Changes

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 after severe exocrine pancreatic disease that also 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 clear in small animals.  

*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 after severe exocrine pancreatic disease that also 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 clear in small animals.  Cats may also suffer from islet amyloidosis in which protein amylin is produced in beta cells at the same rate as insulin and deposited in the tissue, reducing the function of the beta cells.  

*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), [[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), [[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.

*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.  As above, chronic hyperstimulation of the beta cells may result in islet cell exhaustion and insulin insufficiency.   

*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, infection and genetic factors.

*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'''.  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 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==

==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.

*More common in mature dogs, twice as common in females than in males

==Diagnosis==

==Diagnosis==

*'''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.  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.

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

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

*'''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'''.

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

===Diagnostic Imaging===

===Diagnostic Imaging===

Emphysematous cystitis.

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===

===Pathology===

*Pancreas appers 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, amyloidosis is sometimes present in the islets

*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 isletitis - progressive lymphoplasmacytic infiltration and selective destruction of islet cells

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

*Possible vacuolation of islet cells and epithelium of small ducts

===Laboratory Tests===

===Laboratory Tests===

===Other Tests===

===Other Tests===

'''Fructosamine''' refers to the non-covalent 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 >600-700 umol/l (normal 400-500 umol/l).  Low fructosamine levels are found with [[Insulinoma|insulinoma]].

'''Fructosamine''' refers to the non-covalent 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]].

'''Glycosylated haemoglobin'''.

'''Glycosylated haemoglobin'''.

==Treatment==

==Treatment==

===Stabilisation===

===Stabilisation===

===Management===

===Management===

==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]]