Classification

The current classification divides diabetes mellitus into type 1, type 2, and other specific types of diabetes.

Type 1 diabetes is an uncommon cause of diabetes in cats based on histologic studies and absence of islet cell antibodies

Type 2 diabetes appears to be the most common form of diabetes in cats, based on islet histology, risk factors, and clinical behaviour of the disease. Type 2 diabetes is characterised by inadequate insulin secretion and impaired insulin action, that is, insulin resistance. The relative severity of these two defects varies between patients, both feline and human. The defect in beta cell function is usually progressive, and in some cats and humans results in complete loss of insulin secretion

A substantial minority of diabetic cats have other specific types of diabetes, previously called secondary or type 3 diabetes. Diseases in this category that have been reported in cats include diseases causing insulin resistance, and those resulting from non-specific destruction of pancreatic tissue. The most frequent is pancreatic adenocarcinoma, accounting for up to 19% of feline diabetes. Pancreatitis is a common histological finding in diabetic cats, but whether it is a cause or a result of diabetes is unclear. Rare causes of naturally-occurring insulin resistance in cats include growth-hormone producing tumours resulting in acromegaly, and hyperadrenocorticism. Iatrogenic administration of megestrol acetate or long-acting steroids is associated with the development of diabetes in some cats.

Type 2 diabetes

Type 2 diabetes is characterized by insulin resistance and decreased insulin secretion. In humans it has been debated whether reduced insulin secretion or insulin resistance is the predominant initial defect in type 2 diabetes, and it appears that the initial defect varies between individuals. Insulin's ability to control blood glucose is dependent on both adequate insulin concentrations and adequate tissue sensitivity, and decreases in either interact to reduce the capacity to maintain blood glucose. Both insulin resistance and decreased insulin secretion are present once clinical signs of diabetes occur.

Insulin resistance

Insulin resistance is the second major abnormality in type 2 diabetes. Diabetic cats are approximately 6 times less sensitive to insulin than normal cats, and humans with type 2 diabetes have similar magnitudes of insulin resistance.

Insulin resistance and obesity

Obesity is a recognised risk factor for the development of diabetes in cats and humans, although not all cats or humans with type 2 diabetes are overweight. In cats and humans, obesity causes insulin resistance.

Genetics of type 2 diabetes

In humans with type 2 diabetes and in some cats, there is strong evidence for a genetic basis for the disease. Population studies have demonstrated a higher incidence of diabetes within some families of cats and ethnic groups of people.

In humans, it is considered likely that the multiple genes involved in predisposition to type 2 diabetes are both primary genes controlling insulin secretion and action, as well as secondary genes, influencing factors such as propensity to obesity.

Obesity and physical inactivity

Environmental influences interact with genetic influences, and play an important role in the development of diabetes in humans, and most likely in cats. Environmental or lifestyle factors shown to be important in humans and probably in cats, include obesity, physical inactivity, dietary factors, and urban rather than rural residence. The lifestyle of many domestic cats has changed similarly to humans, with inactivity and obesity increasing in urban cats. Exclusively indoor cats are usually less active than outdoor domestic cats that hunt and defend territory, and significantly less active than feral cats, which have to hunt to obtain all their nutrition. In humans and rats, exercise has been shown to increase insulin sensitivity. Lack of exercise impairs insulin action, and adds to the underlying level of genetically-determined insulin resistance.

Diet and type 2 diabetes

In both cats and humans, obesity has been shown to be a major risk factor for diabetes. Overfeeding of highly palatable, calorie-dense food in cats with reduced physical activity, likely contributes to obesity, and hence diabetes. Recent evidence in cats suggests that a high carbohydrate diet increases the demand for insulin secretion when compared to a low carbohydrate, high protein diet. In susceptible cats, this long-term demand for increased insulin secretion may lead to beta cell apoptosis and a decline is insulin secretory capacity, precipitating impaired glucose tolerance and diabetes, as hypothesized by the Carnivore Connection Theory.

Amyloid

Many, but not all cats and humans with diabetes, have amyloid deposition replacing islets cells. Amyloid deposition does not appear to be an essential component of type 2 diabetes in cats or humans, but contributes to beta cell loss and failure of insulin. In a model of induced diabetes in cats, cats with high amylin concentrations tended to have more profound amyloid deposition. Obesity likely contributes to amyloid deposition in susceptible cats by stimulating hyperamylinaemia and hyperinsulinaemia, secondary to insulin resistance.

Glucose and lipid toxicity

Once persistent hyperglycaemia occurs, insulin secretion is reduced through a phenomenon termed glucose toxicity. There is evidence that initially, suppression of insulin secretion is functional and reversible, and is not associated with visible lesions in beta cells. With hyperglycaemia of longer than 2 weeks duration, histologic abnormalities are evident, including glycogen deposition and cell death. The severity of the glucose toxicity effect is dependent on the degree of hyperglycaemia and the duration.

Increased fatty acids produce a similar effect to glucose toxicity, called lipotoxicity. The clinical implications of glucose and lipid toxicity are very important. It is vital that effective therapy be instituted as soon as possible to reduce hyperglycaemia in diabetic cats, if beta cell function is to be preserved. This is important, because data in humans indicates that patients with residual beta cell function have better glycaemic control when treated with insulin, than patients with no significant endogenous insulin secretion. Secondly, it is important because a substantial number of cats will undergo remission of their diabetes, if the effects of glucose toxicity are minimized.

Insulin resistance and chronic hyperglycaemia

Chronically elevated blood glucose also causes insulin resistance. Once overt diabetes mellitus with persistent hyperglycaemia occurs, the added insulin resistance further compounds the problem of inadequate insulin secretion. This has implications for therapy, because once glucose concentrations are decreased with treatment, insulin sensitivity may improve.

Diabetic remission or transient diabetes

Diabetic remission occurs in 20 to 80% of cats if treated adequately. Remission occurs most commonly after 1 to 4 months of insulin therapy, and in some cats, glucose tolerance is normal in remission. Based on experience, remission is more likely if glycaemic control is adequate, so beta cells can recover from glucose toxicity.

Stress hyperglycaemia

Clinicians should be aware that stress hyperglycaemia is likely to affect blood glucose estimations in cats if struggling occurs prior to the sample being taken. Blood glucose may be increased by as much as 10 mmol/l above baseline, resulting in values up to 16 mmol/l in normal cats. In sick cats, hyperglycaemia as high as 34 mmol/l has been reported.

Summary

Understanding the features of feline diabetes is important for good patient management, and may help to decrease the incidence of diabetes.

References

1.  Hoenig M, O'Brien TD: Glipizide leads to amyloidosis in a cat model of type 2 diabetes (Abstract). Diabetologia: A648, 1998

2.  Link KRJ: Feline diabetes: Diagnostics and Experimental Modelling (PhD Thesis), Submitted to The University of Queensland, 2001

3.  Panciera DL TC, Eicker SW, Atkins CE: Epizootiologic patterns of diabetes mellitus in cats: 333 cases (1980-1986). J Am Vet Med Assoc 197: 1504, 1990

4.  Rand JS and Martin GJ: Management of feline diabetes mellitus: Vet Clinics of Nth Am in press 2001

5.  Rand JS, Bobbermien LM, Hendrikz JK, Copland M: Over representation of Burmese cats with diabetes mellitus. Aust Vet J 75: 402, 1997