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Endo > Diabetes mellitus and insulin resistance > Flashcards

Diabetes mellitus and insulin resistance Flashcards

1
Q

What is diabetes mellitus?

A

Insufficiency or inability of insulin/insulin’s functionality

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2
Q

What are the effects of relative/absolute insulin deficiency?

A
  • Decreased tissue utilisation of glucose
  • Increased tissue utilisation of amino acids and fatty acids
  • Increased hepatic glycogenolysis and hepatic gluconeogenesis
  • Leading to hyperglycaemia
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3
Q

What are the different types of diabetes mellitus?

A
  • Type I

- Type II

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4
Q

Describe type I diabetes

A
  • Beta-cell destruction, usually leading to absolute insuline deficiency
  • Immune mediated (including LADA)
  • Idiopathic
  • Inflammation of pancreas leading to damage of islets
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5
Q

Describe type II diabetes

A
  • May range from predominantly insulin resistance with relative insulin deficiency
  • To predominantly secretory defect with or without insulin resistance
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6
Q

What may be some other causes of diabetes mellitus?

A
  • 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
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7
Q

What is the effect of glucose on islet cells?

A

Toxic

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8
Q

Defined by insulin, what are the 2 types of diabetes?

A
  • Insulin dependent

- Non-insulin dependent

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9
Q

Explain how insulin resistance can lead to insulin deficiency

A
  • Insulin resistance, so get glucose increase
  • Glucose toxic to islet cells
  • Destruction, and so further reduction in insulin production
  • Escalates until no insulin production
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10
Q

Describe insulin dependent diabetes mellitus

A
  • 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
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11
Q

Describe non-insulin dependent diabetes mellitus

A
  • Cats: common, obesity induced insulin resistance

- Dogs: insulin antagonism , drugs such as glucocorticoids, progestogens, condition such as dioestrus

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12
Q

Give examples of causes of diabetes mellitus in dogs

A
  • Genetic suscpetibility
  • Immune mediated destruction of beta cells
  • Pancreatitis
  • Obesity induced insulin resistance
  • Insulin antagonistic disease/conditions
  • Insulin-antagonistic drugs
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13
Q

Describe the immune mediated destruction of Beta cells leading to diabetes mellitus

A
  • T cells
  • Autoantibodies against insulin and/or beta cells
  • Progressive decrease in glucose stimulated insulin secretion
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14
Q

Describe pancreatitis as a cause of diabetes mellitus

A
  • Beta-cell destruction
  • Spontaneous inflammation of pancreas with associated residual damage to islets and beta cells
  • Insulin deficiency
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15
Q

Give examples of insulin antagonistic diseases/conditions

A
  • Hyperadrenocorticism (cortisol)
  • Dioestrus
  • Acromegaly (growth hormone)
  • Phaechromocytoma (catecholamines0
  • Glucagonoma (glucagon)
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16
Q

Explain how dioestrus is an insulin antagonistic condition in the bitch

A
  • 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
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17
Q

Give an example of insulin antagonistic drugs

A

Glucocorticoids

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18
Q

Give common causes of diabetes mellitus in cats

A
  • Obesity induced insulin resistance
  • Islet amyloidosis
  • Pancreatitis
  • Insulin antagonistic drugs
  • Insulin antagonistic disease
  • Genetics
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19
Q

How may insulin resistance occur?

A
  • 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
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20
Q

Explain islet amyloidosis in cats

A
  • 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
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21
Q

Explain why polyuria occurs in diabetes mellitus

A
  • Blood glucose over amount that can be absorbed
  • Glucose in tubules, draws out water
  • Osmotic diuresis
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22
Q

Why does polydipsia occur in diabetes mellitus?

A

Compensatory to the polyuria

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23
Q

Explain why polyphagia occurs in diabetes mellitus

A
  • Insulin required to signal satiety to hypothalamus

- No signalling to hypothalamus leads to increased appetite

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24
Q

Explain why weight loss occurs in diabetes mellitus

A
  • 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
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25
Q

Explain why cataracts occur in diabetes mellitus

A
  • 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
26
Q

Explain diabetic ketoacidosis

A
  • 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
27
Q

List the diagnostic tests for diabetes mellitus

A
  • Blood glucose
  • Urinalysis
  • Fructosamine
  • Blood biochemistry
28
Q

Describe blood glucose in the diagnosis of diabetes mellitus

A
  • Persistent fasting hyperglycaemia
  • Blood glucose usually >10mmol/L
  • Often 14-16mmol/L
  • Persistent glucosuria
29
Q

Explain feline stress induced hyperglycaemia

A
  • 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
30
Q

Describe the fructosamine test in the diagnosis of diabetes mellitus

A
  • 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
31
Q

What will be seen on blood biochemistry in diabetes mellitus? Why?

A
  • Hypercholesterolaemia and hypertriglyceridaemia due to fatty acid mobilisation
  • Visible lipid in serum/plasma
  • Increased liver enzymes due to hepatic lipidosis
32
Q

What will be seen on urinalysis in diabetes mellitus?

A
  • USG >1.025 g/ml (increased due to glucose)
  • Glucose
  • +/- ketones
  • UTI (white and red blood cells, bacteria, protein)
33
Q

Explain how ketones are produced

A
  • 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
34
Q

What are the ketones produced in starvation state called?

A
  • Acetoacetic acid
  • Acetone
  • beta-hydroxybutyric acid
35
Q

Why are ruminans particularly susceptible to ketosis?

A

Bacteria within rumen consume all glucose from feed, so ruminants have o generate their own glucose from VFAs

36
Q

Why would obesity make make ketosis worse?

A
  • 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
37
Q

How does diabetes mellitus affect lipid mobilisation from adipose stores?

A
  • Increases mobilisation because HSL is not being inhibited by insulin
38
Q

How does diabetes mellitus affect oxaloacetate production?

A
  • Gluconeogenesis overstimulated
  • Converted back to glucose via gluoneogenesis in DM patient
  • Decreased oxaloacetate so more ketones produced
39
Q

Define insulin resistance

A

A reduced sensitivity to insulin

40
Q

Give examples of physiological causes of insulin resistance

A
  • Pregnancy

- Stress (cortisol is inhibitory to insulin)

41
Q

Give examples of pathological causes of insulin resistance

A
  • Obesity
  • Hereditary predisposition
  • Concurrent diseases
  • Endocrinopathies
42
Q

Give molecular cuases of insulin resistance

A
  • 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
43
Q

What is the effect of insulin resistance on glucose metabolism?

A
  • Impaired uptake into tissues
  • Increased gluconeogenesis (insulin usually suppresses this)
  • Circulating glucose increase
  • Tendency towards hyperglycaemia
44
Q

What is the effect of insulin resistance on lipids?

A
  • 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
45
Q

What is the effect of insulin resistance on proteins?

A
  • 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
46
Q

What is heptaic insulin resistance?

A

When insulin fails to suppress gluconeogenesis within the liver

47
Q

Describe the glucose tolerance test

A
  • 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)
48
Q

Describe measurements of obesity

A
  • 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
49
Q

Describe compensated insulin resistance

A
  • 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
50
Q

Describe uncompensated insulin resistance

A
  • Pancreas unable to keep up due to glucose toxicity
  • Obesity associated
  • beta-cell exhaustion
  • High blood glucose and low insulin
51
Q

What is the result of uncompensated insulin resistance?

A
  • Type 2 diabetes melltius, non-insulin dependent (as the primary cause is obesity and not insulin)
  • Glucosuria (and thus PUPD)
52
Q

What is the effect of increased body fat mass?

A
  • Expansion of adipocytes (hypertrophy)
  • Increased number of adipocytes (hyperplasia)
  • Accumulation in subcut adopose tissue, omental, visceral, abdoinal adipose
53
Q

Describe the anabolic/catabolic imbalance in obesity

A
  • 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
54
Q

Outline what is meant by de novo lipogenesis

A
  • Carbohydrates turned into fat

- Herbivores synthesise fat from carbohydrates has have low fat diet

55
Q

What is the link between obesity and insulin resistance?

A
  • 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)
56
Q

Describe te lipotoxicity theory iin obesity and insulin resistance

A
  • 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
57
Q

How does insulin resistance perpetuate itself through lipotoxicity?

A
  • Insulin resistance promotes lipolysis (no inhibition of HSL)
  • Increases mobilisation of fatty acids into circulation adn tehn to muscle and liver via portal system
58
Q

Outline the proinflammatory theory of insulin resistance and obesity

A
  • 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
59
Q

Outline the adipokine theory

A
  • 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
60
Q

Outline Equine Metabolic Syndrome

A
  • 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

Endo (30 decks)

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