What are the aims of treatment of feline diabetes mellitus?
- Maintain adequate glycaemia control
- Avoid side effects of hyperglycaemia
- Use exogenous insulin to generate glycaemic control then rely on dietary treatment if possible depending on aetiology
What are common side effects of hyperglycaemia in cats?
- Ketoacidosis
- Cataracts
- Pancreatitis
- Nephropathy, retinopathy (both rare)
What treatment options are available for cats with diabetes mellitus?
- Diet alone, can be very effective
- ProZinc and Caninsulin (licensed)
- Insulin glargine (lantus)
- Oral hypoglycaemic agents, but rarely (glipzzide, metformin, chromium, vanadium)
What is the typical dose of Caninsulin used in cats?
0.25-0.5IU/kg BID (start at 0.25)
Outline the feeding of cats with diabetes mellitus
- High protein diet improves glycaemic control
- High fibre can be beneficial as long as low carb
- Low cal/high fibre good in obese diabetic patients to aid weight loss, DO NOT USE for emaciated diabetics
Outline the use of insuin glargine in the treatment of diabetic cats
- Lantus
- Human recombinant insulin analogue, excellent in studies
- Microprecipitate that dissipates of the day
- Difficulty with cascade in EU
Outline the use of oral hypoglycaemia agents in cats with NIDDM
- Very rare
- Only where diet and exogenous insulin are giving sub-optimal control
What is the mechanism of action of glipzide? What are the side effects? Dose?
Sulphonylurea durg, stimulates insulin secretion from functional beta cells (but body already doing this so may be physiologically detrimental)
- Hypoglycaemia, vomiting, icterus, elevated liver enzymes
- 2.5mg/cat
What is the mechanism of action of metformin, in the treatment of diabetic cats? Side effects? Dose?
- Biguanide, no direct effect on beta cells, increases sensitivity of peripheral tissue and liver to insulin, inhibits gluconeogenesis and glycogenolysis
- Side effects: V, D, anorexia
- 25-50mg/cat
What is the mechanism of action of acarbose in the treatment of diabetic cats? Side effects?
- Alpha glucosidase inhibitor, slows intestinal absorption of glucose (inhibits sucrase, maltase, isomaltase)
- Side effects: diarrhoea, weight loss
What is the mechanism of action of chromium in the treatment of diabetic cats?
Increases insulin sensitivity
What is the mechanism of action of vanadium in the treatment of diabetic cats? Side effects?
- Acts at post-receptor site to stimulate glucose metabolism
- Side effects: anorexia, vomiting, renal toxicity
What parameters should be measured in the monitoring of the feline diabetes mellitus patient?
- clinical examination, owner report of clinical signs
- Blood glucose/fructosamine
- Urine glucose
Why is home blood glucose monitoring best in cats with diabetes mellitus?
Removes stress aspect which can increase glucose result
Outline the frequency of monitoring of the feline diabetes mellitus patient?
- Weekly for first 3-4 weeks-
- Then every 2-3 weeks until 4 months
- Then every 4 months
Why is frequent monitoring of feline diabetes mellitus patients important?
- Need to ensure that diabetes is controlled and that the cat has not gone into remission
- Allows checking of owner compliance
When is a cat describe as resistant to the insulin they are receiving?
When they are receiving >2.2 IU/kg BID
What should be investigated if a cat becomes resistant to the insulin being administered?
- Owner compliance
- Infection (e.g. UTI)
- Concurrent endocrinopathy
- neoplasia
- Stress
- True insulin resistance
What is the main risk of remission in diabetic cats?
Hypoglycaemia - will kill them faster than chronic glow grade diabetes
In what aspects of diabetic monitoring should a cat owner be educated?
- Clinical signs, of both uncontrolled diabetes and remission
- What to do in the even of a hypoglycaemic crisis
Outline the potential for remission in a feline diabetes mellitus patient
- Not usually the aim and often only temporary
- Occurs usually after aggressive early treatment (~26% of those in primary care, 60-67% of those in referral), usually occurs within 3 months of starting treatment
Outline the value of urine glucose measurement in the monitoring of diabetes mellitus in the cat
- Only an average of what is occurring between urinations
- Should not be used to alter daily insulin dose
What is the typical signalment for canine diabetes mellitus?
- Peak 7-9yo, generally older dogs
- Females more common than males
Which breeds of dog are predisposed to diabetes mellitus?
Australian terrier, Standard and miniature schnauzer, Bichon Frise, Spitz, fox terrier, miniature poodle, samoyed, cairn terrier, keeshond, maltese, toy poodle, lhasa apso, yorkie, collie, GSD
What are the clinical signs of diabetes mellitus in the dog?
- PUPD
- Polyphagia and weight loss
- Exercise intolerance, lethargy, sleepy
- Diabetic cataracts
- Recurrent infections
- Ketosis (acetone breath)
Why do recurrent infections occur with diabetes mellitus?
- Neutrophil function reduced by high glucose
- Warm bladder filled with glucose, perfect for UTI
What are the acute signs of diabetic ketoacidosis?
- Dull, depressed, weak, possibly comatose
- Often vomiting
- Dehydrated
What are the effects of insulin on carbohydrates?
- Stimulates receptor mediated glucose uptake via GLUT4 in most cells
- In liver, enhances uptake, phosphorylation, glycolysis, glycogen storage and inhibits glycogenolysis
What are the effects of insulin on fat
- Excess glucose -> pyruvate -> AcoA and FFA
- Insulin activates lipoprotein lipase and inhibits hormone sensitive lipase
What is the effect of insulin on protein?
- Increased protein anabolism
- Inhibits gluconeogenesis
Describe the pathology of type I diabetes mellitus
- Beta-cell destruction leading to absolute insulin deficiency
What are potential causes of type I diabetes mellitus in the dog?
- Can be immune mediated
- Idiopathic
- Pancreatitis
- Glucose toxicity
- Chemical toxicity
- Beta loss due to exocrine pacreatic insufficiency/pancreatitis
- Congenital beta-cell loss
Give examples of immune mediated causes of type I diabetes mellitus
- LADA - latent autoimmune diabetes in adults
- Antibodies against islet Ag e.g. insulin, gAD-65, insulinoma antigen-2
What are potential causes of type II diabetes mellitus in the dog?
- Can be mainly IR with relative insulin deficiency or primarily secretory defect +/- IR
- Progesterone/agen leading to increased GH which inhibits insulin
- IR due to glucocorticoids, glucagon, catecholamines, thyroid, obesity
- HAC, exogenous corticosteroids
- IGF-1/GH excess (acromegaly)
Explain how insulin resistance can eventually lead to insulin deficiency
- Reduced response = increased release
- Beta-cell exhaustion and glucose toxicity = hypoinsulinaemia and hyperglycaemia
Explain how diabetes mellitus can develop in the bitch
- Can develop in metoestrus
- High progesterone, causes mammary development
- Leads to increased mammary growth hormone, can leak out and inhibit insulin = hyperglycaemia
What are the potential outcomes for metoestrus diabetics?
- If low basal insulin once presented then have lost insulin production and diabetic for rest of life
- If high basal insulin and therefore maintained islet function, can go into remission and metoestrus diabetes will not return if spayed
Explain the pathophysiology of diabetic cataracts
- Normally glucose in eye metabolised by hexokinase, becomes overwhelmed by hyperglycaemia
- Metabolised by AR (aldose reductase) to sorbitol
- Sorbitol stays in eye and draws in water via osmosis
What tests need to be included when working up a case of suspected canine diabetes mellitus?
- Urinalysis
- Haematology and biochem
- Fructosamine
Explain the interpretation of glucosuria
Glucosuria can indicate diabetes mellitus, but only where hyperglycaemia is also present - where this is not the case, renal tubular disease should be investigated
What findings might be expected on haematology and biochemistry in a case of canine diabetes mellitus?
- Increased ALP and ALT
- Increased cholesterol and TAGs
- Fasting hyperglycaemia
- +/- hyponatraemia
- +/- ketonuria/ketoanaemia
- Fructosamine
What (other than glucosuria) may be found in urinalysis in a case of canine diabetes mellitus?
Positive bacterial culture (i.e. UTI)
What value is indicative of fasting blood hyperglycaemia?
> 12mmol/l usually (>5.5-12mmol/l more challenging to identify)
Why may hyponatraemia occur in diabetes mellitus?
Hyperglycaemia may have osmotic effect, drawing water out of intracellular into extracellular compartment, diluting sodium
What is the renal threshold for glucose?
~10-12mmol/l
Compare the relative doses required to inhibit ketogenesis, stimulate glucose uptake and stimulate K+ uptake
If have enough insulin to stimulate glucose uptake, inevitably have enough to inhibit ketogenesis, and if have enough to stimulate K+ uptake, have enough to stimulate glucose uptake
What are the following signs of in a diabetic canine patient?
Collapsed, vomiting, anorexia
Ketoacidosis
What treatment is required in a diabetic canine patient with the following signs?
PUPD, ketonuria, eating and drinking
Healthy other than PUPD, start insulin therapy, routine management required only and intermediate dose of insulin
What are the aims of diabetic treatment?
- Prevent ketoacidosis
- Abolish clinicla signs
- Restore lost condition/weight
- Reduce risk of complications
- Complete control of blood glucose not necessary as long as is stable and otherwise healthy
What factors need to be taken into consideration when treating a diabetic dog?
- Insulin type and frequency of administration
- Diet
- Body condition
- Lifestyle
- Spaying of intact females
Outline what factors need to be discussed with the owner regarding the treatment of a diabetic dog
- Need to give full explanation of therapy
- Financial commitment required is substantial
- Stability of lifestyle as consistency is critical
- Expectation management
- Provide examples of resources available
What product is licensed in the treatment of canine diabetes mellitus?
Only Caninsulin is licensed
What are the 2 lente forms of insulin available for dogs?
- Caninsulin is a lente insulin zinc suspension
- Semi-lente = soluble crystal of insulin quickly absorbed
- Ultra lente = less soluble form, slower release of insulin
Outline the doses of insulin used in dogs
- Usually given BID but can be SID
- Initial dose 0.5IU/kg BID
- Most required between 0.8-1.2 IU/kg/dose to stabilise
Describe the storage of caninsulin
- Ideally in fridge door (2-8degreesC)
- Rolled gently prior to drawing up dose, not shaken
- May be ineffectual after expiry date
- Keep open for 28 days max
What factors need to be controlled in order to establish a consistent dose of insulin?
Exercise and diet
How should diet be controlled in a diabetic canine patient? How does this differ in obese and thin patients?
- Dry/tinned food
- Keep meal times at a set time and corresponding with insulin dosing
- Calculate patient’s MER in kcal and weigh out food
- Food should be high in complex carbs for minimised post-prandial glucose peaks, high fibre
- Avoid semi-moist foods
- Ideally use a glucomodulation diet
- Increase cal intake gradually if low BCS, careful and monitored weight reduction if high BCS
Outline the control of lifestyle for a diabetic patient
- Consistent regular exercise at a similar time each day
- Maintain lifestyle of owner
- Can learn to adapt food volume for particularly active days
Outline a basic treatment protocol for a canine diabetic patient
- Start insulin 0.5 IU/kg SC BID
- Ensure diet correct and consistent
- Monitor water intake at home
- See again in 7 days and perform 12 hour BG curve if poss
- If control sub optimal, increase dose by 10% and repeat cycle until stable
- If repeated BG curves not an option, use home diary and possibly fructosamine
- Spay entire females
What aspects should be monitored at home by the owner of a canine diabetic?
Water intake, appetite, weight, demeanour
Outline the use of blood glucose cures in canine diabetic monitoring
- Shows effect of insulin
- Can be done at home in some patients
- Identify effect, nadir, duration of action, occurrence of Somogyi
- NB inconsistent curves may occur despite consistent management
Explain the use of glycated haemoglobin in canine diabetic monitoring
- Gives indication of glycaemic control over preceding 2-3 months (glucose non-enzymatically bound to Hb)
- Usedinhuman medicine, value in veterinary unclear
What is Somogyi?
Aka “overswing”, insulin too high, blood glucose drops too far, mechanisms activated to protect from hypoglycaemia (glucagon, cortisol, epinephrine), inducing hypeglycaemia
On a blood glucose curve, what would lack of response to hypoglycaemia following insulin administration suggest?
Glucagon deficient form of pancreatitis as the origin of the diabetes mellitus
On a blood glucose curve, what would a curve with reasonable shape but still hyperglycaemia indicate?
- Insulin too low
- If already >2Iu/kg then curve indicates insulin resistance
What is a possible complication of canine diabetes mellitus treatment? What are the clinical signs?
- Hypoglycaemia
- Hunger, food seeking, altered judgement, ataxia, weakness, collapse, convulsions
What is the treatment for hypoglycaemia in a diabetic patient?
- Dextrose absorbed across gums (owner can do this in emergency by using glucose, jam, honey) - does not need to be ingested
- IV glucose at clinic or glucagon injection if not debilitated
What may be the cause of fluctuating insulin requirements in a canine diabetic patient?
- Insulin related (bottle, batch, dilution)
- Prolonged Somogyi
- Inconsistent administration, absorption, diet, exercise
- Dramatic dose changes
- Unstable illness (sepsis, inflammation, cirrhosis, HAC treatment)
- Spontaneous remission
Give some potential complications in canine diabetic patients
- Clinical hypoglycaemia
- Fatal hypoglycaemia
- GI disturbance
- Bacterial infection
- Pancreatitis
- Keratoconjunctivitis
- Cirrhosis
- Neuropathy
What factors may lead to persistently high insulin requirements in a canine diabetic patient?
- Insulin (species, short acting)
- Diet
- Diabetogenic therapy
- Hyperadrenocorticism
- Hyper/hypothyroidism
- Acromegaly
- Azotaemia
- Progesterone (metoestrus)
- Obesity
- Phaechromocytoma
- Glucagonoma
What is the prognosis for canine diabetic patients?
- Median survival time 2.75 years
- If survive first 6 months post-diagnosis, life expectancy close to age matched controls
What are the potential differentials for hyperkalaemia +/- hyponatraemia?
- Addison’s
- Sodium loss with V/D
- Severe GI disease (incl. duodenal perforation, gastric torsion)
- Renal and urinary tract disease (incl.intrinsic acute renal failure, end stage renal failure, uroabdomen, post-obstructive diuresis)
- Severe liver failure
- Parasitism (whipworms)
- Congestive heart failure
- Pleural effusion (chylothorax)
- DKA, metabolic acidosis, respiratory acidosis
- Tissue cruss injury/reperfusion injury
- Pregnancy
- Artefact
What are the potential differentials for increased BUN?
- Addison’s (pre-renal azotaemia)
- Renal disease
- Gastrointestinal disease
What are the potential differentials for hypercalcaemia?
- Neoplasia
- Addison’s
- Primary hyperparathyroidism
- Renal failure,
- Vitamin D toxicosis,
- Hypercalcemia of growing dogs,
- and granulomatous disease
What are the potential differentials for hypoglycaemia?
- Addison’s,
- Sepsis,
- Liver disease,
- Starvation or severe maldigestion,
- Puppy hypoglycemia,
- Hunting dog hypoglycemia,
- Insulin-secreting pancreatic tumors,
- Other neoplasia,
- Insulin overdose,
- and artifact
What are the potential differentials for hypoalbuminaemia?
- Addison’s
- Decreased hepatic synthesis
- Increased renal loss
- Increased gastrointestinal loss/decreased absorption
What should be considered in a dog with increased liver enzymes and renal azotaemia?
- Addisons
- Infectious disease such as Leptospirosis
What are the differentials for elevated liver enzymes?
- Diabetes mellitus
- Addison’s
- Primary hepatopathy (immune mediated, esp if with hypoglycaemia, hypoalbuminaemia and hypocholesterolaemia)
What are the consequences of diabetic ketoacidosis?
- Ketone body formation in the liver
- Enters metabolic acidosis
- Severe dehydration
- Shock
- Death
What leads to a diabetic ketoacidotic crisis?
Combined insulin deficiency and excess diabetogenic hormones, +/- insulin resistance but does not usually occur due to mismanagement of diabetes, usually due to a second triggering condition/stressor on top of underlying DM
What conditions commonly trigger ketoacidosis in a diabetic patient?
Infections, other endocrine diseases (e.g. hyperadrenocorticism), inflammatory disease (e.g. pancreatitis)
Outline the physiology of diabetic ketoacidosis
High glucagon and low/resistance to insulin leads to increased FFA metabolism producing acetyl-coA which accumulates in the liver and converted to acetoacetyl-coA and ultimately ketone production
How does low insulin contribute to diabetic ketoacidosis?
- Increased lipolysis leading to increased release of FFAs
- Decreased ketone body metabolism
Which ketone bodies are of most concern in dogs and cats?
- Beta-hydroxybutyrate (first one)
- Acetoacetic acid
- Acetone
How do dehydration and hypovolaemia occur in diabetic ketoacidosis?
- Hyperglycaemia and ketonuria leads to severe osmotic diuresis
- Renal loss of water and electrolytes
- Vomiting also leads to fluid loss
- Dehydration eventually leads to hypovolaemia
How does nausea occur in diabetic ketoacidosis?
- Circulating KBs act on the chemoreceptor trigger zone in the brain (CRTZ)
- Leads to nausea which reduces the appetite and water intake
Explain why dehydration exacerbates diabetic ketoacidosis
- Dehydration leads to reduced renal excretion of glucose and ketones due to reduced GFR
- Increased aggregation of ketones aggravating the CRTZ
What are further complications of dehydration in diabetic ketoacidotic crises?
- Hyperviscosity
- Thromboembolism
- Severe metabolic acidosis
- Renal failure
- Electrolyte abnormalities
What conditions may precipitate ketoacidosis in a dog?
- UTI
- Pyometra/dioestrus
- Pancreatitis
- Endocrine disease
- Pneumonia
- Corticosteroid treatment
- Neoplasia
What conditions may precipitate ketoacidosis in a cat?
- UTI
- Cholangiohepatitis
- Pancreatitis
- Airway disease +/- respiratory disease
- CKD
- Endocrine disease
In what scenario may a non- diabetic ketosis occur in cats or dogs?
- Metabolic situations where there is high fat metabolism
e. g. starvation, later stages of pregnancy- - Urine ketones +ve, urine glucose -ve, blood glucose normal
What are the key clinical signs of diabetic ketoacidosis in cats and dogs?
- PUPD
- Vomiting
- Anorexia
- Profuse diarrhoea
- Weak, lethargy, depression
- Pyrexia, tachycardia, poor peripheral pulses
- Tachypnoea
- Prolonged CRT
- Hepatomegaly
- Cataracts (dogs)
- Jaundice
Describe the typical appearance of the vomit produced in diabetic ketoacidosis
Frothy, bilious, large volume
Describe the typical appearance of the diarrhoea produced in diabetic ketoacidosis
Watery, yellow
What specific sign of diabetic ketoacidosis may be seen in cats?
Diabetic neuropathy - plantigrade hindlimb stance, relevant to poorly controlled DM rather than DKA
List potential differentials for a vomiting patient
- Dietary indiscretion
- Non-specific gastritis
- Foreign body
- Intussusception
- Neoplasia
- Infectious
- Pancreatitis
- Acute kidney injury
- Pyometra
- Hepatitis
- Hypoadrenocorticism
- Drugs/toxins
- CNS disease
- Peritonitis
- DKA
What causes the jaundice that may be seen in diabetic ketoacidosis in cats and dogs?
- Dogs: underlying pancreatitis
- Cats: hepatic lipidosis
What may cause the tachypnoea seen in diabetic ketoacidosis?
- Reflects respiratory response to metabolic acidosis
- Potential aspiration pneumonia as a complication of vomiting/weakness
What do you need to know when presented with a vomiting diabetic with a high resp. rate and a prolonged CRT?
- Consider DKA
- Need to know last insulin dose
- If female, when last in season
- Is patient prone to GI signs or usually resistant?
- Any change to routine (diet, insulin, exercise)
What findings would be expected on biochem in diabetic ketoacidosis?
- Hyponatremia
- Hypokalaemia
- Low CO2
- Hyperglycaemia
- High BUN
- Elevated liver enzymes