Changes

{{unfinished}}

{{review}}

==Description==

==Description==

*'''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.   

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

*'''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.

*'''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 electrolytes.  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===

===Pathology===

===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:

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

*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.

===Other Tests===

===Other Tests===

'''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]].

'''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 because 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.

==Treatment==

==Treatment==

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.

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, comatose and severely dehydrated.  Stabilisation would involve the following aspects of care:

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

====Insulin====

====Insulin====

Recombinant insulin is available in a variety of different preparations.  Soluble (or neutral) insulin is short-acting and administered by infusion but, when mixed with zinc and protamine, it has a much longer duration of action.  '''Lente''' insulin (a zinc salt preparation) is used most commonly in dogs and it may given once or twice per day.  '''Protamine zinc insulin''' (PZI) is usually used in cats as this species seems to be able to degrade insulin more quickly and it has a longer duration of action than the Lente preparations.  Bovine insulin is usually used in Lente preparations but, in dogs that are thought to have developed antibodies to this, porcine insulin may be used as it is homologous to canine.  An initial insulin dose should be selected and this should not be changed suddenly for three days to allow the animal to respond fully.  Insulin has more predictable pharmacokinetics if given intra-muscularly.   

Recombinant insulin is available in a variety of different preparations.  Soluble (or neutral) insulin is short-acting and administered by infusion but, when mixed with zinc and protamine, it has a much longer duration of action.  '''Lente''' insulin (a zinc salt preparation) is used most commonly in dogs and it may be given once or twice per day.  '''Protamine zinc insulin''' (PZI) is usually used in cats as this species seems to be able to degrade insulin more quickly and it has a longer duration of action than the Lente preparations.  Bovine insulin is usually used in Lente preparations but, in dogs that are thought to have developed antibodies to this, porcine insulin may be used as it is homologous to canine.  An initial insulin dose should be selected and this should not be changed suddenly for three days to allow the animal to respond fully.  Insulin has more predictable pharmacokinetics if given intra-muscularly.   

In cats, PZI is usually given once per day, followed by a meal after approximately 30 minutes.  A second dose of insulin is not usually required and, if it is required, a zinc-insulin preparation should be used instead of PZI as the latter may cumulative activity.

In cats, PZI is usually given once per day, followed by a meal after approximately 30 minutes.  A second dose of insulin is not usually required and, if it is required, a zinc-insulin preparation should be used instead of PZI as the latter may have cumulative activity.

In dogs, once daily dosing is often used but twice daily dosing (with injections at 12 hour intervals) is also an acceptable protocol.  Meals are offered 30 minutes after each injection.

In dogs, once daily dosing is often used but twice daily dosing (with injections at 12 hour intervals) is also an acceptable protocol.  Meals are offered 30 minutes after each injection.

====Diet====

====Diet====

=====Dogs=====

=====Dogs=====

The diet fed to diabetic animals should be '''consistent''' and, at least initially, it should have a good caloric density to allow animals to regain weight.  If the animal is obese at presentation, a programme of controlled weight loss should be instituted so that insulin resistance is also minimised.  The diet should be '''low in simple carbohydrates''' which may induce the secretion of glucagon and other hormones antagonistic to insulin.  A '''constant feeding schedule''' should be maintained, with the animal usually being fed twice per day at the same times.

The diet fed to diabetic animals should be '''consistent''' and, at least initially, it should have a good caloric density to allow animals to regain weight.  If the animal is obese at presentation, a program of controlled weight loss should be instituted so that insulin resistance is also minimised.  The diet should be '''low in simple carbohydrates''' which may induce the secretion of glucagon and other hormones antagonistic to insulin.  A '''constant feeding schedule''' should be maintained, with the animal usually being fed twice per day at the same times.

It has been shown that a higher dietary '''fibre''' content can help to achieve better stabilisation in cases of diabetes mellitus because this substrate forms a viscous gel in the intestine that slows the absorption of glucose<ref>Graham PA, Maskell E, Rawlings JM, Nash AS, Markwell PJ. '''Influence of a high fibre diet on glycaemic control and quality of life in dogs with diabetes mellitus.''' ''J Small Anim Pract. 2002 Feb;43(2):67-73.''</ref>.  This effect is greatest with soluble fibre but soluble/insoluble fibre mixes are often suitable.

It has been shown that a higher dietary '''fibre''' content can help to achieve better stabilisation in cases of diabetes mellitus because this substrate forms a viscous gel in the intestine that slows the absorption of glucose<ref>Graham PA, Maskell E, Rawlings JM, Nash AS, Markwell PJ. '''Influence of a high fibre diet on glycaemic control and quality of life in dogs with diabetes mellitus.''' ''J Small Anim Pract. 2002 Feb;43(2):67-73.''</ref>.  This effect is greatest with soluble fibre but soluble/insoluble fibre mixes are often suitable.

=====Cats=====

=====Cats=====

Similarly to dogs, the diet should be consistent and not contain a large proportion of simple carbohydrates.  In cats with suspected non-insulin dependent diabetes mellitus, obesity should be corrected as a priority to reduce insulin resistance.  Emaciated cats should be fed a diet with high caloric density.

Similarly to dogs, the diet should be consistent and not contain a large proportion of simple carbohydrates.  In cats with suspected non-insulin dependent diabetes mellitus, obesity should be corrected as a priority to reduce insulin resistance.  Emaciated cats should be fed a diet with high caloric density.

===Instability===

===Instability===

Animals that have previosuly been stabilised may suffer bouts of overt diabetes mellitus and even deteriotrate into DKA.   

Animals that have previosly been stabilised may suffer bouts of overt diabetes mellitus and even deteriotrate into DKA.   

====Causes of Instability====

====Causes of Instability====

There are many documented reasons for this instability, of which the most common are problems with:

There are many documented reasons for this instability, of which the most common are problems with:

*'''Storage and use of insulin''' - Insulin should be stored in a fridge and should only be retained as long as is stated on its 'use by' date.  The insulin should not be shaken vigorously before use and it should be kept out of sunlight.  If it is to be given by infusion, the giving set should be generously run through as the insulin molecules will adsorb to the plastic of the set.   

*'''Storage and use of insulin''' - Insulin should be stored in a fridge and should only be retained as long as is stated on its 'use by' date.  The insulin should not be shaken vigorously before use and it should be kept out of sunlight.  If it is to be given by infusion, the giving set should be generously run through as the insulin molecules will adsorb to the plastic of the set.   

*'''Administration of insulin''' - The insulin should be drawn up into a suitable insulin syringe and injected intramuscularly.  Subcutaneous injection will result in variable pharmacokinetics.

*'''Administration of insulin''' - The insulin should be drawn up into a suitable insulin syringe and injected '''intramuscularly'''.  Subcutaneous injection will result in variable pharmacokinetics.

*'''Response to insulin''' - Some animals will show signs of marked hypoglycaemia after administration of insulin but then begin to show signs of polyuria/polydipsia.  If the dose is too great for the animal, antagonistic hormones will be released that will result in a rebound hyperglycaemia after a period of hypoglycaemia, a phenomenon called a '''Somogyi overswing'''. This is remedied by reducing the dose of insulin given to prevent the release of antagonistic hormones.

*'''Response to insulin''' - Some animals will show signs of marked hypoglycaemia after administration of insulin but then begin to show signs of polyuria/polydipsia.  If the dose is too great for the animal, antagonistic hormones will be released that will result in a rebound hyperglycaemia after a period of hypoglycaemia, a phenomenon called a '''Somogyi overswing'''. This is remedied by reducing the dose of insulin given to prevent the release of antagonistic hormones.

*'''Rapid metabolism of insulin''' - Some animals metabolise insulin faster than others and begin to show signs of diabetes mellitus before their next dose is due.  If insulin is given in the morning, glycosuria will often be detected in a morning urine sample. This is managed by increasing the insulin dosage or, preferably, giving two doses of insulin twelve hours apart.

*'''Rapid metabolism of insulin''' - Some animals metabolise insulin faster than others and begin to show signs of diabetes mellitus before their next dose is due.  If insulin is given in the morning, glycosuria will often be detected in a morning urine sample. This is managed by increasing the insulin dosage or, preferably, giving two doses of insulin twelve hours apart.

*'''Insulin resistance''' - Failure to respond to insulin may occur due to an immune response to the recombinant drug or because of some underlying disease that results in the production of factors antagonistic to insulin.  If an immune response is suspected, porcine insulin should be used in preference to bovine as it is homologous to the canine molecule.  Disease that cause insulin resistance are listed above but the most common causes of instability are infections (particularly cystitis or skin infections), dioestrus, pregnancy or stress.  Infections should be treated and female animals should be neutered after they have been stabilised.

*'''Insulin resistance''' - Failure to respond to insulin may occur due to an immune response to the recombinant drug or because of some underlying disease that results in the production of factors antagonistic to insulin.  If an immune response is suspected, porcine insulin should be used in preference to bovine as it is homologous to the canine molecule.  Disease that cause insulin resistance are listed above but the most common causes of instability are infections (particularly cystitis or skin infections), dioestrus, pregnancy or stress.  Infections should be treated and female animals should be neutered after they have been stabilised.

A full history should be taken a complete clinical examination performed to try to determine whether any concurrent disease may be contributing to the clinical signs documented.  Complete biochemical and haematological analysis of blood samples and examination of a urine sample may be indicated for the same reasons, especially to rule out the presence of a urinary tract infection.

A full history should be taken a complete clinical examination performed to try to determine whether any concurrent disease may be contributing to the clinical signs documented.  Complete biochemical and haematological analysis of blood samples and examination of a urine sample may be indicated for the same reasons, especially to rule out the presence of a urinary tract infection.

If the animal is not thought to suffer from stress-induced hyperglycaemia, it should be hospitalised and blood glucose concentrations should be measured every two hours after insulin has been administered and food offered in the normal pattern for the patient.  Hourly blood samples may be necessary in some cases as the nadir of a Somogyi overswing may occur rapidly. The pattern of change of blood glucose concentration over time should help to define the cause of the instability.

If the animal is not thought to suffer from stress-induced hyperglycaemia, it should be hospitalised and blood glucose concentrations should be measured every two hours after insulin has been administered and food offered in the normal pattern for the patient.  Hourly blood samples may be necessary in some cases as the nadir of a Somogyi overswing may occur rapidly. The pattern of change of blood glucose concentration over time should help to define the cause of the instability.

    

    

==Prognosis==

==Prognosis==

[[Category:Liver_-_Degenerative_Pathology]][[Category:Cat]][[Category:Dog]]

[[Category:Liver_-_Degenerative_Pathology]][[Category:Cat]][[Category:Dog]]

[[Category:To_Do_-_James]]

[[Category:To_Do_-_James]]

[[Category:To_Do_-_Review]]

[[Category:Expert_Review]]