Diabetes mellitus in cats (Proceedings)

Classification

The classification of diabetes mellitus has changed over the years in both human and veterinary patients. Initially human diabetics were classified according to their age at onset of signs as either juvenile or adult-onset diabetics. Diabetics were subsequently classified as insulin or non-insulin dependent based on whether they required insulin to control their signs. As a better understanding of the pathophysiology of diabetes mellitus developed, diabetics were classified by their ability to produce insulin and tissue sensitivity to insulin. The primary classifications using this scheme are Type 1, individuals which can not produce insulin, and Type 2, individuals that produce inadequate amounts of insulin and exhibit insulin resistance. The vast majority of feline diabetics are initially diagnosed with non-insulin dependent or Type 2 diabetes mellitus. There are a few cats that are initially diagnosed with insulin dependent or Type 1 diabetes mellitus. There is a secondary or Type 3 diabetes mellitus that occurs with certain insulin antagonistic drugs (glucocorticoids, progestins) or diseases (hyperthyroidism, hyperadrenocorticism, acromegaly) that is primarily due to carbohydrate intolerance in the presence of normal or increased insulin production.

Etiology

The cause of diabetes mellitus in cats is thought to be multi-factorial. Risk factors in cats include male sex, obesity and increasing age. In man and dogs there is evidence of an autoimmune component to the development of Type 1 diabetes mellitus. As a result of progressive destruction of the beta cells, little to no insulin is produced. Although beta cell autoantibodies have been identified in diabetic dogs, there is no evidence of antibodies directed against pancreatic beta cells in cats.

Genetics may play a role in cats. Burmese cats in Australia and the United Kingdom appear to be at an increased risk for developing diabetes mellitus. This suggests a hereditary component to this disease.

There is a theory known as the Carnivore Connection that, in part, explains insulin resistance in man by stating that insulin resistance developed historically in certain human populations as a result of an adaptation to low carbohydrate/high protein diets consumed during the Ice Age. Animals, such as cats, that have traditionally consumed diets consisting of only a small amount of carbohydrate would have developed a similar insulin resistance. This resistance makes cats more susceptible to developing hyperglycemia when their diet is changed to include more carbohydrates. This is the type of diet change that has historically occurred in the domestic cat.

Obesity is a known cause of insulin resistance in cats, dogs and humans although not all diabetic cats are obese. Cats have replaced much of their predatory, active behaviors with a less active indoor lifestyle. This predisposes cats to over feeding and obesity. Recently, a protein that increases insulin sensitivity, adiponectin, was found to be decreased in obese cats and dogs. A decrease in this protein may contribute to the insulin resistance seen in obesity. There is also evidence that certain genes involved in insulin signaling in tissues are decreased in obese cats. Weight loss in obese cats improves insulin resistance.

Amylin (islet amyloid polypeptide, IAPP) is a protein co-secreted with insulin from the pancreas. Its exact role is unknown but when insulin resistance occurs, the pancreas increases insulin, and thus amylin, secretion. Increased serum amylin has been associated with increased amyloid deposition in the pancreas. Amyloid is found in the pancreas of non-diabetic cats but in even higher quantities in diabetic cats. Amyloid contributes to loss of functional beta cells and insulin secretion.

Persistent hyperglycemia also results in loss of functional beta cells through glucose toxicity. Hyperglycemia initially results in decreased insulin levels that is reversible and does not result in morphologic changes in the islets. With chronic hyperglycemia, histologic abnormalities develop in the islets and results in loss of beta cells. Hyperglycemia also contributes to insulin resistance.

Diet

Recommendations are generally for high protein and low carbohydrate diets. It is these diets that have reported remission rates up to 68%. There are, however, cats that obtain diabetic remission on moderate to high fiber diets. As discussed above, higher protein, lower carbohydrate diets are more appropriate for the 'relative' decreases in insulin production and sensitivity in carnivores such as cats. Cats have increased protein requirements for energy and other cellular functions. This species is not able to adapt to low protein states as well as omnivores. Cats also have decreased intestinal and hepatic enzyme activity needed to digest and metabolize carbohydrates. Cats primarily use amino acids and fat in the diet for energy so carbohydrates contribute more to hyperglycemia. High protein diets help reduce postprandial glucose and insulin concentrations. These diets also help decrease weight in obese cats, decrease insulin requirements, result in better glycemic control and can result in remission in some cats.

Oral hypoglycemics

Oral hypoglycemics include sulfonylureas (glipizide), biguanides (metformin), thiazolidinediones (triglitazone) and alpha-glucosidase inhibitors (acarbose). The sulfonylureas require beta cell function because their primary mechanism of action is increased release of insulin from beta cells. Approximately 40% of cats respond to sulfonylurea (glipizide) monotherapy and some newly diagnosed cats have gone into diabetic remission. Side effects are uncommon but include anorexia, vomiting and icterus that should resolve on discontinuation. It is now believed that increased demand on functional beta cells might lead to beta cell exhaustion and loss so stimulation with sulfonylureas has fallen out of favor. Biguanides work primarily by increasing the tissue sensitivity to insulin and decreasing glucose production by the liver so they also require pancreatic secretion of insulin or exogenous insulin administration. Biguanides have not been used successfully in cats because vomiting and anorexia are common at doses required to achieve glucose-lowering effects. Thiazolidinediones also increase tissue sensitivity to insulin so will require endogenous or exogenous insulin. There have been no published studies on the use of thiazolidinediones in diabetic cats. Alpha-glucosidase inhibitors inhibit a-glucosidase in the intestinal brush border slowing absorption of glucose from the intestinal tract. A study was performed on cats in which they were given a high protein diet, acarbose and insulin (n = 17) or glipizide (n = 1) that resulted in improved glycemic control in all cats and remission in 11/18 cats. Unfortunately in this study these cats were given insulin and a high protein diet which also improve glycemic control and lead to diabetic remission. Chromium and vanadium are trace elements that have insulin-like effects in-vitro. There have been no reports of chromium use in diabetic cats. Vanadium, utilized with insulin, was shown to improve glycemic control over insulin alone in a group of diabetic cats.

Insulin therapy

Insulin therapy is recommended early in the course of disease to reverse glucose toxicity and ensure survival of functional beta cells. Early treatment with insulin and dietary modification has led to remission, particularly in newly diagnosed diabetics. Maintenance insulin options for cats at this time are human recombinant neutral protamine hagedorn (NPH), porcine lente (Caninsulin®, Vetsulin®), beef or beef/pork PZI, glargine and detemir.

NPH and lente are intermediate-acting insulin's. NPH is relatively potent and often causes a rapid peak effect (within 2 hours) and a rapid return to baseline leading to poor glycemic control even when given twice daily so it is not used routinely in this species. Porcine lente has been used successfully as a twice daily insulin in cats. Fifteen to 75% of cats that receive porcine lente twice daily in addition to a high protein/low carbohydrate diet go into remission.

Protamine zinc insulin (PZI) and insulin glargine are long-acting insulins. A beef/pork PZI was produced by IDEXX® until recently. Protamine zinc insulin usually requires twice daily administration for adequate control. There is a new human recombinant PZI that has been used in cats and appears to be as effective in lowering blood glucose and controlling clinical signs as beef/pork PZI. There are no studies available looking at remission rates of human recombinant PZI, just animal origin products. Once daily glargine provides adequate control of clinical signs in most cats but twice daily glargine gives better glycemic control. Glargine has been associated with higher remission rates (up to 100%) in newly diagnosed diabetic cats than PZI or lente insulin.

Monitoring

Diabetic monitoring includes the patient history (weight, water intake, urination, grooming), physical exam (weight, coat quality) as well as blood glucose monitoring. Glucose curves are recommended in newly diagnosed and poorly regulated diabetics. Curves are usually done on newly diagnosed diabetics until a stable insulin regimen has been established. Poorly regulated diabetics are individuals with signs of hyperglycemia (polyuria, polydipsia, polyphagia, weight loss, progressive neuropathy) or hypoglycemia (lethargy, anorexia, vomiting). Glucose curves are problematic in cats because of stress hyperglycemia and this is why home glucose curves are done with increased frequency by owners. Stress hyperglycemia and potential inter-patient and day-to-day variability are problematic with both in-hospital and at home glucose curves. For glucose curves it is important to evaluate a pre-insulin glucose followed by measurements every 2 hours (intermediate formulations) to 4 hours (long-acting analogues) until the next dose. This should allow for evaluation of important components of the glucose curve including the peak glucose concentration, glucose nadir and duration of response.

Fructosamine is a measurement of glycated serum proteins, particularly albumin. Fructosamine is helpful in evaluating glucose control over 2 to 3 weeks. Glycosylated hemoglobin is commonly used in diabetic humans. Glycosylated hemoglobin looks at glucose levels over 2 to 3 months. Fructosamine is used more commonly in small animals because it is usually necessary to make adjustments in periods shorter than 3 months. Fructosamine is helpful in monitoring diabetics and differentiating stress hyperglycemia from diabetes mellitus.

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