized by peripheral insulin resistance and in cats, the deposition of amyloid in the islets of the pancreas. More than 80% of cats with DM have type II DM; the remaining cases are usually secondary to other conditions such as acromegaly, pancreatitis, or neoplasia.
CLINICAL SIGNS AND PHYSICAL CHANGES
All of the clinical signs observed in pets with DM are associated with the short- or long-term effects of hyperglycemia and aberrations in carbohydrate, fat, and protein metabolism. Polydipsia, polyuria, polyphagia, and/or weight loss are usually the first signs observed. Cataracts are a consistent long-term complication of DM in dogs. 38 Many cats also develop evidence of lens opacification as well. 39 The microvascular effects of diabetes can contribute to the development of renal disease in some animals. Polyneuropathy develops in some cases and can present as weakness, depression, or urinary and bowel incontinence. In cats, this is often seen clinically as a plantigrade stance. 40 Bacterial infections, especially of the bladder, are common in animals with poor glycemic control. 41. and 42. Recently, a small case-controlled study with 20 diabetic cats reported that diabetic cats had a significantly increased risk of heart disease–related death when compared with their matched cohorts. 43 Because only a small number of cats were examined, additional studies are needed to explore this relationship.
Many of the health complications of DM can be minimized or prevented through stringent control of blood glucose levels. The general therapeutic goals in diabetes management are to minimize postprandial (after-meal) hyperglycemia, prevent hypoglycemia when insulin is being administered, resolve and minimize clinical signs, prevent or delay long-term complications, and improve overall health. For some cats, management goals can also include achieving remission (transient diabetes). Successful diabetic management can be achieved through exogenous insulin administration, administration of oral hypoglycemic agents, diet, weight loss (if indicated), exercise, and the control of concurrent illness. Oral hypoglycemic drugs may increase the deposition of amyloid in the pancreas in cats and so are not often prescribed for cats. The remainder of this chapter focuses primarily on the role of diet and weight control in managing DM in dogs and cats.
DIETARY TREATMENT
Dietary goals for dogs and cats with type I DM are to improve regulation of blood glucose by delivering nutrients to the body during periods when exogenous insulin is active and to minimize postprandial fluctuations in blood glucose levels. Dietary management does not eliminate the need for insulin replacement therapy, but it can be used to improve glycemic control. Dietary treatment for pets with type II DM can be instrumental in improving glycemic control and making the need for lifelong exogenous insulin therapy less likely. Factors that must be considered when developing an appropriate diet for a diabetic pet include the consistency and type of diet, its nutritional adequacy and nutrient composition, the pet’s caloric intake and feeding schedule, and the presence of any other diseases.
Consistency and Type of Diet
Dogs and cats with diabetes should be fed a food that contains consistent amounts and sources of nutrients. Specifically, the type and quantity of nutrients that are delivered to the body should remain constant from day to day, and the proportions of calories in the diet that are supplied by carbohydrate, protein, and fat should stay the same. For pets with type I diabetes, the provision of a consistent diet allows the insulin dosage to be adjusted to closely fit the needs of the animal. Similarly, if pets with type II diabetes are being treated with oral hypoglycemic agents, the provision of a consistent diet is helpful in maintaining normal blood glucose levels. Changes in the ingredients or nutrient composition of a diet can disrupt the tight coupling of blood glucose levels with insulin activity that is needed for proper glycemic control. Therefore only pet foods that are guaranteed to use a fixed formulation should be selected for diabetic pets (see Section 3, p. 168). Manufacturers that use fixed formulations ensure that the nutrient composition and ingredients of a food remain consistent between batches. In contrast, manufacturers that use variable formulations may change ingredients depending on the availability and market prices. If information about the formulation type is not readily available, it can be obtained by contacting the manufacturer directly. In most circumstances, homemade diets should also be avoided with diabetic pets because of difficulties with maintaining nutrient consistency.
The type of commercial product that is fed is also of importance. Semimoist pet foods or snacks should not be fed to diabetic pets. Postprandial blood glucose and insulin responses have been shown to be highest when dogs are fed semimoist foods, compared with when they are fed either canned or dry pet foods. 44 This increase appears to be caused by the high level of simple carbohydrate found in semimoist products. These nutrients require minimal digestion in the small intestine and are rapidly absorbed following a meal. In contrast, the digestible carbohydrates found in dry and canned foods are made up primarily of complex carbohydrates (starch). Starches require enzymatic digestion to simple sugars before they can be absorbed into the body. This process slows the rate of delivery of glucose to the bloodstream. Complex carbohydrates and certain types of fiber also affect the rate of food passage through the gastrointestinal tract and the absorption of other nutrients in the diet. Dry pet foods generally contain higher levels of both complex carbohydrates and plant fiber than semimoist or canned foods do.
Foods selected for diabetic dogs and cats should contain consistent amounts and sources of nutrients. The type and quantity of nutrients that are delivered to the body should remain constant from day to day, and the proportions of calories in the diet that are supplied by carbohydrate, protein, and fat should stay the same. In addition, because of their high simple carbohydrate content, semimoist foods should not be fed to diabetic pets, even as treats.
Nutritional Adequacy and Nutrient Composition
The first consideration when identifying a food for a diabetic pet is the nutritional adequacy of the diet. Because long-term management is involved, the food must be nutritionally complete and balanced and must supply optimum levels of all the essential nutrients required by the pet. The methods discussed in Section 3 can be used to determine the nutritional adequacy of a commercial product. As discussed previously, the labels of over-the-counter pet foods will indicate if feeding trials have been conducted or if the food has been formulated to meet the Association of American Feed Control Officials’ (AAFCO’s) Nutrient Profiles. A food that has been tested using the AAFCO’s animal feeding test protocols or that has been formulated to meet AAFCO’s Nutrient Profiles should be selected. If a veterinary diet is prescribed, the label may not show this information, but the veterinarian should have literature available that fully describes the selected product.
Energy-Containing Nutrients
Diabetes is a disorder that affects the body’s ability to metabolize carbohydrate, protein, and fat. Therefore the proportion of these nutrients in foods designed for managing DM is an important consideration. Overall energy content of the food must also be considered, especially in cases of underweight or overweight animals. Overweight animals with DM should be fed a food that is formulated for both weight and glycemic control. 45 Conversely, underweight animals should be fed foods with higher energy density to maintain or improve body condition.
PROTEIN
In human diabetics, high-protein diets are not recommended because of the incidence of diabetic nephropathy, a condition that may be exacerbated by the intake of large amounts of protein. However, this complication of diabetes is uncommon in dogs and cats, and protein restriction for diabetic dogs and cats is neither necessary nor recommended. Rather, diabetic dogs should be fed high-quality protein in amounts that meet their daily requirements. The protein content in foods for diabetic cats should be moderate or higher (≥30%, dry-matter basis), replacing digestible carbohydrate. Protein rather than fat is used to replace carbohydrate because dietary fat increases insulin resistance and decreases glucose tolerance. When dogs or cats are supplied with a reduced carbohydrate diet, increased protein is theorized to support hepatic gluconeogenesis and promote normalized blood glucose concentrations in diabetic cats. Large postprandial fluctuations in blood glucose concentrations are avoided because glucose produced via hepatic gluconeogenesis is released into the circulation at a slow and steady rate. In addition, reduced carbohydrate is believed to shift metabolism from glucose oxidation toward fat metabolism as the body’s primary energy source. Benefits of this shift for diabetic animals include reduced insulin secretion, a shift from lipogenesis to lipolysis, and increased use of free fatty acids as a preferred energy source. In cats, increased fat metabolism leads to an increase in the ketone body beta-hydroxybutyrate. However, the levels observed in cats fed a high-protein, low-carbohydrate food are moderate and reportedly do not approach the dangerous levels seen during metabolic acidosis associated with uncontrolled DM. 45
It is important to correctly diagnose the presence of concurrent illnesses when considering a food with increased protein and decreased carbohydrate for diabetic cats. Cats with concurrent renal disease may experience increased blood urea nitrogen when fed a food containing even moderately increased protein. In these cases, moderate protein restriction may be needed to control azotemia and clinical signs (see Chapter 32, pp. 417-419). Similarly, foods containing reduced protein and fat are often recommended for cats with pancreatitis as an approach to reducing cholecystokinin release. Increased protein diets are always contraindicated for animals with severe liver disease.
Diabetic dogs should be fed high-quality protein in amounts that meet their daily requirements and the protein content in foods for most diabetic cats should be modestly increased. In cases when increased protein is contraindicated because of concurrent renal or liver disease, moderate protein restriction may be needed, and a food containing moderately increased fiber should be fed to control glycemia.
FAT
Fat intake by diabetic dogs and cats should be moderately restricted if the pet is overweight. Alterations in lipid metabolism can cause the development of hypercholesterolemia and hepatic lipidosis in some diabetic animals. Restricted fat intake helps to prevent or minimize these changes and facilitates weight loss or weight management when it is needed. One potential advantage of dietary fat in the nutritional management of diabetes is its effects upon gastric motility. High levels of dietary fat delay gastric emptying and consequently may modulate the postprandial glycemic response. 46 In humans, diets containing monounsaturated fats have been shown to decrease serum total cholesterol, very–low-density lipoproteins (VLDLs), and triglycerides without increasing blood glucose levels. However, this advantage is offset by the potentiating effect of dietary fat upon insulin resistance and its potential to exacerbate the blood lipid abnormalities that occur as complications of diabetes. Because of these discrepant effects and because of the contribution of dietary fat to energy density, the diet for many diabetic pets should be relatively low in fat while still containing adequate levels of essential fatty acids (EFAs) (BOX 29-1 and BOX 29-2).
BOX 29-1
Nutritionally complete and balanced
Consistent proportion of carbohydrate, fat, and protein
Consistency of ingredients (fixed formulation)
Greater than 40% of calories supplied by complex carbohydrate
Carbohydrate includes starch sources that minimize glycemic response
Moderate fiber level
High-quality protein source
Moderately restricted in fat (≤20% of total calories)
BOX 29-2
Nutritionally complete and balanced
Consistent proportion of carbohydrate, fat, and protein
Consistency of ingredients (fixed formulation)
Carbohydrate includes starch sources that minimize glycemic response
Moderately restricted in fat (≤20% of total calories)
Increased protein and decreased carbohydrate (if not contraindicated) OR
Optimal protein and selected carbohydrate/fiber blend, and reduced caloric content (if weight loss is needed)
CARBOHYDRATE
The carbohydrate content of diets for diabetic dogs and cats is an important consideration because this nutrient has the greatest influence upon postprandial blood glucose levels. A pet food that minimizes the glycemic response is desirable because lessening fluctuations in blood glucose contributes to better control of diabetes and its associated complications. The term glycemic index refers to a ranking system that categorizes foods based upon their effects on blood glucose levels. In general, complex carbohydrates (starches) have a lower glycemic index than simple carbohydrates because they are more slowly digested and absorbed. 47 Types of starch also differ in their glycemic effects depending upon the plant source, its physical form, and the type of cooking and processing used. For example, whole-grain starches have a lower glycemic index than highly refined starches. 48 Human subjects demonstrate higher blood glucose and insulin responses when refined forms of wheat starch are consumed, compared with the response to potato or barley starches. 49. and 50. Barley in particular has been identified as a starch source that may be well-suited for diabetic diets. 50
Similar variations in glycemic response have been observed in dogs and cats. In one study, diets containing 30% starch from corn, wheat, barley, rice, or sorghum were fed to healthy adult dogs for a minimum of 2 weeks. 51 Feeding rice resulted in the highest postprandial glycemic and insulin responses of the five starches that were studied. In comparison, feeding sorghum resulted in a comparatively lower glycemic response, and feeding barley resulted in a moderate glucose response and a reduced insulin response. Wheat and corn generally resulted in intermediate glycemic and insulin responses. In a study with cats, two diets formulated to contain a similar starch content (33%) from different sources (sorghum and corn versus rice) were fed free-choice to overweight cats. 52 Cats fed the food containing rice consumed more food and gained more weight than cats fed the sorghum and corn diet. The cats fed the rice-containing food were also more likely to experience higher blood glucose and insulin levels following a meal.
Several factors may be responsible for these differences. The proportion of amylose and the amount of dietary fiber that are associated with a starch source both affect the glycemic response. 53 Different types of rice contain varying amounts of amylose. Those with a high amylose content result in a higher glycemic response. 48 The relatively low glycemic index of barley has been attributed to its high amount of associated fiber and beta-glucan. 54 Because glycemic response is an important consideration when selecting foods for diabetic pets, these results indicate that both the amount and the source of the starch in the diet must be considered. While feeding rice may increase postprandial hyperglycemia, feeding barley or sorghum modulates the glucose and insulin response and therefore may be a better choice for diabetic pets.
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