Carmel T. Mooney, MVB, MPhil, PhD, DECVIM-CA, MRCVS
University College Dublin Veterinary Hospital, UCD, Belfield, Dublin, Ireland
Traditionally, diabetes mellitus has been classified in dogs and cats based on clinical presentation and the need for routine (insulin, diet ± oral hypoglycaemic agents) or more intensive (intravenous insulin, fluid and electrolyte therapy) therapies. However, the value of such a classification system is questionable, because it fails to consider the significant pathophysiological differences between the various types of diabetes mellitus, and how addressing these may improve the prognosis for each individual animal. As a consequence, there has been a move to attempt to apply the human classification system, particularly to cats, and to institute more aggressive and targeted therapy if it is possible to do so.
Diabetes Mellitus in Humans
Diabetes mellitus is one of the most significant diseases encountered in human medicine. WHO estimates suggest that there were 171 million people in the world with diabetes mellitus in 2000, a figure projected to increase to 366 million by 2030. It is associated with reduced life expectancy and quality, significant morbidity because of microvascular complications (retinopathy, nephropathy and neuropathy) and a significantly increased risk of various macrovascular complications (ischaemic heart disease, stroke and peripheral vascular disease). In 2002, the estimated annual national cost of diabetes in the USA was €132 billion with an expected increase to €192 billion by 2020.
In humans, diabetes mellitus is classified into type 1, type 2, other specific types and gestational diabetes. Although other subcategories are recognised, type 1 disease tends to occur most commonly in young lean individuals who are totally dependent on insulin to prevent ketoacidosis and death (hence previously known as juvenile onset or insulin dependent). It results from autoimmune destruction of the β-cells of the pancreas. Autoantibodies to islet cells or their components are found in the majority (85–90 %) of patients. Environmental triggers are important but the disease has a strong genetic component. Although the progression can be variable, it is usually fairly rapid in younger individuals, but may be slower in adults [often classified as latent autoimmune diabetes of adults (LADA)]. Type 1 disease only accounts for 5–10 % of patients with diabetes mellitus.
By contrast, type 2 disease (previously known as adult onset and non-insulin dependent) is more common accounting for 90–95 % of patients. It is characterised by impaired insulin secretion and insulin resistance. It tends to occur in older patients who are obese and who do not exercise, are resistant to the development of ketosis and who can often be managed by weight control and oral hypoglycaemic agents alone. Pancreatic amyloid deposition is common. It is associated with a strong genetic predisposition although it is complex and poorly defined.
Other specific types of diabetes are less common, but include some genetic disorders of insulin secretion or action, diseases of the pancreas (pancreatitis, carcinoma etc.), various endocrinopathies (growth hormone, cortisol, glucagon and catecholamine excess) or prolonged diabetogenic drug administration. Whether diabetes resolves depends on whether the primary disease process can be treated and if irreversible damage has yet occurred.
Diabetes Mellitus in Cats
Diabetes mellitus is one of the most common endocrinopathies affecting cats with an estimated prevalence of between 1 in 100 and 1 in 400 depending on the population being studied. Today, the prevalence is undoubtedly increasing, as it is in humans. In one study, the prevalence of feline diabetes mellitus at veterinary teaching hospitals increased significantly from 8 cases per 10,000 in 1970 to 124 per 10,000 in 1999.
Undoubtedly, the majority of cats tend to develop type 2 disease, while type 1 disease appears to be rare. Similar to humans, major risk factors appear to be increasing age, obesity and physical inactivity. Most cats are in excess of 7 years at the time of diagnosis. Obesity is considered to increase the risk of diabetes 3- to 5-fold. Neutered cats have nearly twice the risk and male cats 1.5 times the risk of developing diabetes. There is a strong genetic predisposition with Burmese cats overrepresented in many countries. Histopathological examination of pancreatic tissue from affected cats shows that pancreatic amyloid deposition occurs. However, there are significant differences between humans and cats. The majority are/or ultimately become insulin dependent and many develop ketoacidosis. This may be related to delayed recognition/diagnosis, or because cats appear more susceptible to the effects of glucose toxicity in impairing insulin secretion or because many develop pancreatitis. As a consequence, treatment regimens differ between cats and humans. Dietary management and exercise modification are at least as important in managing the condition. However, many of the traditional, human oral hypoglycaemic agents are less efficacious in cats in the face of glucose toxicity and may enhance the progression to insulin dependency by further exacerbating amylin deposition in the pancreas. Insulin therapy is therefore preferred, as it is more likely to reduce hyperglycaemia and the effects of glucose toxicity.
The factors (*not proven) that contribute to impaired insulin secretion and insulin resistance characteristic of type 2 diabetes mellitus in cats are listed below. Many of these can be addressed, thereby increasing the chances of successful management and even remission.
Other factors can contribute in any individual (e.g., glucocorticoid-induced insulin resistance) that may require specific additional treatment.
Current Treatment Strategies
Given the previous knowledge of factors affecting insulin secretion and insulin resistance, therapy should be aimed at
1. Reducing factors known to cause insulin resistance - obesity, physical inactivity, concurrent illnesses, drug therapies
2. Addressing factors that promote insulin secretion - decrease amyloid deposition by providing insulin, decrease hyperglycaemia and hypertriglyceridaemia through the use of potent hypoglycaemic agents (e.g., insulin), provide an appropriate diet
In the newly diagnosed but healthy diabetic cat, treatment usually surrounds insulin administration and dietary control. However, the intensity of the monitoring strategy has implications for frequency of dosing changes and outcome.
A wide variety of insulin preparations are available for maintenance therapy and isophane (NPH), lente, ultralente, protamine zinc insulin (PZI), glargine and detemir have all been used with varying success in diabetic cats. The type of insulin chosen is often dependent on local availability. NPH and lente insulin have an intermediate duration of action and require twice-daily dosing. Ultralente and PZI are longer acting insulins and can sometimes be effective when administered on a once-daily basis. The blood glucose response is often less predictable with longer acting insulin and in many cats they are better given twice daily. Glargine is a long-acting insulin analogue that can be administered once or preferably twice daily. However, it is not licenced for veterinary use. Similarly, detemir is an insulin analogue with an extended duration of action that is not licenced for cats, but when used is preferably administered twice daily.
Although the species of origin of insulin has few implications in cats as opposed to dogs, there have been recent difficulties in the supply of insulin of bovine origin, and bovine lente and PZI preparations previously licenced for cats are no longer available. Porcine lente (Caninsulin, Intervet Schering Plough) and recombinant human PZI insulin are licenced for cats and available as 40 IU/mL solution. They are frequently used in diabetic management. All other insulins are 100 IU/ml solutions.
Insulin Protocol and Short-Term Monitoring
For most insulin preparations, a safe starting dose is 0.25–0.5 IU/kg bodyweight, with a maximal dose of 2 IU per injection, adjusting the dose based on the severity of the hyperglycaemia. Stabilisation in the hospital is not strictly necessary, but it may be prudent to evaluate the nadir blood glucose concentration (may require assessment of blood glucose concentrations multiple times) after the first few injections to ensure hypoglycaemia has not occurred. The protocol for insulin dose adjustment then varies depending on the insulin used and whether home or hospital management is selected. For intermediate-acting insulin, it is possible to adjust doses based only on the nadir blood glucose concentrations. However, for the longer acting preparations, where there may be a carry-over effect, assessment with both nadir and pre-insulin blood glucose concentrations are required. Cats can then be discharged and asked to return for a repeat blood glucose concentration every three to seven days with incremental dose adjustments of 1 IU, if required, until stability is achieved. Most cats eventually stabilise on 2 to 5 IU per injection per cat. For home monitoring, multiple blood glucose samples can be assessed per day with frequent insulin dose adjustments aiming to maintain blood glucose concentrations within a narrow range (approximately 3–11 mmol/L). Such a monitoring strategy may increase the likelihood of diabetic remission, but also increases the risk of hypoglycaemia.
The optimal proportion of dietary protein, carbohydrate, and fat for diabetic cats is still largely unknown. However, it does appear that diets with a higher protein and lower carbohydrate content are preferable and significantly increase the frequency of diabetic remission. Obviously obese diabetic cats will benefit from an appropriate weight-loss programme, although low-carbohydrate diets should also be used. It is generally recommended that cats are fed twice daily at the time of insulin injection.
The most appropriate method for monitoring diabetic cats long-term is controversial. One of the primary aims of therapy of diabetic cats is resolution of clinical signs, and it is therefore important to regularly monitor water intake and body weight. Blood glucose curves are frequently recommended, but are problematic if performed in the hospital because of the effects of stress on blood glucose concentrations in cats. Although owners can obtain blood samples from their own cats, there may still be widely variable responses in individual cats from day to day despite a consistent insulin and food regimen. The glycated protein, fructosamine is a useful indicator of glycaemic control in diabetic cats. There is an overlap in results between untreated diabetics, poorly controlled diabetics, well-controlled diabetics, and normal cats. However, trends in individual cats are useful and a fructosamine concentration that approaches the reference range may indicate diabetic remission.
Undoubtedly, the likelihood of remission is highly dependent on adequate treatment and the intensity of the monitoring strategy. Some estimates suggest that remission rates of over 80 % are possible in cats with type 2 disease if treated appropriately. In practice, remission rates of between 30 and 40 % are probably more realistic. Many owners would prefer to know the likelihood of remission before choosing a given treatment protocol. Unfortunately, it is difficult to predict which cats will go into remission and which will not. Remission is more likely in cats intensively treated soon after (< 6 months) first diagnosis, in cats recently treated with glucocorticoids, in older cats and in those without signs of peripheral neuropathy. Gender, weight (including obesity), presence of diabetic ketoacidosis, renal disease or hyperthyroidism, and frequency of hypoglycaemia are not predictors of remission. Approximately 25–30 % of cats in remission will relapse, and repeat remission, although possible, becomes less likely. It may also be worthwhile testing for acromegaly early on, given it is associated with insulin resistance, thereby decreasing the likelihood of remission. Acromegaly may be an underdiagnosed condition and has been recognised in 25 % of diabetic cats, where only 1 in 4 was phenotypical of the disease.
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