Diabetes mellitus in cats: Risk factors and treatment (Proceedings)

Incidence

Diabetes mellitus (DM) is the second most common endocrine disorder in cats, with an estimated incidence of 0.5% (1 in 200-250 cats). Its incidence appears to be increasing, probably due to an increase in obesity in the cat population. Several risk factors for DM have been identified: age, obesity, neutering and gender. Age has been identified as the single most important risk factor. Diabetes occurs in a wide age range of cats, but most cats are over 6 years of age when diagnosed. The average age at diagnosis is 10 years and the peak incidence is between 9 and 13 years. Diabetes in young cats is extremely rare. Obesity increases the risk of developing diabetes 3- to 5-fold. Given that the prevalence of obesity in cats between 5 and 11 years old in the U.S. is over 40%, the high prevalence of feline diabetes mellitus is understandable. Neutered cats have nearly twice the risk of developing DM and male cats 1.5 times the risk. Genetics may play a role in some breeds (e.g., Burmese cats in Australia).

Pathophysiology

Type 2 diabetes, the most common form of DM in cats, is characterized by variable loss of insulin secretory capacity and insulin resistance. Secondary forms of diabetes can develop with pancreatic destruction from pancreatitis and pancreatic adenocarcinoma. Diabetes in cats closely resembles human type 2 diabetes clinically and pathologically. The age of onset of feline DM parallels the onset of DM in middle-aged human patients. Other similarities include the association with obesity, resistance to ketosis, low but measurable fasting insulin concentration, and specific characteristics of the first and second phase insulin secretion curves. Islet amyloidosis is an almost invariant feature of feline diabetes and human type 2 DM, and is associated with significant loss of beta cells in the pancreatic islets. Interestingly, islet amyloidosis occurs only in human beings, macaques, and cats, and usually only in conjunction with diabetic syndromes associated with aging. Veterinary pathologists have long noted that amyloidosis is a common feature in the pancreata of aging cats. It is also recognized that not all glucose-intolerant cats have islet amyloid, and that the degree of amyloidosis does not correlate well with functional defects. Our understanding of the relationship between islet amyloidosis and the development of DM has been greatly advanced by the discovery that the precursor protein of this form of amyloid is a 37 residue polypeptide hormone named islet amyloid polypeptide (IAPP) or amylin. The pancreatic islets are the predominant site of IAPP production. It is co-secreted with insulin and, in its soluble form, is thought to play a role as a regulator of glucose homeostasis. Since all cats and humans normally produce IAPP, additional factors must explain the development of islet amyloidosis and DM.in some individuals. This area has been the subject of intensive investigation in recent years. It appears that islet amyloidosis is caused by chronically increased stimulus for beta cells to secrete IAPP (and insulin), as occurs with the chronic insulin resistance invoked by obesity. IAPP-derived amyloid fibrils have been found to be cytotoxic, causing apoptotic cell death and necrosis by mechanisms that remain to be fully elucidated. As a fascinating side note, the in vitro cytotoxic effects of human IAPP are identical to those of the fibrillar protein that forms amyloid deposits in Alzheimer's disease.

In diabetic cats, factors such as insulin resistance, deposition of islet amyloid, pancreatititis, and glucose toxicity contribute to loss of pancreatic beta cells. The term "glucose toxicity" is used to describe the situation where beta cells are damaged by chronically high blood glucose concentrations, suppressing insulin secretion. Obesity causes reversible insulin resistance and is a major underlying cause of feline diabetes. Hormones produced by adipose tissue, such as leptin and adiponectin, may have a role in the pathogenesis of obesity and diabetes. Hyperglucagonemia has been documented to develop in obese cats and may be important in the progression from obesity to diabetes as glucagon increases insulin resistance and may hasten exhaustion of beta cells. Insulin antagonism also develops with conditions such as hyperthyroidism, bacterial infections, and steroid therapy; these can trigger the onset of diabetes or precipitate a ketoacidotic crisis in a previously stable diabetic. Cats are very sensitive to the diabetogenic effect of some hormones, particularly corticosteroids, growth hormone and progestins.

Goals for managing non-ketotic diabetes mellitus in cats

The basic objective of therapy is to eliminate the clinical signs of diabetes mellitus while avoiding associated complications, especially hypoglycemia. Other common complications include weakness, ataxia and a plantigrade stance caused by peripheral neuropathy, poor hair coat from lack of grooming, weight loss, recurring ketosis, and poor glycemic control secondary to concurrent infection, inflammation, neoplasia or hormonal disorders. Another important treatment goal is to maximize the chances of attaining diabetic remission. The devastating chronic complications of human diabetes require several decades to develop and are uncommon in diabetic cats. As such, the need to establish near normal blood glucose concentrations is not necessary in cats. Most owners are happy and most cats are relatively asymptomatic if most blood glucose concentrations are kept between 100 and 250 mg/dl.

Initial insulin therapy

Insulin glargine (Lantus, Aventis Pharmaceuticals) is a long-acting insulin analog that forms microprecipitates at the site of injection from which small amounts of insulin glargine are slowly released. This synthetic insulin differs from human insulin in that an amino acid is replaced by glycine and two arginines. Glargine (dosed at 0.25 U/kg ideal body weight if the blood glucose at diagnosis is <360 mg/dl or 0.5 U/kg if the blood glucose at diagnosis exceeds 360; SQ) has become the insulin of choice in cats for most endocrinologists as the highest rate of diabetic "remission" has been shown to occur with use of this insulin preparation (in combination with a low carbohydrate diet). Regardless of the type selected, insulin should be administered BID to cats from the outset of therapy. Remission (i.e. reverting to a non-insulin requiring state) usually occurs within one month of beginning insulin therapy, but can occur as late as 4-5 months. Insulin glargine appears to have a duration of effect ranging from 10 to 16 hours in most diabetic cats. The response of diabetic cats to detemir insulin (Levemir) appears to be very similar to glargine but the pharmacokinetics have not yet been studied in cats and there is no published information on its use. Successful glycemic control can also be achieved with PZI or lente (Vetsulin or Caninsulin) insulin but a lower rate of diabetic remission occurs. NPH insulin should be avoided due to it's short half-life in cats.

Adjustments in insulin therapy

Diabetic cats require several days to equilibrate to changes in insulin dosage or preparation. Therefore newly-diagnosed diabetic cats are typically hospitalized for no more than 24 to 48 hours to finish the diagnostic evaluation and begin insulin therapy. During hospitalization, blood glucose concentrations are typically determined at the time insulin is administered and about 3, 6 and 9 hours later. The intent is to identify hypoglycemia (blood glucose < 80 mg/dl) in those cats that are unusually sensitive to the actions of insulin, not to establish glycemic control before sending the cat home. If hypoglycemia occurs, the insulin dosage is decreased prior to sending the cat home. The glargine insulin dosage is not adjusted in those cats which remain hyperglycemic during these first few days of insulin therapy. The objective during this first visit is to begin to reverse the metabolic derangements induced by the disease, allow the cat to equilibrate to the insulin and change in diet, teach the owner how to administer insulin, and give the owner a few days to become accustomed to treating the diabetic cat. Adjustments in insulin therapy are made on subsequent evaluations that typically occur weekly until an effective insulin treatment protocol is identified. Excellent websites for information and support for owners of newly diagnosed diabetic cats are www.felinediabetes.com, www.petdiabetes.wikia.com and www.veterinarypartner.com.

Dietary recommendations

Correction of obesity and minimizing the impact of the diet on postprandial blood glucose concentration are important dietary considerations in diabetic cats. Insulin resistance caused by obesity can resolve as obesity is corrected. Following weight reduction, glycemic control often improves and some diabetic cats revert to a subclinical diabetic state. The central theme in studies evaluating the impact of diet on glycemic control in diabetic cats is restriction of carbohydrate absorption by the gastrointestinal tract, variously by inhibiting starch digestion (acarbose), inhibiting intestinal glucose absorption (high fiber foods), or decreasing carbohydrate ingestion (low carbohydrate, high protein foods). It has been observed that high protein diets reduce the insulin requirements of diabetic cats. It has been reported that obese cats (>28% body fat) had a better response (diabetic remission) to a low carbohydrate, protein-replete diet than did cats with <28% body fat (improved glycemic control not remission). Interestingly, obese cats exhibited an increase body weight associated with an increase in lean body mass, despite a decrease in percentage of body fat, over the 4 months of the study. Current practice is that non-obese diabetic cats be fed ad libidum. Consumption of numerous small meals throughout the day minimizes blood glucose fluctuation and optimizes glycemic control in human diabetics, compared with eating larger, less frequent meals. In cats, this strategy follows the cats' natural feeding pattern of eating 10-20 small meals a day. Results from a recent study, however, have challenged this approach, as ad libitum feeding of normal cats resulted in significantly higher insulin concentrations than once daily feeding. This could place a greater demand on the beta cells for insulin secretion and contribute to hyperinsulinemia and beta cell exhaustion in susceptible cats. This study, however, was in nondiabetic cats and results were compared after 4 weeks on different feeding schedules; longer term feeding trials may not support this hypothesis.

Monitoring

During the first 24 hours of therapy, perform spot blood glucose measurements to check for evidence of hypoglycemia (every 3 - 4 hours for initial 12 - 18 hours). If no hypoglycemia occurs, discharge the cat equilibration at home. Whenever insulin therapy is initiated or changed, the cat should be allowed to "equilibrate" at home for 4 - 7 days before response to insulin therapy is assessed. At each recheck,, the owner's assessment of thirst and urine production, and an accurate weight measurement are very important. A blood glucose curve (a series of timed measurements of blood glucose, such as every 2 hours for 12 hours) is recommended every 10-14 days until an appropriate insulin dose is achieved and thereafter as necessary for monitoring (usually every 2-4 months). An alternative monitoring schedule that primarily uses the blood glucose concentration drawn immediately prior to the next scheduled glargine dosing time to decide on changes in insulin dosage is outlined in reference #1 (Rand).

Cats are more prone than dogs to development of the Somogyi phenomenon (hypoglycemia-induced glucose counterregulation), even at conservative doses of insulin. When a cat's blood glucose drops too low, release of catecholamines, glucagon, glucocorticoids, and growth hormone cause a rapid release of glucose into the blood. It is important to be aware of this phenomenon in order to avoid being tempted to increase the insulin dose, as this would accentuate the problem and eventually cause a hypoglycemic crisis. Starting diabetic cats on low-dose, twice a day insulin therapy at the time that insulin treatment is initiated is helpful in avoiding the Somoygi phenomenon.

Glucose reagent strips (chemstrip BG) read using a glucose meter are used as only one drop of blood is required for each glucose measurement. Some owners are willing to monitor blood glucose at home, which eliminates the effect of hospital stress on results. Teaching the owner to obtain BG profiles at home (using a lancet device to obtain capillary book samples from the ear - Microlet Vaculance®) eliminates the effects of hospital stress on glucose profile results. An excellent training resource is the video on the website VeterinaryPartners.com (click on cats, then search diabetes). Monitoring urine glucose is not recommended and insulin dosage adjustments should not be made based on the presence or absence of glycosuria.

Serum fructosamine concentration may be used every 3-4 months in lieu of serial glucose profiles as long as history, clinical signs, and random blood glucose measurements also suggest good glycemic control. Fructosamines are glycated proteins found in blood. They result from an irreversible, nonenzymatic, insulin-independent binding of glucose to serum proteins. They reflect the mean blood glucose concentration over the circulating life span of the protein (2-3 weeks). Note that this test cannot be used as a solo test to diagnose DM as values for normal cats and diabetic patients overlap.

One important factor that affects monitoring of diabetic cats is the propensity to develop stress-induced hyperglycemia caused by frequent visits to the veterinary hospital for blood samplings. Once the insulin dose has been stabilized, serial blood glucose curves should be done when there is a perceived need to change insulin therapy. The determination of good versus poor control of glycemia should be based on the owner's subjective opinion of presence and severity of clinical signs and overall health of their pet, ability of the cat to jump, it's grooming behavior, findings on physical examination, and stability of body weight. Generation of serial blood glucose curves is generally reserved for newly-diagnosed and poorly-controlled diabetic cats. If stress-induced hyperglycemia is suspected, switch from reliance on serial blood glucose curves generated in the veterinary hospital to a curve generated by the owner in the home environment or monitor sequential serum fructosamine concentrations.

Summary

When treating a diabetic cat, the primary goals are to control clinical signs without causing clinical hypoglycemia and to maximize the chance of acheiving diabetic remission. Identification and treatment of concurrent disease plays an integral role in the successful management of the diabetic cat. Concurrent diseases, such as urinary tract infection and pancreatitis, can interfere with tissue responsiveness to insulin, making glycemic regulation difficult and predisposing to episodes of ketosis. Minimizing the impact of food type and feeding method on postprandial blood glucose concentration and correction of obesity are important dietary considerations in diabetic cats. A low carbohydrate, high protein diet is recommended but should not be given as the sole therapy in an overtly diabetic cat. Insulin glargine is the insulin of choice in cats to maximize their chances of going into diabetic remission. Establishing control of glycemia is easier, and hypoglycemia less likely to occur, when twice daily insulin therapy is initiated at the time insulin treatment is begun.

Selected Readings

Rand, J. Feline diabetes mellitus. In Veterinary Clinics of North America, January 2005.

Henson MS and O'Brien TD. Feline models of type 2 diabetes mellitus. ILAR Journal 2006; 47(3):234-242.

Kley S et al. Evaluation of long-term home monitoring of blood glucose concentrations in cats with diabetes mellitus: 26 cases (1999-2002). J Am Vet Med Assoc 2004; 225: 261-266.

Mazzaferro et al. Treatment of feline diabetes mellitus using an alpha-glucosidase inhibitor and a low-carbohydrate diet. J Fel Med and Surg 2003; 5: 183-189.

O'Brien TD. Pathogenesis of feline diabetes mellitus. Molecular and Cellular Endocrinology 2002; 197:312-219.

Rhett M and Rand JS. Insulin glargine and a high protein-low carbohydrate diet are associated with high remission rates in newly diagnosed diabetic cats. Proc Amer College of Vet Intern Med Annual Forum (abstract), 2004.

Sennello KA et al. Systolic blood pressure in cats with diabetes mellitus. J Amer Vet Med Assoc 2003; 223:198-201.

Thoresen SI and Bredal WP. Clinical usefulness of fructosamine measurements in diagnosing and monitoring feline diabetes mellitus. J Small Anim Pract 1996; 37:64-68.