Changes

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.

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:

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 [[Pancreas, Endocrine - Degenerative Pathology|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|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.  

*Failure to produce insulin resulting in an '''absolute deficiency''' - This may be due to [[Pancreas, Endocrine - Degenerative Pathology|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|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 with several studies giving conflicting results as to the presence of autoantibodies directed at the beta cells at the point at which the disease is first diagnosed.   

 

Cats may suffer from islet amyloidosis in which the protein amylin is deposited in the tissue and has directly cytotoxic effects on the beta cells.  Amylin is a protein which is produced normally in the beta cells at the same rate as insulin and has synergistic effects on many aspects of metabolism.  In situations where the synthesis of insulin is increased due to insulin resistance (see below), amylin is also produced in excess and it then forms aggregates that are deposited in the pancreatic tissue.

*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 '''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 [[Canine Hyperadrenocorticism - Cushing's Disease|hyperadrenocorticism]] (due to corticosteroids), [[Hypersomatotrophism - Acromegaly|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.

*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 [[Canine Hyperadrenocorticism - Cushing's Disease|hyperadrenocorticism]] (due to corticosteroids), [[Hypersomatotrophism - Acromegaly|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.

*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.

*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.

 

 

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 are released by hydrolysation of triglycerides ('''lipolysis''') in adipose tissue and these are converted to ketone bodies (mainly beta hydroxy-butyrate and acetoacetate) by oxidation in the liver ('''ketogenesis''').  Normally, insulin would act to limit the oxidation of fatty acids and a deficiency of the hormone therefore allows ketone bodies to be produced.  The ketone bodies may be used as an energy source by many tissues.   

 

In response to hyperglycaemia, insulin normally inhibits hepatic '''gluconeogenesis'''.  When insulin is deficient, this process continues and, together with dietary glucose, this results in the hyperglycaemia observed in diabetes mellitus.  As the blood glucose concentration exceeds the level at which it can be reabsorbed in the proximal convoluted tubules (the '''renal threshold'''), it is lost into the urine.  This creates an '''osmotic diuresis''' as water moves by osmosis into the tubular filtrate and affected animals therefore develop polyuria and compensatory polydipsia.

 

Diabetic ketoacidosis (DKA) occurs in animals with unstable diabetes mellitus.  It may occur days to months after the initial clinical signs of disease are observed and, in humans, it is related to the sudden excessive production of hormones antagonistic to insulin, chiefly glucagon.  DKA may therefore be caused by entry into dioestrus or stressful events.  The antagonistic hormones cause further lipolysis, ketogenesis and gluconeogenesis.

 

As glucose and ketone bodies exceed their respective renal thresholds, the extent of the osmotic diuresis worsens causing '''dehydration'''.  Electrolytes are also lost in the urine as cations (sodium, potassium and magnesium) move to balance the negative charge of the ketone bodies.  Progressive dehydration leads to reduced cardiac output, tissue perfusion and renal output. 

 

The elevated concentration of acidic ketone bodies produces a '''metabolic acidosis''' as the buffering capacity of the plasma is overwhelmed, a phenomenon which is exacerbated by the production of lactic acid as underperfused tissues switch to anaerobic glycolysis and by the losses of extracellular fluid in vomiting and diarrhoea.

 

Reductions in renal output allow ketone bodies and glucose to increase to ever higher concentrations in the blood.  Water moves from the intracellular space to compensate for this high plasma osmolality and the alterations in cellular hydration may result in comas or seizures.

 

 

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.  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.

 

Diabetic animals may suffer from '''peripheral neuropathies''' and '''retinopathy''' and they will have some level of '''immunosuppression'''.  Affected animals are therefore predisposed to the development of chronic skin and urinary tract infections.

==Signalment==

==Signalment==

===Clinical signs===

===Clinical signs===

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

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.   

*'''Polyuria''' and '''polydipsia''' because the blood glucose concentration exceeds the renal threshold.  The owner may complain of nocturia.   

*'''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'.

*'''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.

*'''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.

*'''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.

*'''Cataracts''' develop as the metabolism of the lens is altered to compensate for hypergycaemia.   

*'''Peripheral neuropathy''', manifesting as plantigrade stance.

*'''Peripheral neuropathy''', manifesting as plantigrade stance.

*'''Chronic or recurrent pyoderma''', '''urinary tract infection''' or '''respiratory tract infection''' due to relative immunosuppression.

*'''Chronic or recurrent pyoderma''', '''urinary tract infection''' or '''respiratory tract infection''' due to relative immunosuppression.

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

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

*'''Dehydration'''

*'''Dehydration'''

*'''Depression''' and coma

*'''Depression''', lethargy and coma

*'''Inappetance'''

*'''Inappetance'''

*'''Vomiting''' and diarrhoea

*'''Vomiting''' and diarrhoea

*'''Ketotic breath''', whose odour resembles that of pear drops

*'''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

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

===Diagnostic Imaging===

===Diagnostic Imaging===

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:

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

*The pancreas may appear normal or reduced in size due to fibrosis

*In cats, amyloidosis is sometimes present in the islets

*In cats, deposition of amyloid (aggregated plaques of the protein amylin) is often observed.

*Fatty change is consistently present in the liver and kidneys

*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.

*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.

*The islet cells and the epithelium of the small ducts may be vacuolated.

===Laboratory Tests===

===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.  

The defining indicator of diabetes mellitus is persistent fasting hyperglycaemia with glycosuria.  Single measurements demonstrating hyperglycaemia are not sufficient to make a diagnosis as transient hyperglycaemia frequently occurs after stress, eating or excitement, particularly in cats.  Urine glucose is therefore measured to confirm the diagnosis but this test is also not sufficient in isolation because glycosuria may occur independently of hyperglycaemia in a number of other diseases, including Fanconi Syndrome and primary renal glycosuria.  If there is any doubt as to the cause of hyperglycaemia, repeated measurements may be made to determine whether it persists over time or blood may be submitted for measurement of fructosamine levels (see 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.

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===

===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|insulinoma]].

'''Fructosamine''' refers to the product of 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 indication 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|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.

'''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.

'''Urine''' samples are easy to obtain and may provide supportive evidence for a diagnosis of diabetes mellitus.  Ketonuria may be apparent on a dipstick but, if this develops acutely, only beta hydroxy-butyrate will be present and this is not detected by standard dipsticks.  The urine would therefore need to be oxidised by mixing with hydrogen peroxide to convert beta hydroxy-butyrate to acetoacetate.  In cases of cystitis, proteinuria, haematuria and pyruia would be expected and bacteria may be observed on cytological examination of the sample.

 

An '''electrocardiogram''' should be performed in cases of DKA to assess the degree of cardiac compromise caused by hyperkalaemia.  Common findings in this condition include bradycardia, reduced R wave amplitude, reduced or absent P waves, spiked T waves, a reduced Q-T interval and an increased P-R interval.

==Treatment==

==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.

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

===Stabilisation===

===Stabilisation===

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

Animals presenting with DKA are often collapsed, comatose and severely dehydrated.  Stabilisation would involve the following aspects of care:

*'''Intra-venous fluid therapy''' with a suitable product.  Ultimately, the priority of fluid therapy is to hydrate the animal and prevent further damage due to poor tissue perfusion and the exact choice of the fluid product may appear somewhat academic.  Some clinicians recommend the use of sodium choride solutions (0.9% saline) as it will not exacerbate the severe hyperkalaemia encountered in animals with DKA.  Others prefer to use compound sodium lactate (Hartmann's solution) as it provides some buffering capacity and, because its potassium content is much lower than that of normal plasma, it is unlikely to worsen any hyperkalaemia.

===Management===

===Management===

Insulin

Insulin