Diabetes Mellitus

Description

The clinical syndrome described by the term diabetes mellitus results from intolerance to glucose. It is a chronic disease caused by an absolute or relative deficiency of insulin and, although all body systems are ultimately affected, it is primarily a disorder of carbohydrate metabolism.

Insulin is produced in the beta cells of the pancreatic islets of Langerhans and is released into the circulation to act on specific cell-surface receptors. Its release is stimulated by rising blood glucose concentration and it is principally insulin which is responsible for the post-prandial gluconeogenesis observed in humans and dogs. Several hormones (including corticosteroids, progesterone, oestrogen, growth hormone, glucagon and catecholamines) have an antagonistic effect to insulin and cause the blood glucose concentration to increase. Interruptions at any stage in this pathway may produce the clinical syndrome of diabetes mellitus, including:

• Failure to produce insulin resulting in an absolute deficiency - This may be due to degenerative changes in the beta cells or it may occur with severe exocrine pancreatic disease that disrupts the islets of Langerhans. The major example of the latter disease process is pancreatitis and, in cases of this diesase, diabetes mellitus is often found concurrently with exocrine pancreatic insufficiency. Degeneration of the beta cells, whether it involves the immune system or not, results in type 1 diabetes mellitus and miniature Poodles, Dachshunds and terriers appear to be predisposed to this condition. In humans, it is speculated that immune responses directed at certain pathogens (notably coxsackie virus B1) may cross-react with antigens expressed on the surface of beta cells resulting in immune-mediated destruction of these cells. Whether type 1 diabetes mellitus is associated with a similar misdirected immune response is not yet clear in small animals. Cats may also suffer from islet amyloidosis in which the protein amylin is produced in beta cells at the same rate as insulin and deposited in the tissue, reducing the function of the islets.
• Presence of specific antibodies in the blood that reduce the effective concentration of insulin - This is a form of immune-mediated disease that has no apparent initiating factor.
• Presence of high concentrations of hormones that are antagonistic to insulin - This occurs with many endocrine diseases that result in elevated levels of particular hormones. Examples include hyperadrenocorticism (due to corticosteroids), acromegaly (due to growth hormone) and phaeochromocytoma (due to catecholamines). Pregnancy is maintained by high blood concentrations of progesterone in small animals and this may cause gestational or type 3 diabetes and a similar phenomenon may occur during dioestrus. Iatrogenic diabetes mellitus may be induced when high doses of corticosteroids or megoestrol acetate (a synthetic progestagen) are administered. Even when the antagonisitic factor is withdrawn, the signs may remain if the islets of Langerhans are in a state of islet cell exhaustion, a form of degeneration that results from chronic hyperstimulation.
• Failure of peripheral tissues to respond to insulin, resulting in resistance - This is the cause of type 2 diabetes mellitus which is described most commonly in obese cats. This form of the disease occurs due to downregulation of insulin receptors, a process which is reversible initally. As above however, chronic hyperstimulation of the beta cells may result in islet cell exhaustion and insulin insufficiency.
• Other factors are likely to be involved in the aetiopathogenesis of the disease, including stress, concurrent illness and genetic factors, including possible associations with particular dog leucocyte antigen (DLA) haplotypes.

The deficiency or insufficiency of insulin means that peripheral tissues are not able to utilise glucose as an energetic substrate. Affected animals begin to catabolise fat and protein reserves to meet their metabolic energy requirement resulting in wastage of skeletal muscle, loss of fat reserves and overall weight loss. In spite of this weight loss, animals with diabetes mellitus have a ravenous appetite and marked polyphagia. Fatty acids released by hydrolysation of triglycerides are converted to ketone bodies (mainly beta-hydroxy butyrate and acetoacetate) and these may be used as an additional energy source by many tissues. However, exposure to high levels of ketone bodies may produce neurological and metabolic signs in diabetic ketoacidosis (DKA), a disease that requires emergency treatment. Prolonged exposure to high concentrations of glucose also has negative consequences for a number of other tissues. Cataracts develop due to changes in ocular glucose metabolism and diabetic animals often suffer from peripheral neuropathies and retinopathy. Diabetes mellitus is also associated with a degree of immunosuppression and affected animals are predisposed to the development of chronic skin and urinary tract infections.

Signalment

Diabetes mellitus is most common in mature dogs and it is twice as common in females than in males. Miniature Poodles, Dachshunds and terriers may suffer from degenerative changes and type 1 disease.

Diagnosis

The diagnosis of diabetes mellitus may be challenging, especially in collapsed animals presenting with diabetic ketoacidosis.

Clinical signs

The following signs are common in unstabilised dogs and cats with type 1 diabetes mellitus:

• Polyuria and polydipsia because the blood glucose concentration excedes the renal threshold for reabsorption in the proximal convoluted tubules.
• Polyphagia in the face of weight loss because peripheral tissues are not able to utilise blood glucose and body reserves of carbohydrate, fat and protein are degraded to meet the metabolic energy requirement. This pair of clinical signs are sometimes romantically described as resembling 'starvation in the face of plenty'.
• Muscle wasting occurs in advanced cases when body protein reserves are mobilised.
• Hepatomegaly results from increased storage of glucose as glycogen in hepatocytes. Individual hepatocytes shown signs of hydropic change or 'cloudy swelling' as they accrue increasing amounts of glycogen.
• Cataracts develop as the metabolism of the lens is altered to compensate for hypergycaemia. Glucose is usually degraded to water and carbon dioxide via the conventional Ebden-Meyerhoff pathway but, when this pathway is saturated, it is also converted to fructose and sorbitol by the enzyme system aldose reductase. This sorbitol and fructose leave the lens slowly and their presence leads to the osmotic movement of water into the lens, producing a cataract.
• Peripheral neuropathy, manifesting as plantigrade stance.
• Chronic or recurrent pyoderma, urinary tract infection or respiratory tract infection due to relative immunosuppression.

Older cats may present with type II diabetes mellitus and these animals are often obese.

Animals with unstable diabetes mellitus may progress into diabetic ketoacidosis, a state that requires emergency treatment. Such animals often show:

• Dehydration
• Depression and coma
• Inappetance
• Vomiting and diarrhoea
• Ketotic breath, whose odour resembles that of pear drops

Many of these clinical signs are underlain by the reduced cardiac output that occurs with DKA due to the renal loss of water and sodium. Blood pressure and peripheral perfusion are therefore reduced, leading to eventual circulatory collapse, coma and death

Diagnostic Imaging

Radiographs or ultrasonography of the bladder may reveal evidence of cystitis, such as a thickened bladder wall and presence of (struvite) cystoliths. Animals with diabetes mellitus, due to the high glucose concentration in their urine, may have bacterial fermentation within the bladder resulting in the formation of gas bubbles in a disease called emphysematous cystitis. The gas can be detected by either imaging modality.

Pathology

Pancretic biopsies are not generally used to diagnose diabetes mellitus. On gross and histological examination of tissues from affected animals, the following changes may be observed:

• The pancreas may appear normal or reduced in size due to fibrosis
• In cats, amyloidosis is sometimes present in the islets
• Fatty change is consistently present in the liver and kidneys
• In immune-mediated islet cell destruction, progressive lymphoplasmacytic infiltration and selective destruction of islet cells is observed.
• The islet cells and the epithelium of the small ducts may be vacuolated.

Laboratory Tests

The defining indicator of diabetes mellitus is persistent fasting hyperglycaemia. A single measurement of hyperglycaemia is not sufficient to make a diagnosis as transient hyperglycaemia frequently occurs after stress, eating or excitement, particularly in cats. Repeated measurements should therefore be made (preferably when the animal is calm) and further tests should be considered, as detailed below.

A biochemical profile may reveal mildly elevated ALP, ALT and AST due to widespread hepatic hydropic change. Hepatomegaly may also cause slight hepatic cholestasis.

Other Tests

Fructosamine refers to the non-enzymatic addition of glucose molecules to plasma proteins that are exposed to high blood glucose concentrations. Since these modifications occur slowly and becase plasma proteins have a relatively long half life, the level of fructosamine gives an indicator of the average blood glucose concentration over the previous 2-3 weeks. Animals with diabetes mellitus are expected to have a fructosamine concentration >500 umol/l (normal <400(-500) umol/l). Low fructosamine levels are found with insulinoma.

Glycosylated haemoglobin can be measured as a similar indicator to fructosamine as it is also formed by a non-enzymatic reaction between glucose and protein. Levels greater than 7% are supportive of a diagnosis of diabetes mellitus but the test is not widely available.

Urine samples are easy to obtain and may provide supportive evidence for a diagnosis of diabetes mellitus. The diagnosis should NOT be made on the basis of a single positive dipstick as transient hyperglycaemia (with stress or excitement) may also exceed the renal threshold. Animals with diabetes mellitus will have persistently high levels of urine glucose and dipsticks can be givens to owners to monitor the level of control they are achieving with insulin therapy.

Treatment

Treatment is generally based around supplementing insulin and making alterations to the management of the animal that result in stabilisation of the condition. Animals with DKA require immediate stabilisation.

Stabilisation

Animals presenting with DKA are often collapsed and comatose. Insulin supplementation and intra-venous fluid therapy are required urgently.

Management

Insulin

Prognosis

Insulin