Changes

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.

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 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  Even when the antagonisitic factor is withdrawn, the signs may remain if the islets of Langerhans are in a state of '''islet cell exhaustion''', a form of degeneration that results from chronic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 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.   

*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.

*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.

===Classification===

===Classification===

In humans, diabetes mellitus is traditionally classified into type 1 (caused by reduced insulin production by the beta cells) and type 2 (caused by insulin resistance).  It is difficult to categorise the disease in this way in animals because the exact cause of the clinical signs and the importance of any autoimmune response are unclear.  For this reason, the disease is more often divided based on clinical presentation into 'insulin dependent' or 'non-insulin dependent' forms.

In humans, diabetes mellitus is traditionally classified into type 1 (caused by reduced insulin production by the beta cells) and type 2 (caused by insulin resistance).  It is difficult to categorise the disease in this way in animals because the exact cause of the clinical signs and the importance of any autoimmune response are unclear.  For this reason, the disease is more often divided based on clinical presentation into ''''insulin dependent'''' or ''''non-insulin dependent'''' forms.

Insulin dependent diabetes mellitus is the most common form of the disease, accounting for almost all cases in dogs and at least half of those in cats.  In cats, it is likely that there is a continuous spectrum of disease depending on the severity of disease in the islets and the degree of insulin resistance.  Animals that have suffered a severe insult to their beta cell population are likely to be insulin dependent whereas, for those with early or mild disease, the form of diabetes mellitus will depend on the degree of insulin resistance due to obesity, concurrent illness, endocrine disease or exogenous pharmaceuticals.  Fluctuations in the level of this insulin resistance may alter the nature of the clinical signs observed.

Insulin dependent diabetes mellitus is the most common form of the disease, accounting for almost all cases in dogs and at least half of those in cats.  In cats, it is likely that there is a continuous spectrum of disease depending on the severity of disease in the islets and the degree of insulin resistance.  Animals that have suffered a severe insult to their beta cell population are likely to be insulin dependent whereas, for those with early or mild disease, the form of diabetes mellitus will depend on the degree of insulin resistance due to obesity, concurrent illness, endocrine disease or exogenous pharmaceuticals.  Fluctuations in the level of this insulin resistance may alter the nature of the clinical signs observed.

===Pathophysiology===

===Pathophysiology===

====Acute Disease====

====Acute Disease====

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.   

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.

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.

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.   

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.

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.  

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.