Diabetes mellitus and insulin resistance Flashcards
What is diabetes mellitus?
Insufficiency or inability of insulin/insulin’s functionality
What are the effects of relative/absolute insulin deficiency?
- Decreased tissue utilisation of glucose
- Increased tissue utilisation of amino acids and fatty acids
- Increased hepatic glycogenolysis and hepatic gluconeogenesis
- Leading to hyperglycaemia
What are the different types of diabetes mellitus?
- Type I
- Type II
Describe type I diabetes
- Beta-cell destruction, usually leading to absolute insuline deficiency
- Immune mediated (including LADA)
- Idiopathic
- Inflammation of pancreas leading to damage of islets
Describe type II diabetes
- May range from predominantly insulin resistance with relative insulin deficiency
- To predominantly secretory defect with or without insulin resistance
What may be some other causes of diabetes mellitus?
- Disease of exocrine pancreas - inflammation of pancreas in general may lead to damage of islets showing as type ! diabetes
- Endocrinopathies e.g. Cushing’s, acromegaly, phaechromocytoma, glucagonoma, hyperthyroidism, produciogn of excess insulin antagonistic (more similar to type 2)
- Genetic defects, drugs, chemical induced, infections
What is the effect of glucose on islet cells?
Toxic
Defined by insulin, what are the 2 types of diabetes?
- Insulin dependent
- Non-insulin dependent
Explain how insulin resistance can lead to insulin deficiency
- Insulin resistance, so get glucose increase
- Glucose toxic to islet cells
- Destruction, and so further reduction in insulin production
- Escalates until no insulin production
Describe insulin dependent diabetes mellitus
- Insulin deficiency
- i.e. the primary problem is lack of insulin
- Need to treat with insulin or will die
- Common in dogs
- In cats may be able to treat by changing diet to low carb to bring glucose back to manageable level
Describe non-insulin dependent diabetes mellitus
- Cats: common, obesity induced insulin resistance
- Dogs: insulin antagonism , drugs such as glucocorticoids, progestogens, condition such as dioestrus
Give examples of causes of diabetes mellitus in dogs
- Genetic suscpetibility
- Immune mediated destruction of beta cells
- Pancreatitis
- Obesity induced insulin resistance
- Insulin antagonistic disease/conditions
- Insulin-antagonistic drugs
Describe the immune mediated destruction of Beta cells leading to diabetes mellitus
- T cells
- Autoantibodies against insulin and/or beta cells
- Progressive decrease in glucose stimulated insulin secretion
Describe pancreatitis as a cause of diabetes mellitus
- Beta-cell destruction
- Spontaneous inflammation of pancreas with associated residual damage to islets and beta cells
- Insulin deficiency
Give examples of insulin antagonistic diseases/conditions
- Hyperadrenocorticism (cortisol)
- Dioestrus
- Acromegaly (growth hormone)
- Phaechromocytoma (catecholamines0
- Glucagonoma (glucagon)
Explain how dioestrus is an insulin antagonistic condition in the bitch
- High progesterone
- Stimulates systemic increase in growth hormone and growth factor
- Inhibit insulin
- Usually ok when enoguh can be produced to overcome this but in some circumstances may not be able to
Give an example of insulin antagonistic drugs
Glucocorticoids
Give common causes of diabetes mellitus in cats
- Obesity induced insulin resistance
- Islet amyloidosis
- Pancreatitis
- Insulin antagonistic drugs
- Insulin antagonistic disease
- Genetics
How may insulin resistance occur?
- Diminished ability of cells to respond to action of insulin in transporting glucose from blood to tissues
- Insulin resistance may be due to inadequate number of receptors
- Defective receptor structure
- Cell signalling pathway defect
- Defective GLUT4 transport or translocation to membrane
- Interference with function of GLUT4
Explain islet amyloidosis in cats
- Amylin
- Co-secreted with insulin by feline beta cells
- Chronic increased secretion (high carb diet) with obesity and insulin resistant states
- Consequence of chronic hyperglycaemia/glucose toxicity
- Amylin deposited in iselts as amyloid
- Amyloid fibrils are cytotoxic, cause apoptosis of islet cells, leading to defective insulin secretion
- Progressive can lead to diabetes mellitus
Explain why polyuria occurs in diabetes mellitus
- Blood glucose over amount that can be absorbed
- Glucose in tubules, draws out water
- Osmotic diuresis
Why does polydipsia occur in diabetes mellitus?
Compensatory to the polyuria
Explain why polyphagia occurs in diabetes mellitus
- Insulin required to signal satiety to hypothalamus
- No signalling to hypothalamus leads to increased appetite
Explain why weight loss occurs in diabetes mellitus
- No inhibition of catabolic processes
- Use up sotres
- Decreased peripheral tissue utilisation of glucose
- Insulin:glucagon ratiofalls, promoting starvation process
- AAs used for gluconeogenesis
- Increased protein breakdown leading to muscle wasting
Explain why cataracts occur in diabetes mellitus
- Glucose uptake into lens
- Normally metabolised to lactate which diffuses out using hexokinase
- Excess glucose converted into fructose and sorbitol that do not diffuse out (catalysed by aldose reductase)
- trapped fructose and sorbitol draw water into lens
Explain diabetic ketoacidosis
- Glucose does not enter cells easily
- Shift to fat metabolism for energy
- Mobilise fatty acids
- More fatty acids leads to ktones
- Ketones gbuild up leading to metabolic acidosis
- Animals appear ill: vomiting, diarrhoea, anorexia, dehydration, often present collapsed
List the diagnostic tests for diabetes mellitus
- Blood glucose
- Urinalysis
- Fructosamine
- Blood biochemistry
Describe blood glucose in the diagnosis of diabetes mellitus
- Persistent fasting hyperglycaemia
- Blood glucose usually >10mmol/L
- Often 14-16mmol/L
- Persistent glucosuria
Explain feline stress induced hyperglycaemia
- Stress induces cortisol and catecholamine release
- This leads to hyperglycaemia
- Ensure sample is stress free (i.e. taken at home) to show a representative glucose result
Describe the fructosamine test in the diagnosis of diabetes mellitus
- Glycosylated serum proteins (albumin)
- Non-enzymatic reaction, proportional to blood glucose concentration
- Reflects previous 2-3 weeks of blood glucose
- High glucose for long period leads to more fructossamine
- Over 400umol/L
What will be seen on blood biochemistry in diabetes mellitus? Why?
- Hypercholesterolaemia and hypertriglyceridaemia due to fatty acid mobilisation
- Visible lipid in serum/plasma
- Increased liver enzymes due to hepatic lipidosis
What will be seen on urinalysis in diabetes mellitus?
- USG >1.025 g/ml (increased due to glucose)
- Glucose
- +/- ketones
- UTI (white and red blood cells, bacteria, protein)
Explain how ketones are produced
- Ketones are produced from excess fatty acids
- During starvation state
- Fatty acids into TCA by using oxaloacetate
- Oxaloacetate comes from glucose
- Where there is not enough glucose and too many FFAs, they are diverted into ketone production
What are the ketones produced in starvation state called?
- Acetoacetic acid
- Acetone
- beta-hydroxybutyric acid
Why are ruminans particularly susceptible to ketosis?
Bacteria within rumen consume all glucose from feed, so ruminants have o generate their own glucose from VFAs
Why would obesity make make ketosis worse?
- Likely to have insulin resistance and so less likely to be able to use glucose that is present/being produced
- Greater source of fatty acids as more can be mobilised from adipose
- Insulin’s inhibition of HSL lost and so will be more active in TAG mobilisation
How does diabetes mellitus affect lipid mobilisation from adipose stores?
- Increases mobilisation because HSL is not being inhibited by insulin
How does diabetes mellitus affect oxaloacetate production?
- Gluconeogenesis overstimulated
- Converted back to glucose via gluoneogenesis in DM patient
- Decreased oxaloacetate so more ketones produced
Define insulin resistance
A reduced sensitivity to insulin
Give examples of physiological causes of insulin resistance
- Pregnancy
- Stress (cortisol is inhibitory to insulin)
Give examples of pathological causes of insulin resistance
- Obesity
- Hereditary predisposition
- Concurrent diseases
- Endocrinopathies
Give molecular cuases of insulin resistance
- Inadequate number of insulin receptors
- Defective insulin receptor structure
- Defective cell signalling pathway
- Defective GLUT4 transport proteins
- Problems with translocation of GLUT4 to membrane
- Interference with function of GLUT4
What is the effect of insulin resistance on glucose metabolism?
- Impaired uptake into tissues
- Increased gluconeogenesis (insulin usually suppresses this)
- Circulating glucose increase
- Tendency towards hyperglycaemia
What is the effect of insulin resistance on lipids?
- Increased lipolysis due to reduced suppression of HSL
- Higher blood FFA levels
- Increases disproportionately when triggered by negative energy balance
- repartitioning:fats stored in adipose tissue, some fat storage in skeletal muscles, increase in blood fatty acid levels shift more lipid into skeletal muscle
- Lipid can interfere with insulin signalling
What is the effect of insulin resistance on proteins?
- AAs used for gluconeogenesis
- Inhibition of AA uptake by tissues (anabolic effects suppressed)
- Hepatic insulin resistance also adds to increased gluconeogenesis, more AAs used up
What is heptaic insulin resistance?
When insulin fails to suppress gluconeogenesis within the liver
Describe the glucose tolerance test
- Dynamic test to stress system and reveal inadequacies
- IV injection of dextorse and serial blood samples
- Assess ability to reduce blood glucose and the amount of insulin needed for this
- Normal: insulin increased, glucose decreased
- Compensated IR: very high insulin, controlled glucose
- Uncompensated IR: very high insulin, very high glucose (or no increased insulin due to secondary insulin deficiency due to glucose toxicity)
Describe measurements of obesity
- Body condition scoring
- Ultrasound measurement of subcut fat (esp pigs before slaughter, rump fat)
- Bioelectrical impedance
- Dual energy x-ray absorptiometry (DEXA, similar to CT or MRI, rare)
- Objective definition of degree of “crestiness” in horses
Describe compensated insulin resistance
- Initially make more insulin to make up for resistance
- Obesity associated
- Normal concentrations unable to remove glucose from blood, pancreas secretes more insulin, leads to hyperinsulinaemia
Describe uncompensated insulin resistance
- Pancreas unable to keep up due to glucose toxicity
- Obesity associated
- beta-cell exhaustion
- High blood glucose and low insulin
What is the result of uncompensated insulin resistance?
- Type 2 diabetes melltius, non-insulin dependent (as the primary cause is obesity and not insulin)
- Glucosuria (and thus PUPD)
What is the effect of increased body fat mass?
- Expansion of adipocytes (hypertrophy)
- Increased number of adipocytes (hyperplasia)
- Accumulation in subcut adopose tissue, omental, visceral, abdoinal adipose
Describe the anabolic/catabolic imbalance in obesity
- Faster input into storage (anabolism) than output
- More fatty acids from diet, and fat produced from carbohydrates
- Slower output from storage pool due to lower demand, differences in metabolic activity between individuals i.e. good doers/easy keepers
Outline what is meant by de novo lipogenesis
- Carbohydrates turned into fat
- Herbivores synthesise fat from carbohydrates has have low fat diet
What is the link between obesity and insulin resistance?
- Obese animals more likely to suffer from IR
- Not always the case, but common
- 3 theories to explain this association: lipotoxicity, pro-inflammatory theory and adipokine theory (last 2 very closely linked)
Describe te lipotoxicity theory iin obesity and insulin resistance
- Failure to store in subcut adipose leads to ectopic lipid in visceral fat and insulin sensitive tissues e.g. liver and skeletal muscle
- Tissues develop state of lipotoxicity
- Insulin signalling and action altered, deterioration of glucose tolerance in whole body
- Cytoplasmic and intercellular functions impaired
- As lipid accumulates within myocytes, insulin signalling pathways disrupted
- Disrupted signalling transduction leads to insulin resistance
How does insulin resistance perpetuate itself through lipotoxicity?
- Insulin resistance promotes lipolysis (no inhibition of HSL)
- Increases mobilisation of fatty acids into circulation adn tehn to muscle and liver via portal system
Outline the proinflammatory theory of insulin resistance and obesity
- Adipose tissue reaches capacity for fat storage
- Stressed adipocytes release inflammatory cytokines (adipokines), create proinflammatory state
- Alter intracellular signal transduction pathway, leading to IR
- Stretching adipocyte releasing leptin and inflammatory factors, decreased release of adiponectin
- Combined will promote insulin resistance and inflammation
Outline the adipokine theory
- Adipocytes produce cytokines that can be classed as hormones (adipokines)
- Obesity alters balance of adipokines produced by adipocytes
- For example, adiponectin production decreases as obesity develops
- Adiponectin enhances action of insulin
- Lower adiponectin levels contribute to IR
Outline Equine Metabolic Syndrome
- Peviousy known as peripheral Cushing’s
- Strong link with obesity/regional adiposity
- Primary disorder in EMS is insulin resistance
- Most common clinical sign is laminitis
- High levels of insulin and glucose in ponies with EMS
