Physiology of diabetes mellitus and insulin resistance Flashcards
A
Insulin
B
Glucagon
Insulin resistance
the diminished ability of cells to respond to the action of insulin in transporting glucose from the blood into tissues.
Potential physiological causes of insulin resistance
- Pregnancy
- Stress
Potential pathological causes of insulin resistance
- Obesity
- Hereditary predisposition
- Concurrent diseases
- Endocrinopathies
- Hyperadrenocorticism
- Acromegaly (GH excess)
Outline the pathway from initial insulin resistance to Type 2 diabetic
Insulin resistance (compensated) → insulin resistance (uncompensated) → Type 2 diabetic
Compensated insulin resistance
‘normal’ concentrations of insulin are unable to remove glucose from the bloodstream; the pancreas then secretes more insulin leading to hyperinsulinaemia (i.e. compensating)
Uncompensated insulin resistance
beta cell exhaustion (glucose toxicity): the beta cells can no longer maintain the insulin levels required to overcome the insulin resistance
Diabetes mellitus
Relative or absolute insulin deficiency
Of the following processes, explain how they could lead to hyperglycaemia:
- Reduced tissue utilisation of glucose
- Increased tissue utilisation of amino acids and fatty acids
- Increased hepatic glycogenolysis
- Increased hepatic gluconeogenesis
- Reduced tissue utilisation of glucose → increased circulating glucose
- Increased tissue utilisation of amino acids and fatty acids → ???
- Increased hepatic glycogenolysis → increased circulating glucose
- Increased hepatic gluconeogenesis → increased circulating glucose
Type 1 diabetes
beta cell destruction, usually leading to absolute insulin deficiency. May be idiopathic or immune-mediated.
Type 2 diabetes
May range from predominantly insulin resistance with relative insulin deficiency to predominantly secretory defect with or without insulin resistance.
Reasons why diabetes could arise - issues with insulin production
- Pancreatectomy
- Pancreatitis
- Autoimmunity
- Islet cell hypoplasia
- Chemical toxicity
Changes to which hormones could lead to diabetes
- Progesterone/progestagens
- Growth hormone
- Glucocorticoids
- Glucagon
- Catecholamines
- Thyroid hormones
What are some potential sites of dysfunction in obesity-induced insulin resistance?
- Inadequate number of insulin receptors
- Defective insulin receptor structure
- Cell signalling pathway
- Defective GLUT4 transport proteins
- Problems with translocation of GLUT4 to the membrane
- Interference with the function of GLUT4
What is IDDM and which species is it common in?
Insulin-dependent diabetes mellitus
- Most common form of diabetes
- The animal has a permanent insulin deficiency and requires exogenous insulin
- Almost 100% of dogs, 50-70% of cats
What is NIDDM and which species is it common in?
Non-insulin dependent diabetes mellitus
- Obesity-induced insulin resistance
- The animal can produce some insulin but there is resistance to it/perhaps it is being antagonised by something
- Common in cats but rare in dogs
True/false: IDDM is the same as Type 1 diabetes mellitus.
True, but it’s complicated.
In small animals:
IDDM = consistent with Type 1 diabetes mellitus
IDDM or NIDDM = consistent with Type 2 diabetes mellitus
What are the potential causes of canine diabetes mellitus? (common causes in bold)
- Immune-mediated (T cell) destruction of beta cells (may have genetic susceptibility to this)
- Pancreatitis with beta cell destruction
- Obesity-induced insulin resistance
- Insulin-antagonistic disease/conditions
- Insulin-antagonistic drugs e.g. glucocorticoids
Describe how immune-mediated destruction of beta cells could lead to canine diabetes mellitus
- Autoantibodies against insulin and/or beta cells
- Progressive decrease in glucose-stimulated insulin secretion
- Breed predisposition does exist
Describe how pancreatitis with beta cell destruction could lead to canine diabetes mellitus
- Spontaneous inflammation of pancreas with damage to islets and beta cells
- May take one severe bout or several over time
Describe how insulin-antagonists disease/conditions could lead to canine diabetes mellitus
- e.g. hyperadrenocorticism, met/dioestrus
- Specific hormones e.g. cortisol and growth hormone can antagonise the action of insulin and induce peripheral insulin resistance
- These are the counter-regulatory hormones usually evoked in hypoglycaemia → excessive amounts of any of them can promote diabetes
Excessive amounts of which hormones (and what disease processes) can lead to diabetes mellitus?
(because they are insulin-antagonistic in action)
- Cortisol e.g. may be due to HAC or iatrogenic
- Growth hormone e.g. in acromegaly
- Catecholamines e.g. phaeochromocytoma
- Glucagon e.g. glucagonoma
- Progesterone e.g. diestrus/gestation
Give the possible causes of feline diabetes mellitus
- Obesity-induced insulin resistance
- Islet amyloidosis
- Pancreatitis
- Insulin-antagonistic drug e.g. glucocorticoids
- Insulin-antagonistic disease e.g. acromegaly
- Genetics
Describe how islet amyloidosis can lead to feline diabetes mellitus
- The cat is obese and becomes insulin resistant
- Amylin (a.k.a. islet amyloid polypeptide) is secreted in greater amounts in obese/insulin-resistant states
- This may be a consequence of chronic hyperglycaemia/glucose toxicity
- Amylin is deposited in the islets as amyloid
- Amyloid fibrils are cytotoxic and cause apoptosis of the islet cells
- This leads to defective insulin secretion
- If the deposition is progressive → diabetes mellitus
What disease, previously known as Peripheral Cushing’s, shows high levels of insulin and glucose in affected ponies?
Equine Metabolic Syndrome
Describe the difference between these two images
Left: normal islet
Right: beta cell vacuolation (=pathology)
What is the primary disorder in Equine Metabolic Syndrome (EMS)?
Insulin resistance
Which animals is EMS most commonly seen in?
- Ponies
- Associated with obesity/ regional adiposity
What is the most common clinical sign associated with EMS?
Laminitis
Describe how insulin resistance/diabetes mellitus leads to PUPD
- Normally, glucose is filtered by the kidney into urine and then reabsorbed
- When blood glucose is too high, it exceeds the renal threshold.
- Glucose remains in the urine and acts as an osmotic particle, drawing water into the renal tubule
- This dilutes the urine and increases urine volume (osmotic diuresis)
- There is polyuria and compensatory polydipsia
Describe how insulin resistance/diabetes mellitus leads to polyphagia
- Relates to hypothalamic satiety centre
- Glucose entry into the centre → decreased hunger.
- Glucose entry into cells here is via GLUT4 receptors, therefore it requires some insulin to be present also.
- Diabetes mellitus (esp. type 1/IDDM) = lack of insulin
- There is thus a failure to inhibit the appetite centre and polyphagia despite hyperglycaemia.
Describe how insulin resistance/diabetes mellitus leads to weight loss
- Entry of glucose into cells is mediated by insulin. In DM there is a lack of insulin.
- The insulin:glucagon ratio falls and promotes the starvation processes
- Amino acids are used for gluconeogenesis and increased protein breakdown required for this leads to muscle wasting.
- This is ‘starvation in the midst of plenty’
Describe how insulin resistance/diabetes mellitus leads to cataracts
- There is excess circulating glucose due to absence/ineffectiveness of insulin
- There is therefore glucose uptake into the lens; at normal levels, this can be metabolised to lactate which diffuses out. However, excess glucose is converted to fructose and sorbitol that do not diffuse out.
- Trapped fructose and orbital draw water into the lens.
How does diabetic ketoacidosis develop?
- In the animal with diabetes mellitus, there is a lack of insulin. This means glucose does not enter cells easily, and the disturbed insulin:glucagon ratio favours catabolism.
- There is thus a shift to fat metabolism for energy.
- Mobilisation of fatty acids → excessive fatty acids levels → ketones
- Buildup of ketone → metabolic acidosis
What clinical signs will an animal with diabetic ketoacidosis present with?
- Vomiting
- Diarrhoea
- Anorexia
- All the above contributing to dehydration
What are some diagnostic tests for diabetes mellitus?
- Blood glucose levels
- Blood liver enzyme levels (shows hepatic lipidosis)
- Blood markers that indicate hypercholesterolaemia/hypertrigyceridaemia/visible lipid in serum plasma (=mobilisation of fatty acids from adipose tissue)
- Urinanalysis
- Fructosamine levels
How could blood glucose be used to diagnose an animal with diabetes mellitus?
- Persistent fasting hyperglycaemia
- Normal glucose = 3.5-5.5 mmol/L
- Diabetic = >10 mmol/L
What are the issues with diagnosing diabetes mellitus from glucosuria?
- Feline stress-induced hyperglycaemia can occur
- Stress induces catecholamines and cortisol, and therefore can cause hyperglycaemia
- Usually there is not glucosuria unless the animal has been previously stressed; recheck in a non-stressed environment
How can fructosamine levels be used to diagnose an animal with diabetes mellitus?
- Fructosamine = glycolated serum proteins
- Non-enzymatic reaction occurs and is proportional to blood glucose concentration
- Fructosamine reflects the previous 2-3 weeks of blood glucose concentration
- Abnormal = >400µmol/L
What findings might you see in the urinalysis from an animal with diabetes mellitus?
- USG increased by glucosuria; often >1.025
- May find glucose and potentially ketones in urine
- May see UTI (WBCs, bacteria, protein) attracted by high glucose levels
A
Diabetes mellitus
B
Stress
