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152 Cards in this Set

  • Front
  • Back
What molecules are responsible for the alkalinity of blood under normal circumstances? (3)
Bicarbonate

Phosphate

Proteins
What happens to bicarbonate levels in metabolic acidosis?
Bicarbonate levels fall in metabolic acidosis.
What is the plasma half-life of insulin?
4 minutes
What are glargine and detemir?
Very long acting insulin analogues
What is the onset and duration of short acting insulin?
Onset: within 30 minutes

Duration: 6-8 hours
What is the major advantage of premixed insulin combinations?

What is their major disadvantage?
The major advantage of premixed insulin is that it is simple to use.

The major disadvantage is that the ratio is fixed and so meals must be fairly regimented in timing and content.
How long is the duration of action of the very long acting insulin analogues such as glargine and detemir?
~ 24 hours
What is C-peptide?
A 35 amino acid polypeptide that is cleaved from proinsulin to produce insulin.
What is GLUT-2?

Where is it expressed? (5)

What is its role in each place?
GLUT-2 is a high capacity monosaccharide channel.

It is expressed in:

- the liver (insulin-independent glucose uptake)

- pancreatic β cells (blood glucose-sensing)

- hypothalamus (blood glucose-sensing)

- basolateral membrane of the small intestine (monosaccharide absorption)

- basolateral membrane of the renal tubule (glucose reabsorption)
Describe the hypothesised process of insulin secretion (5 steps).
Glucose enters β cells via GLUT-2

Glucose is phosphorylated by glucokinase and thus trapped.

K+ channels close, reducing the membrane potential.

Voltage-dependent Ca++ channels open, causing immediate release of superficial insulin granules.

Ca++ activates kinases, leading to slower exocytosis of deeper secretory granules.
T/F: Pancreatic β cells are innervated by both divisions of the ANS.
True
T/F: Insulin and glucagon inhibit each other's release.
False - insulin inhibits glucagon release, but glucagon is a potentiator for glucose-stimulated insulin release.
Describe the effect of glucagon on pancreatic β cells.
Glucagon primes the β cell during fasting periods by activating adenylate cyclase.

The raised cAMP levels increase glucose-stimulated insulin release.
Name three hormones which stimulate or potentiate insulin release.
Glucagon

Glucagon-like polypeptide 1

Gastric inhibitory polypeptide
Describe the biphasic insulin response to glucose.

What happens to this response in type II diabetes?
First phase: rapid, high amplitude insulin spike

Second phase: longer, lower amplitude release.

In type II DM, the first phase is 'blunted', i.e. the amplitude is reduced.
What is the molecular basis of the first phase of insulin release?
Superficial pools of insulin granules which are directly attached to voltage-dependent calcium channels are released immediately and en masse.
T/F: A fall in blood insulin level causes intracellular cAMP to rise.
True
What effect does a fall in blood insulin have on glycogen phosphorylase activation in the liver?

What results from this?
Gylcogen phosphorylase activity is increased in the absence of insulin, causing the degradation of glycogen and glucose release from the liver.
How does an increase in fatty acid oxidation help to conserve glucose?
By providing an alternative energy source for muscle and liver cells.

By inhibiting glycolysis due to an increase in ATP and acetyl CoA.
Why can't fatty acids be used by the brain as fuel?
Because they don't cross the blood-brain barrier.
T/F: The Cori cycle is more active when insulin levels are high.
False - when insulin is low, the Cori cycle is important as a way of recycling glucose from lactate.
Name three ways that low insulin levels will raise blood sugar levels.
Decreased uptake of glucose.

Inhibition of glucose breakdown via glycolysis.

Increased gluconeogenesis from amino acids and lactate.
How does hyperglycaemia cause thirst? (2 ways)
By increasing the osmolality of the blood (this stimulates osmoreceptors in the hypothalamus).

By increasing urine output, thus stimulating RAAS and ADH activation.
T/F: Diabetic ketoacidosis causes hyperkalaemia by causing K+ to be pumped out of cells in exchange for H+ ions.
False - organic acids such as those produced in ketoacidosis do not cause K+ to be pumped out of cells - the hyperkalaemia results from other mechanisms.
How does diabetic ketoacidosis cause hyperkalaemia? (4 ways)
Increased K+ export from cells due to hyperosmotic dehydration.

Increased K+ export from cells due to protein catabolism.

Decreased renal excretion due to dehydration

Increased renal reabsorption due to tubular acidosis
What effect does insulin have on intracellular cAMP levels?

What is the mechanism?
It decreases cAMP by stimulating its breakdown by phosphodiesterase.
What is the difference between type 1A and 1B diabetes mellitus?
Type 1A is autoimmune

Type Ib is idopathic, with no anti-islet cell antibodies detectable.
T/F: Having a father with type 1 diabetes confers a greater risk than having a mother with it.

(What are the relative risks?)
True - your chances of developing DM are 2-3% if your mother is affected, 6% if your father is.
What is the concordance rate for type 1 DM in monozygotic twins?
50%
T/F: Type 1 diabetes has a autosomal recessive inheritance pattern.
False - the mode of inheritance for type 1 DM is not clear, but certainly not as simple as AR.
T/F: MHC I molecules are more important in predisposing someone to type 1 DM than MHC II.
False - MHC II molecules are more important than MHC I.
What is the IDDM1 locus?

What percentage of a person's risk of DM comes from variation in this region?
6p21

This HLA-coding region contributes about 40-50% of a person's risk of type 1 DM,
Which HLA subtypes will predispose to type 1 DM?

What percentage of patients have at least one copy?

What is the general prevalence?
HLA DR3 and DR4

90-95% of type 1 DM cases have at least one copy, compared with 50% of the general population.
T/F: If you have a HLA DR3 or DR4 - which increase your risk of type 1 DM - you are also more likely to have a high risk copy of a DQ gene, such as DQ 2.1 or 3.2.
True - this high risk alleles are in linkage disequilibrium, i.e. they tend to be inherited together.
What combinations of HLA DR and HLA DQ alleles confer a high risk of type 1 DM?

Which DQ allele seems to be protective?
HLA DR3 with HLA DQB 2.1

HLA DR4 with HLA DQB 3.2

HLA DQB 6.2 seems to reduce risk.
T/F: A low variable number of tandem repeats (VNTR) in the insulin gene decreases your risk of type 1 diabetes.

Explain how.
False - it increases it by decreasing thymic expression of insulin and hence tolerance.
Name three established type 1 diabetes mellitus 'susceptibility genes'.
HLA

Insulin

CTLA-4
Name five auto-antigens involved in the development of type 1 DM (plus abbreviations).
Glutamic acid decarboxylase (GAD)

Insulin (IAA)

Tyrosine phosphatase (IA-2)

Zinc transporter (ZnT8)

Islet cells (ICA)
What factors are used (currently only in the research context) to evaluate a person's risk of type 1 diabetes? (3)
Family Hx

Auto-antibodies to islet cell antigens

HLA DR and DQ genotype
T/F: post-natal rubella infection increases the risk of type 1 diabetes mellitus.
False
What four hormones are released in hypoglycaemia?
Glucagon

Adrenaline

Cortisol

Growth hormone
T/F: Release of counter-regulatory hormones such as adrenaline occurs at blood sugar levels of 4.3 mmol/L.
False - at this BSL, the body responds with decreased insulin production. Hormones such as glucagon are not released until the BSL drops below 3.8 mmol/L.
At what approximate blood sugar level do cognitive functions start to decline?
~ 2.7 mmol/L
How does prolonged consumption of alcohol affects a diabetic person's blood sugar levels?
BSLs fall in ongoing alcohol consumption because alcohol inhibits gluconeogenesis.
T/F: The maintenance of near-normoglycaemia increases the risk of severe hypos by 200-300%.
True
What are the two drugs of choice for topical treatment of mild to moderate thrush?
An imidazole antifungal agent such as ketoconazole.

Amphotericin B
T/F: The risk of cervical cancer is not affected by recurrent candidiasis.
True
Which type of diabetic complications are not significantly affeted by the degree of glycaemic control?

What (2) interventions are used to minimise the risk of these complications?
The macrovascular ones - cardiovascular, cerebrovascular and peripheral vascular disease.

Prevention of these relies on:

- anti-hypertensive medication

- lipid-reducing drugs
Which type of diabetic retinopathy is characterised by microaneurysms, soft and hard exudates and dot-and-blot haemorrhages?
Non-proliferative retinopathy
What causes the soft exudate seen in non-proliferative retinopathy?
Local ischaemia due to microvascular occlusion.
What causes the hard exudates seen in non-proliferative retinopathy?
Lipid deposition.
Which two pathological findings in diabetic retinopathy are considered 'vision threatening'?

How are they treated?
Macular oedema

Proliferative retinopathy

They are treated with laser photocoagulation.
When might intraocular injection be considered for diabetic retinopathy?

What agents are used in each case?
Proliferative retinopathy - may be treated with anti-VEGF agents (MAbs or glitazones)

Macular oedema - may be treated with steroids.
T/F: Glycaemic control has minimal effect on the progress of nephropathy once proteinuria is present.
True - after the development of proteinuria, glycaemic control has less effect on progression to renal failure.
When should type 1 diabetics be assessed for complications?
Five years after diagnosis then annually
When should type 2 diabetics be assessed for complications?
At diagnosis, then annually
Name four possible mechanisms by which poor glycaemic control is hypothesised to cause diabetic complications.
Formation of advanced gycation end products

Accumulation of sorbitol

Increased extracellular matrix deposition

Oxidative stress via activation of protein kinase C
T/F: Obesity is the most common non-communicable disease
True
How much has the prevalence of overweight and obesity increased worldwide over the last ten years?
It has doubled
What fraction of Australian men and women were overweight or obese in 2000 respectively?
Two-thirds of men

Half of women
T/F: Obesity increases a woman's risk of breast, cervical and uterine cancer
True
Name four gender neutral cancers that are more common in obese people.
Oesophagus

Colon

Pancreas

Kidney
T/F: Waist and/or hip circumference are better indicators of cardiovascular risk than BMI
True - BMI does not show a significant association with risk when results are adjusted for other factors.
Why is abdominal visceral fat so important in diabetes and heart disease?
Because centrally distributed fat stores are more insensitive to insulin and are more readily mobilised, contributing to the risk of atheroma formation.
What waist circumferences correspond to 'increased risk' of metabolic and cardiovascular disease for men and women respectively?

(What is 'normal' in each case?)
Men: > 102cm (< 94cm)

Women: > 92cm (< 80cm)
How do abdominal (visceral) adipocytes differ from peripheral ones in terms of hormone sensitivity?
Central adipocytes are more insensitive to insulin and more sensitive to catecholamines.
Why is it easier to lose weight from your stomach than from your thighs?

What does this mean for CV risk?
Abdominal fat is:

resistant to insulin

sensitive to catecholamines

so is broken down more easily.

This also means that plasma fatty acids are more likely to be elevated, causing CVD.
T/F: Overweight or obese people have higher adiponectin levels
False - although this is an adipokine, people of normal BMI tend to have higher levels than overweight or obese people,
Name 5 adipokines.

Which (*) is protective against heart disease?
Adiponectin*

IL-6

TNF-α

Leptin

Resistin
T/F: Fat cells produce angiotensinogen
True - though the main site of production is the liver
What molecule produced by adipose tissue is thought to cause an increased risk of thrombosis in overweight and obese people?
Plasminogen activator inhibitor-1 - by inhibiting tPA-mediated fibrinolysis.
T/F: Overweight and obese people have an increased risk of thrombosis due in part to increased plasma fibrinogen levels.
True
What percentage of women of reproductive age are affected by PCOS?
5-10%
T/F: Weight loss will decrease a person's resting metabolic rate.
True
What percentage of a person's total energy expenditure is due to physical activity?
30%
What is NEAT?

What kinds of things does it include?
Non-exercise activity thermogenesis

It includes things like fidgeting, posture maintenance, ADLs and spontaneous muscle contraction.
What percentage of a person's total energy expenditure is due to the thermic effect of feeding?
10%
What processes cause the so-called 'thermic effect of feeding'? (3)
Digestion

Absorption

Storage
T/F: People who are force-fed extra calories will generally fidget more.
True - in most people an excess of calories is partly compensated for by an increase in NEAT.
T/F: Leptin and insulin are both secreted in proportion to a person's fat mass.
True
Name five single gene causes of obesity
Leptin deficiency

Leptin resistance

POMC deficiency

MC4R deficiency

Prohormone convertase-1 deficiency
T/F: Endocrine causes of weight gain are less likely if it exceeds 10kg
True
T/F: Maternal nutritional deprivation (famine) has been linked to later insulin resistance in the offspring.
True
T/F: The effect of maternal starvation on a baby's insulin sensitivity increases with the gestational age at which it occurs.
True
T/F: Fats, while containing more calories per gram, cost more to store (in terms of energy expenditure) than carbohydrates.
False
T/F: Overweight and obese people under-report their dietary fat intake by more than lean people
True
T/F: Dietary surveys and consumer purchasing statistics both indicate that dietary fat levels are increasing
False - dietary surveys suggest it is falling (because people are under-reporting more).
T/F: Alcohol consumption in the evening increases nocturnal hyperglycaemia in type 1 diabetics
False - by inhibiting gluconeogenesis, it increases rates of hypoglycaemia.
T/F: Consuming alcohol with food will reduce its negative effects on glycaemic control for type 1 diabetics
True
T/F: Weight loss is the best intervention for all diabetics
False - while it is useful for all diabetics, it is less important for type 1 diabetics than rigorous carbohydrate counting and insulin titration.
T/F: Modest weight loss (5-7%) improves glycaemia, insulin sensitivity and BP, but not dyslipidaemia.
False - it improves them all
T/F: Neither low-fat nor low-carb diets are effective for long-term weight loss
True
What effect does a low carb diet have on cholesterol levels?
Low-carb diets can increase HDL, LDL and total cholesterol.
What is the main concern regarding low-carb diets?
Increased mortality due to CVD or renal problems.
How do free fatty acids travel in the blood?
Bound to albumin
Name two hormones which activate hormone-sensitive lipase
Glucagon

Adrenaline
What happens to free fatty acids upon uptake by cells?
They are esterified with CoA, forming fatty acyl CoA
Where do storage and oxidation of fatty acyl CoA occur in the cell?
Storage - cytoplasm

Oxidation - mitochondria
How many steps are there in the oxidation of a fatty acid?

What are they (generically speaking)?
4

Oxidation

Hydration

Oxidation

Thiolysis
How many molecules of NADH+H and FADH2 are produced by the oxidation of one molecule of palmitoyl CoA?
7 of each
What are the two possible fates of acetyl CoA?
Further oxidation (citric acid cycle)

Ketone body generation
T/F: Glucagon levels increase in diabetic ketoacidosis
True - insulin normally suppresses glucagon release, so this rises when it is absent.
What causes the rise in plasma free fatty acids seen in ketoacidosis?
Increased glucagon and decreased insulin stimulate hormone-sensitive lipase.
What effect do raised plasma fatty acid levels have on the liver?
FFAs stimulate gluconeogenesis
What is mTOR?

What does it do?
mTOR: mammalian target of rapamycin

It mediates the anabolic effects of insulin, IGF-1 and other growth factors
What is Akt?

What does it do?
Akt is a key participant in the insulin pathway - it upregulates mTOR, causing increased protein synthesis, and inhibits Fox0, causing reduced protein degradation.
How does insulin inhibit fatty acid oxidation?
By increasing acetyl CoA conversion to malonyl CoA - this blocks mitochondrial uptake of FAs.
What happens to acetyl CoA levels in diabetic ketoacidosis?

Why?
Acetyl CoA levels rise because of the increased fatty acid release and oxidation.
What happens to the acetyl CoA in diabetic ketoacidosis?

Why?
Acetyl CoA is converted to ketone bodies because its further oxidation is limited by the low oxaloacetate levels.

(Oxalacetate is converted into glucose in gluconeogenesis)
What molecules contribute to the acidosis component of ketoacidosis? (3)
Ketone bodies

Free fatty acids

Fatty acid oxidation
What happens to plasma potassium levels in ketoacidosis?

What about total body potassium?
K+ rises early, but total body potassium is generally depleted at the same time due to urinary losses.
T/F: Muscle glycogen stores are a small be essential source of blood glucose during fasting.
False - muscle cannot release glucose derived from glycogen breakdown - but it can release lactic acid for the Cori cycle.
What effect does phenytoin have on insulin release?
Inhibitory
What effect do thiazide diuretics have on insulin release?
Inhibitory
What effect does somatostatin have on insulin release?
Inhibitory
How does insulin cause increased uptake of fats into cells?
By upregulating the LDL receptor
T/F: Insulin directly inhibits ketogenesis
True
T/F: High plasma amino acids stimulate both glucagon and insulin release
True - however, the glucagon response is almost absent if blood glucose levels are also raised, such as after a balanced meal.
What effect does a high protein, low carb meal have on blood insulin and glucagon levels?

What is the physiological utility of this?
Both insulin and glucagon are raised in response to a low carb, high protein diet.

The insulin enables the AAs to be taken up and assimilated efficiently.

The glucagon ensures that the low carb intake and effects of insulin don't cause hypoglycaemia.
What is a 'normal' fasting plasma glucose (FPG) level?
< 6 mmol/L
What is a 'normal' 2hr post-prandial glucose (2hr PG) level?
< 7.8 mmol/L
What is a 'diabetic' fasting plasma glucose (FPG) level?
7 mmol/L or higher
What is a 'diabetic' 2hr post-prandial glucose (2hr PG) level?
11.1 mmol/L or higher
T/F: The pathogenic factor in type 1 diabetes is autoantibodies directed against antigens found in the islet cell.
False - islet cells are destroyed by a T cell-mediated mechanism.
What is meant by the term 'relative insulin deficiency'?
Relative insulin deficiency refers to the situation of high blood glucose despite high insulin levels.
T/F: Both type 1 and type 2 diabetics can experience blurred vision, increased infection rates, poor healing and lethargy
True
What signs and symptoms (4) are suggestive of diabetic ketoacidosis?
Dehydration

Abdominal pain

Metabolic acidosis

Hyperkalaemia
T/F: Insulin requirements for type 1 diabetics generally decrease during illness
False - they increase
T/F: Diabetic retinopathy can be proliferative or non-proliferative
True
T/F: The effect of multiple risk factors (HT, high cholesterol, smoking) on a diabetic's relative risk of CVD is additive
False - the total risk is more like the product of the individual relative risks.
How do smoking, HT and high cholesterol compare as relative risk factors for CVD in diabetics?
High cholesterol is the worst (RR: 4)

Smoking is the least detrimental (RR: 1.6)
What is the RR for CVD in a diabetic who smokes and has high cholesterol (> 8.5 mmol/L) and severe HT (SBP >190)?
RR: 16
Name five antibodies associated with type 1 diabetes.
Anti-islet cell

Anti-GAD

Anti-IA2

Anti-insulin

Anti-ZnT8 (zinc transporter)
Name three circumstances in which admission would be the best option for a newly diagnosed type 1 diabetic.
An acute presentation - severe dehydration, ketoacidosis or distress

Concomitant infection or illness

Social or intellectual inability to cope without intensive support
T/F: An intercurrent illness with measurable ketones in a type 1 diabetic should be treated by increasing the basal insulin dose by 20%
False - the basal dose should not be changed but a 20% dose (relative to the basal dose) of extra short-acting insulin should be given every 2-3 hours until the ketones disappear
T/F: Basal insulin should be administered once or twice a day if possible
True
What percentage of total insulin units should be given as basal doses?
50-60%
How much insulin does a typical type 1 diabetic need each day when otherwise well?
~ 0.5 units per kg
T/F: Adolescent type 1 diabetics typically need twice as much insulin per kg as adults
True - adolescence, because of growth hormone and other factors, is a time of relative insulin resistance.
Name the generic insulin types in order of increasing duration of action.
Insulin analogues (lispro, glulisine etc)

Human regular (humulin R)

Human NPH (humulin N)

Glargine (Lantus) and detemir
Name the rapid-acting insulin analogues (3).
Lispro

Aspart

Glulisine
What is the duration of action of humulin N (Human NPH) insulin?
Intermediate (4-12 hours)
What is the duration of action of humulin R (human regular) insulin?
Short (2-5 hours)
T/F: The terms rapid-, short-, intermediate- and long-acting refer to the onset of insulin subtypes
False - it refers to their time of peak action (intermediate-acting Human NPH takes as long or longer to come on than glargine, for example)
When is the activity peak for the long-acting analogues glargine (Lantus) and detemir?
They don't have one as such.
How can neuropathic and vascular ulcers be differentiated?
Location:

Neuropathic ulcers are generally on load bearing areas.

Ischaemic ulcers are usually peripheral (e.g. toes) where blood flow is weakest
What feature makes Strep. pyogenes, Aeromonas hydrophilia and Vibrio vulnificans especially dangerous as cellulitis pathogens?
The ability to dissect tissue planes
In what context would Aeromonas and Vibrio be more likely to be the causative agent in cellulitis?
Injuries sustained in water
Name five examples of opportunistic pathogens which can cause cellulitis given the appropriate opportunity
Staph ss.

Clostridia ss.

Aeronomonas hydrophiilia

Vibrio vulnificans

Pseudom
T/F: The causative agent of cellulitis in a diabetic patient is most likely to be S. pyogenes.
False - S. aureus is more likely
What is erysipelas?
A cellulitis accompanied by fever and systemic toxicity
What pathogen should be suspected in cellulitis that produces crepitation on palpation?

What causes this sign?
C. perfringens - due to gas formation.