Feline Diabetes Mellitus

Chapter 48


Feline Diabetes Mellitus



Diabetes mellitus is the second most common endocrinopathy in cats and affects approximately 1 in 50 to 1 in 400, depending on the population studied. Risk factors include advanced age, male sex, breed, obesity, physical inactivity, confinement indoors, and administration of glucocorticoids or progestins. Breeds reported at risk are Burmese in Australia, New Zealand, and the United Kingdom and Maine coon, domestic longhair, Russian blue, and Siamese in the United States.


Diagnosis of diabetes mellitus is based on the finding of persistently increased blood glucose concentration. In most cats, diabetes is usually not diagnosed until relatively late in the disease process when extensive β-cell function has been lost. The diagnosis is typically made when blood glucose concentration is above the renal threshold (i.e., >250 to 290 mg/dl [14 to 16 mmol/L]) and signs of polyuria, polydipsia, and weight loss are apparent. In contrast, in humans with type 2 diabetes, diagnosis is made earlier in the disease process. Because of this difference in diagnosis and extent of β-cell failure, most humans but only the minority of cats can be managed satisfactorily with oral hypoglycemic drugs.


At the present time, there is no consensus in the veterinary literature regarding the minimal blood glucose concentration in cats that should be classed as diabetic. Based on data in other species, blood glucose concentrations below the renal threshold but persistently greater than normal are likely associated with adverse effects, such as glucotoxic damage to β cells. Persistently mild hyperglycemia (e.g., >117 mg/dl fasted or >145 mg/dl unfasted to <180 mg/dl [>6.5 mmol/L fasted or >8.0 mmol/L unfasted to <10 mmol/L]) could be considered in cats to represent impaired fasting glucose, a state between normal and diabetic, which in human patients is considered to be prediabetic. Research is urgently required to define the cut-point between impaired fasting glucose and diabetes in cats; persistent blood glucose concentrations of 180 mg/dl (10 mmol/L) or greater likely indicate diabetes. In human patients with diabetes, 50% are undiagnosed, and there are more patients with prediabetes than diabetes. This is likely also the case in cats.


With the current availability of low-carbohydrate feline diets, research is needed to determine the most appropriate blood glucose concentration for institution of dietary management. Logically, if there are no contraindications such as azotemia, cats should be changed to a low-carbohydrate, high-protein diet whenever a persistently increased blood glucose concentration is present (e.g., >144 mg/dl [8 mmol/L] unfasted), and the diet is fed to achieve an ideal body weight. Cats should be monitored on a regular basis (e.g., every 3 to 6 months).



Pathogenesis of Diabetes in Cats


To manage diabetic cats effectively, an understanding of the pathogenesis and main features of feline diabetes is required. In developed countries, most owned cats with diabetes likely have type 2 diabetes, which is characterized by a relative lack of insulin secretion and insulin resistance. Insulin resistance reduces the glucose-lowering effect of a given amount of insulin. Diabetic cats are on average six times less sensitive to insulin than healthy cats, representing a similar magnitude of insulin resistance to that identified in humans with type 2 diabetes. Insulin resistance results from numerous mechanisms, and more than one mechanism is likely operating in most diabetic cats. A small percentage of cats have other specific types of diabetes resulting from β-cell destruction associated with pancreatitis and neoplasia or have marked insulin resistance from excess growth hormone or corticosteroids. In referral practice, cats with other specific types of diabetes account for a substantial proportion of diabetic cats; acromegaly (growth hormone–producing tumor) has been reported in 25% to 30% of diabetic cats, and pancreatic neoplasia was reported in necropsy specimens of 8% to 18% of diabetic cats at referral institutions in the United States. Pancreatitis is likely an underdiagnosed cause of diabetes, and anecdotal data indicate it might be a cause of diabetes in cats that achieve remission as well as cats that remain dependent on insulin throughout their life. Hyperthyroidism results in glucose intolerance and insulin hypersecretion, both of which are exacerbated in some cats after treatment of hyperthyroidism and might be the result of weight gain and resultant obesity.



Insulin Resistance


In humans, the most important causes of insulin resistance are genotype, obesity, and physical inactivity. These same factors are also the most likely causes of insulin resistance in cats. It is important to be aware of these predisposing factors so that they are appropriately managed. Obesity markedly decreases insulin sensitivity in cats. An increase in body weight from an ideal weight of 4 kg to 6 kg decreases insulin sensitivity by 50% in cats. Management of body condition is a vital part of therapy for prevention and management of feline diabetes as well as prevention of relapse in cats that have achieved diabetic remission. Physically inactive cats have been shown to be at risk of diabetes, and increasing physical activity improves insulin sensitivity in other species. One study in cats also found that active play for 10 minutes daily produced the same rate of weight loss as calorie restriction.


Genetic predisposition is likely a risk factor for insulin resistance and diabetes in cats. Lean cats with insulin sensitivity values below the median of the population were at three times greater risk of developing impaired glucose tolerance when they gained weight than cats with higher insulin sensitivity. Impaired glucose tolerance is the glycemic state between normal and diabetic. It is likely that these cats had underlying insulin resistance associated with genotype and that obesity would result in diabetes in some of these cats with time. Burmese cats are at increased risk of diabetes in Australia, New Zealand, and the United Kingdom and appear to have underlying insulin resistance.


High blood glucose concentration also contributes to insulin resistance. In dogs, it has been shown that this effect has a relatively short-term influence, with insulin resistance related more closely to glycemia over the previous 48 hours rather than over longer periods. This finding is relevant especially in the initial phases of treatment, and clinicians need to be aware that insulin sensitivity is increased with decreasing blood glucose concentration.


Drugs such as glucocorticoids and progestins produce insulin resistance and increase the risk of diabetes particularly when administered as long-acting preparations or given repeatedly. Glucocorticoids and progestins increase the risk of relapse in cats that have achieved diabetic remission.



Impaired Insulin Secretion


Insulin secretion is decreased in feline diabetes through many mechanisms, some of which are reversible. Loss of β cells in type 2 diabetes is thought to result from apoptosis triggered by factors associated with obesity and insulin resistance, including release of inflammatory adipokines. Loss of β cells also occurs as a result of islet amyloid deposition and intracellular formation of toxic amyloid fibrils. Reversible suppression of insulin secretion occurs when blood glucose or lipid concentrations are high. These conditions are called glucotoxicity and lipotoxicity, and both may act through similar intracellular mechanisms in the β cell. With time, chronic hyperglycemia irreversibly damages β cells, and they are permanently lost, which can lead to insulin-dependent diabetes.


Loss of β cells also occurs through pancreatitis, and approximately 50% of diabetic cats have histologic evidence of pancreatitis. In most cats, the severity of the lesion is not sufficient by itself to cause diabetes but potentially contributes to loss of β cells. However, pancreatitis is likely an underdiagnosed cause of diabetes in cats, and it is recommended that feline pancreatic lipase be measured in all newly diagnosed diabetic cats, especially cats with any signs that could be consistent with pancreatitis.


When insulin resistance is not involved, clinical signs of diabetes ensue once approximately 80% to 90% of β cells are lost. If insulin sensitivity is reduced, clinical signs of diabetes occur earlier with smaller loss of β cells. With obesity-induced insulin resistance, cats need 30% more insulin to maintain fasting glucose concentration than when they were lean, and so logically, they would develop diabetes earlier with less β-cell loss. Veterinarians need to impress on owners the importance of attaining an ideal body condition in their diabetic cats, cats at risk of diabetes, and cats in diabetic remission.



Diabetic Remission


Within days to months of beginning treatment with insulin, a proportion of diabetic cats are able to maintain euglycemia without therapy. This is called diabetic remission. The proportion of cats that achieve diabetic remission depends on how early tight glycemic control is instituted, the type of therapy, and the underlying cause of the diabetes. Cats require functioning β cells to attain remission. It is believed that reversal of glucotoxicity and lipotoxicity leads to diabetic remission. Therapies that provide the best glycemic control are likely to lead to the highest remission rates.


Factors shown to be associated with increased probability of remission include institution of rigorous glycemic control within 6 months of diagnosis (remission rate 84% compared with 34% after 6 months), use of a long-acting insulin (glargine or detemir), feeding a low-carbohydrate diet, and careful monitoring of blood glucose concentrations together with appropriate adjustment of insulin dosage. Recent treatment with corticosteroids was positively associated with remission in one study. Other factors associated with remission are mean blood glucose less than 290 mg/dl (16 mmol/L) within 3 weeks of initiation of treatment and older age of cat. Cats less likely to achieve remission have increased serum cholesterol concentration, evidence of plantigrade stance, and requirement of a higher maximum dosage of insulin to gain glycemic control (median dosage was 50% higher—0.66 U/kg versus 0.43 U/kg).


Cats in remission may relapse in weeks to months, and it is important that they are carefully monitored and managed in remission, ideally with weekly home blood glucose monitoring. With early reinstitution of insulin therapy, some cats can achieve remission again. Persistent mildly increased blood glucose concentrations, that is, impaired fasting glucose (145 to 180 mg/dl [8 to 10 mmol/L]); more severe glucose intolerance (first return to baseline glucose concentration at 5 hours after 1 g/kg glucose intravenously); obesity; and use of glucocorticoids or progestins likely increase the probability of relapse.



Management of Diabetes


The most important goals of therapy are to achieve diabetic remission in cats with newly diagnosed diabetes; resolve clinical signs; and avoid clinical hypoglycemia, which can be life-threatening. The best way to resolve clinical signs is to achieve diabetic remission. Treatments available for management of feline diabetes include dietary modification, insulin, and oral hypoglycemic drugs. The prevalence of diabetes is increasing as risk factors such as obesity and physical inactivity become more common. These risk factors also need to be addressed in management and prevention of diabetes. Maintaining ideal body weight and avoiding drugs such as corticosteroids and progestins are important for maintaining remission.



Diet


Diet is an important component of therapy, and a low-carbohydrate diet is vital for cats achieving diabetic remission because it decreases mean daily glucose concentration, an important contributor to recovery of β cells from glucose toxicity (see also Chapter 46). A high-carbohydrate diet (50% of energy from carbohydrate) can increase mean blood glucose concentrations 4 to 18 hours after eating by 20% to 25% and peak glucose concentrations by more than 30% compared with a moderate-carbohydrate diet (25% energy from carbohydrate); comparison with a low-carbohydrate diet is even more pronounced. Remission rates were significantly higher (68% versus 42%) in cats fed a low-carbohydrate diet (12% of energy from carbohydrate; 3.5 g/100 kcal ME) compared with cats fed a higher carbohydrate diet (26% of energy from carbohydrate; 7.6 g/100 kcal ME), despite similar protein content of the two diets. Cats eating an ultra-low-carbohydrate diet (5% of energy; 1.8 g/100 kcal ME) have even greater reduction in blood glucose concentration; however, no studies comparing remission rates in cats fed low-carbohydrate and ultra-low-carbohydrate diets have been published. Ultra-low-carbohydrate diets are often nearly all meat or fish, may not be complete or balanced, and are high in phosphorus, which is of concern given the frequency of chronic kidney disease in diabetic cats.


Reducing carbohydrate content of the diet also decreases the demand on β cells to secrete insulin. Cats in diabetic remission likely have reduced β-cell mass. From the limited testing reported, most of these cats have impaired glucose tolerance, and about one third have impaired fasting glucose, meaning a glucose concentration above normal (117 mg/dl [6.5 mmol/L]) but less than diabetic (180 mg/dl [10 mmol/L]). It is vital that cats in remission be fed diets that minimize the amount of insulin required to be secreted to control postprandial glycemia. Feeding a low-carbohydrate diet once diabetic remission is achieved would likely prolong remission.


To achieve and maintain remission, it is important to attain an ideal body weight because of the negative impact of obesity on insulin sensitivity. Diet is also important for achieving weight loss. A minority of cats fed canned low-carbohydrate, high-protein diets self-restrict energy intake and lose weight spontaneously after their diet is changed. For most cats, energy intake needs to be restricted to achieve weight loss. Physical activity promotes weight loss and improves insulin sensitivity in other species, independent of body weight. Encouraging owners to engage in active play with their cat is likely beneficial.




Choice of Insulin Type


In a trial of 24 cats, all 8 cats with newly diagnosed diabetes treated with glargine and an ultra-low-carbohydrate diet (5% of energy from carbohydrate; Nestle Purina DM canned) achieved remission compared with 3 of 8 treated with PZI and 2 of 8 treated with porcine Lente. These findings compare with 20% to 30% remission rates reported using other insulin preparations and a standard feline maintenance diet (typically 30% to 40% of energy from carbohydrate). One study reported 60% remission rates using PZI or Lente insulin and a low-carbohydrate diet. Trials using either glargine or detemir in cats previously treated with other insulins, predominantly Lente, achieved remission rates of 84% and 81% if cats were changed to intensive blood glucose monitoring and glargine or detemir therapy within 6 months of diagnosis of diabetes.


Glargine and detemir are long-acting insulins, and although their long duration of action is achieved by different modifications to the insulin molecule, they have similar clinical effects in cats. In cats with newly diagnosed diabetes, remission rates of greater than 80% to 90% often can be achieved using glargine or detemir combined with a low-carbohydrate or ultra-low-carbohydrate diet and frequent monitoring of blood glucose concentration and appropriate adjustment of insulin dosage. Lower remission rates occur in cats with long-term diabetes changed to glargine or detemir therapy. Diabetic remission is rare in cats that have been diabetic for more than 2 years.


Because of the huge advantage to the client and the cat in achieving diabetic remission, it is strongly recommended that the first choice of insulin for diabetic cats be glargine or detemir. If there is a legal requirement to use a veterinary insulin product first, PZI would be the first choice because it has a longer duration of action than Lente insulin. However, recombinant PZI is not yet licensed for veterinary use in Europe.


Lente and NPH insulins have too short a duration of action for optimal blood glucose control in cats. Using Lente or NPH insulin, even with an optimal dosage and the nadir glucose concentration in the normoglycemic range, most cats have a period of at least 2 to 4 hours before each insulin injection when there is no exogenous insulin action, and high blood glucose concentrations ensue, often 360 mg/dl (20 mmol/L) or greater. Because the blood glucose concentration is very high, administering a potent insulin such as Lente or NPH may result in a rapid decrease in blood glucose concentration. The hypothalamic neurons detect a decreasing blood glucose concentration and trigger counterregulatory mechanisms before hypoglycemia occurs. These neurons control their intracellular glucose concentration by limiting glucose uptake when plasma glucose concentration is high; with a rapidly decreasing blood glucose concentration, the neurons become hypoglycemic even at relatively high blood glucose concentration, and the resultant counterregulatory mechanisms are often triggered when blood glucose concentration is still above the normal range. Cortisol, epinephrine, and glucagon are released, increasing blood glucose concentrations. The end result is further shortening of insulin action, which for some cats treated with Lente insulin is only about 3 hours. The counterregulatory response also results in insulin resistance, and the following insulin injections may result in little appreciable glucose-lowering effect.

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