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MSE-2016-0 Basic Clinical Biochemistry > Lecture 3: Glucose disorders > Flashcards

Lecture 3: Glucose disorders Flashcards

1
Q

What is the reference range for fasting blood glucose?

A

3.2 - 5.8 mmol/L

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2
Q

What are 3 main enzymes associated with proteolysis?

A

Pepsin, trypsin and chymotrypsin.

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3
Q

What problems can occur when control mechanisms that regulate glucose go wrong?

A

Hypoglycaemia and hyperglycaemia.
The reference range based on fasting blood sample is 3.2-5.8mmol/L

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4
Q

What processes are used to produce glucose during fasting?

A

Gluconeogenesis and glycogenolysis.

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5
Q

What hormones control the conc. of blood glucose?

A

Insulin and glucagon.

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6
Q

Why is insulin important in regulation of glucose?

A

It is important because it inhibits glycogenolysis, gluconeogenesis, lipolysis and ketogenesis.

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7
Q

What is glycogenolysis?

A

Breakdown of glycogen to glucose and other intermediate products.

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8
Q

What is glycogenesis?

A

Conversion of glucose to glycogen (liver and muscle).

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9
Q

What is gluconeogenesis?

A

Formation of glucose from-noncarbohydrate sources such as glucogenic amino acids, glycerol (breakdown of lipids) or lactate.

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10
Q

What is hypoglycaemia?

A

When glucose levels in the blood are below normal levels (Plasma glucose <2.2mmol/L). Mild hypoglycaemia in healthy individuals may occur during exercise, after fasting, or as a result of alcohol ingestion. Severe cases of hypoglycaemia are around <1.0mM.

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11
Q

What are the symptoms of hypoglycaemia?

A
  • Shaky or jittery
  • Sweaty
  • Hungry
  • Headaches
  • Blurred vision
  • Fatigue
  • Dizzy and confused
  • Pale
  • Uncoordinated
  • Irritable/Nervous
  • Changed behaviour
  • Can’t concentrate
  • Weak
  • Fast heartbeat

In severe cases (<1.0 mmol/L)
- Unable to eat or drink
- Seizures and convulsions
- Unconsciousness (Neuroglycopenia)

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12
Q

What can cause hypoglycaemia?

A

Inborn errors of metabolism:
- Glycogen storage diseases (lack of glycogenolysis enzymes)

  • Galactosaemia (lack of enzyme galactokinase, one step in turning galactose into glucose-6-phosphate), so galactose builds up.
  • Hereditary fructose intolerance (defective aldolase b/fructose-1-phosphate aldolase).

Can be a complication of diabetes mellitus, dysfunctional insulin mechanisms.

Insulinoma, a tumour in pancreas that produces excess insulin.

Liver disease, because glycogen cannot be accessed as easily, alcoholics, psoriasis patients, etc.

Endocrine disease:
- Adrenal failure
- Epinephrine, norepinephrine, cortisol plays key roles in glucose regulation.
- Cortisol raised in stress, signals raise in blood sugar.
- Adrenal hormones signal glycogenolysis and gluconeogenesis.

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13
Q

What is hyperglycaemia? Name the 3 P’s of hyperglycaemia.

A

The presence of too much sugar in the blood: >6mM.
Polyphagia - Excessive hunger.
Polydipsia - Excessive thirst.
Polyuria - Excessive urination.

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14
Q

What is the most common cause of hyperglycaemia?

A

Diabetes Mellitus

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15
Q

What is type 1 diabetes?

A

A dysfunctional glucose metabolism caused by a complete lack of insulin. Insulin is absent because insulin-producing beta-cells in pancreas are destroyed by the immune system.
This therefore makes T1DM insulin dependent.

Present in 8% of all diabetics

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16
Q

What is type 2 diabetes?

A

A dysfunction of glucose metabolism due to a systemic insensitivity to insulin, leading to increased insulin production and subsequent overworking and damage to beta-cells in the pancreas.
Therefore T2DM is non-insulin dependent.

Makes up 90% of all diabetes cases.

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17
Q

What acute metabolic disturbances can occur with diabetes-mellitus?

A

Diabetic ketoacidosis, due to build up of acetyl-CoA, which the body converts to ketone bodies by thiolase.

Hyperosmolar non-ketotic hyperglycaemia, caused by imbalances in ions such as sodium, potassium, bicarbonate, etc., this can cause metabolic acidosis, respiratory acidosis, metabolic alkalosis.

Hypoglycaemia.

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18
Q

What chronic metabolic dysfunctions arise with diabetes-mellitus?

A

Damage to organs, such as nephropathy, neuropathy, retinopathy.

Atherosclerosis (build up of plaque in arteries), can lead to stroke or coronary artery disease, and subsequently a potential myocardial infarction.

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19
Q

What other forms of diabetes mellitus are there?

A

Gestational diabetes (increased insulin demand from foetus development)
Acromegaly-induced (overproduction of growth hormone in pituitary)
LADA (latent autoimmune diabetes in adults)
Diabetes insipidus (dysfunction of kidney filtration, polyuria and polydipsia, unrelated to glucose metabolism)

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20
Q

How can acromegaly occur and how can it cause diabetes?

A

Acromegaly is when the pituitary gland releases too much growth hormone, usually from a non-cancerous tumour. Growth hormone is a counter-regulatory hormone for insulin, and decreases its effectiveness, leading to overproduction and beta-cell damage.

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21
Q

What is the pathogenesis of Type 1 diabetes?

A

It is due to cell mediated auto-immune destruction of beta-cell in the Islets of Langerhans. 80-90% destruction of beta cells before symptoms appear.
This destruction is more rapid in children than adults, therefore will occur mostly in people of under 20 years of age.

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22
Q

What genes are implicated in T1DM?

A

HLA antigens D3 and D4, resulting from defective genes on chromosome 6. These genes are expressed in 90% of T1DM cases.
Viral infections are also implicated, especially coxsackievirus B.

23
Q

What stages are there in T1DM?

A

Stage 1: Presence of autoantibodies and absence of dysglycaemia.
Stage 2: Presence of both autoantibodies and dysglycaemia.
Stage 3: This corresponds to symptomatic T1DM, since first two stages are largely asymptomatic.

By stage 3, 3Ps (Polyuria, polydipsia and polyphagia) are more evident.

24
Q

What is the pathogenesis of T2DM?

A

There are two pathological defects:
- Insulin resistance
- Beta-cell destruction

The insulin resistance can be from abnormal insulin, lack of receptors, or defective secondary messenger to glucose transporter.

T2DM is heavily associated with obesity and unhealthy lifestyle. Typically develops after 40 years of age, but there is a complex correlation with genetics.

25
Q

What happens in insulin resistance?

A

Insulin may be itself faulty, or loss of functional insulin receptors, or inability to signal GLUT4 receptors after binding to insulin.

26
Q

What differences are there between type 1 and type 2 diabetes?

A

The onset of T1DM is usually below the age of 20, whereas for T2DM it is usually over 40 years. Insulin synthesis in T1DM is absent, whereas in T2DM it is impaired, with insulin resistance present.
in T1, plasma conc. is low or absent, in T2, it can be low, normal or high.
HLA is associated with T1, not in T2, as that is more polygenic.
T1 will have islet cell antibodies, T2 won’t.
Obesity is uncommon in T1, but is common in T2.
Ketoacidosis is more prevalent in T1, and only occurs in T2 after major stress.

27
Q

How is Diabetes Mellitus diagnosed?

A

In type 1 diabetes, beta-cell autoantibodies can be tested for via a test such as ELISA.

Looking at fasting blood glucose to look for hyperglycaemia. If fasting blood glucose is over 7mM, or in a random sample around over 11mM.

Diagnosis of T1DM is easier, patients have classic symptoms (polyuria, polydipsia, polyphagia, weight loss and fatigue).

Diabetes is unlikely if fasting glucose is under 5.5mM

Important to know if any drugs are causing abnormal blood glucose results.

Oral glucose test can be carried out.

28
Q

What plasma glucose distinguishes between prediabetes and diabetes?

A

Prediabetic patients would have slightly higher levels. Random tests appear the same as normal. Fasting: 6.1 to 6.9mM. 2 hour postprandial: 7.8 to 11.0mM

In diabetes, random: >11mM, fasting: >7mM, and 2 hour postprandial: >11mM.

Normal would be random: Below 11mM, fasting: 3.2 - 6.1mM, and 2 postprandial: Below 7.8mM

Fasting normal: 3.2 - 6.1mM
Fasting prediabetes: 6.1 - 6.9mM
Fasting diabetes: >7mM

29
Q

What is the oral glucose tolerance test? (OGTT)

A

A test to look at how long it takes for glucose to be cleared from the blood.

Must be performed in controlled conditions.

Used when diagnosis is in doubt, such as fasting and random plasma glucose are ambiguous.
If the patient has unexplained glycosuria.
If the patient has clinical features of DM but has normal blood glucose concentrations.

30
Q

How must the patient be prepared for the OGTT?

A

The patient should not be acutely ill (sickness reduces glucose tolerance) and should be relaxed, no exercise.

Certain drugs may influence the test, try and stop therapy for 3 days prior, any drugs that cannot be stopped should be noted.

Normal carbohydrate diet 3-5 days prior (>200 g/day carbohydrates).

31
Q

How is OGTT performed?

A

Overnight fast is preferable. Should only drink water on the day the test is performed.

Test is performed in the morning. After a fasting blood glucose sample is taken.

A glucose solution is the be ingested, this solution is 75g of glucose and 200ml of water.
Another 100ml of water should be drank within 5 minutes.

Patient should remain seated for test duration.

Take another blood glucose sample after 120 minutes. (2 hour postprandial)

32
Q

How is the glucose blood sample taken?

A

It can be taken as a whole blood test, plasma or serum. This is taken in the grey top vacutainer, containing fluoride-oxalate, which stops metabolism of glucose by blood.

Value will appear higher in plasma samples because the water concentration is higher, carrying more glucose. (12% - 15% higher).

Value will be lower if sample taken from a vein, this is because of uptake from tissues.

33
Q

What laboratory practices are carried out to determine glucose concentration.

A

Glucose Oxidase, and peroxidase.

Hexokinase and G-6-P dehydrogenase.

34
Q

Describe the process of the glucose oxidase method of quantifying blood glucose.

A

The sample is mixed with glucose oxidase to produce gluconic acid in the presence of oxygen, and 2 hydrogen peroxide, (only D-beta-glucose reacts).

Phenol and 4-aminophenazone are added along with peroxidase, and the H2O2 will be oxidised and quinoneimine dye is produced.

Chromophore produced can be measured at 500-520nm.

35
Q

Describe the process of the hexokinase method of blood glucose quantification.

A

Hexokinase converts glucose to glucose-6-phosphate in the presence of ATP and Mg2+.

Glucose-6-phosphate is converted to 6-phosphogluconate in the presence of NADP+, also releasing NADPH.

NADPH can be measured at 340 nm. With a blank specimen being used to calibrate the spectrometer, as some molecules also absorb 340 nm (certain drugs, excessive haemolysis and lipaemia.

36
Q

What problems are there with peroxidase in glucose quantification?

A

Peroxidase is non-specific, and certain molecules will interfere in test, giving low values. Uric acid, ascorbic acid and bilirubin.

37
Q

How are the results of an OGTT interpreted?

A

A diabetic patient’s result will be over 11mM, a prediabetic will have a result of 7.8 - 11mM and a normal results would be under 7.8mM.

38
Q

What long term consequences are associated with hyperglycaemia?

A

Nephropathy

Retinopathy

Atherosclerosis

Cataracts

Neuropathy

Angiopathy (High levels of glucose cause damage in numerous ways to blood vessels)

More prone to infections such as ulcerations and gangrene, thus can lose limbs. (lack of circulation and nerve damage, etc.)

Hyperlipidaemia (raised triglycerides, cholesterol, and VLDL)

Development of thrombus or embolus, resulting in loss of circulation and tissue damage

39
Q

What is diabetic ketoacidosis?

A

An extremely dangerous acute side effect of diabetes when there is a complete lack of insulin. Ketone bodies acetoacetic acid and beta-hydroxybutyric acid build up and cause a drop in pH.

Because lack of insulin results in the inability of GLUT4 to be presented on cells, no glucose enters cells. The liver responds to this lack of glucose by breaking down fats, and because beta-oxidation is more efficient than glycolysis, there is more acetyl-CoA.
Acetyl-CoA is converted to ketone bodies to compensate for the high concentration.

40
Q

What reactions convert acetyl-CoA into ketone bodies?

A

2 acetyl-CoA molecules will get converted into acetoacetyl-CoA by thiolase, leaving 1 CoA-SH.

Acetoacetyl-CoA is then converted into beta-hydroxy-beta-methylglutaryl-CoA by HMG-CoA synthase, requiring another acetyl-CoA molecule and leaving a CoA-SH.

beta-H-beta-MG-CoA is then converted into acetoacetic acid/acetoacetate by HMG-CoA lyase.

Acetoacetate can be converted into D-hydroxybutyrate/D-hydroxybutyric acid, or degrade into acetone.

41
Q

What causes symptoms of diabetic ketoacidosis?

A

Due to unchecked gluconeogenesis, hyperglycaemia occurs.

Osmotic diuresis (more glucose filtered into urine, drawing more water into urine to be excreted), this causes dehydration.

Because ketone bodies are acidic, they dissociate into ions and anions, causing anion-gap acidosis.

42
Q

What pathological pathway is associated with insulin deficiency? Concerning only hyperglycaemia.

A
  1. Insulin deficiency leads to hyperglycaemia
  2. Hyperglycaemia leads to hyperosmolarity, drawing water out of important organs. Hyperglycaemia also causes glycosuria, which leads to more water being filtered out in kidneys.
  3. Glycosuria leads to dehydration, and an increase in water in extracellular space from hyperosmolarity dilutes electrolytes, for example hyponatraemia.
  4. High glucose concentration leads to glomerular damage, resulting in larger molecules being filtered out, such as electrolytes and proteins (albuminuria).
  5. A combination of hyperosmolarity (causing extra water to be lost with extra glucose), which leads to dehydration, can cause waste products to build up and damage kidneys (uremia), as well as cause inflammation which can further damage them. Hypovolemia can also occur from dehydration and thus damage the kidneys. Renal failure occurs as a result of all of these factors.
  6. Renal failure can lead to shock, because toxins can build up in the blood, and because of an already reduced blood pressure and electrolyte imbalances. This shock can ultimately lead to CV collapse and death.
43
Q

What pathological pathway is associated with insulin deficiency?
Concerning its effect on lipolysis.

A
  1. A decrease in the supply of glucose in tissues results in fat tissue being used instead.
  2. Increased lipolysis results in more free fatty acids being converted into acetyl-CoA.
  3. A high concentration of acetyl-CoA causes the body to convert more of it into ketone bodies through thiolase. HMG-CoA synthase, and HMG-CoA lyase.
  4. More ketone bodies decreases blood pH, causing acidosis, which can decrease cardiac output by disrupting electrical signals, which lowers blood pressure. Electrolyte imbalances also can affect this, less potassium affects blood vessels in the heart. Lower blood pressure can lead to the heart being unable to function and fail.
44
Q

What is diabetic nephropathy?

A

A progressive kidney disease caused by damage to the capillaries in the kidneys’ glomeruli. Characterized by nephrotic syndrome and diffuse scarring of glomeruli, increased size of glomerular fenestrations.
Major cause of premature death in DM, most common cause of end stage renal cancer (ESRC).
Can be treated by angiotensin converting enzyme inhibitors.

45
Q

Describe glomerular histology.

A

Renal artery carries blood through the glomerulus help in bowman’s capsule, entering through the afferent vessel and leaving through the efferent vessel, The afferent vessel is larger than the efferent, so there is a high pressure. About 1/5th of the plasma is filtered in glomerulus (this whole structure is renal corpuscle).

Proximal convoluted tubule reabsorbs 2/3 of filtered water and salts. Almost all glucose is reabsorbed as well as amino acids. Uric acid, urine, creatine, ammonium.

Loop of Henle comes next, and more ions are reabsorbed here. The descending limbs has aquaporins to let water leave, since the loop of Henle descends into the medulla of the kidney, which is salty due to NACl being pumped out of the ascending loop of Henle, which is water insoluble. This lets water leave and be reabsorbed into the blood.

In the distal convoluted tubule, hydrogen, potassium and ammonium are absorbed by the blood.

Collecting duct collects end product to be excreted, can be acted on by anti-diuretic hormone.

46
Q

What would a proteinuria dipstick test result look like for a normal individual vs someone with diabetic nephropathy?

A

A normal urine albumin concentration would be <20 mg/l if any.
A dip-stick positive result would be around >200 mg/l

47
Q

What is microalbuminuria?

A

An increase in the level of albumin in the urine but not enough that it shows up on a dip-stick test.

An assay can be used instead that are specific for albumin.

48
Q

What ways can urine albumin be measured? How can results be interpreted?

A

24-hour urine collection, to find the albumin excretion rate, and give a more accurate result than random test.

Measure albumin : creatinine ratio, in early morning urine test.

Normal 24hr: <30 mg/24
Micro 24hr: 30-300 mg/24
Proteinuria 24hr: >300 mg/24

Normal ACR: <2.5 - 3.5 mg/mmol
Micro ACR: 3 - 30 mg/mmol
Proteinuria ACR: >30 mg/mmol

49
Q

How does sorbitol accumulation occur?

A

Glucose is normally converted to sorbitol through aldose reductase, then sorbitol to fructose via polyol dehydrogenase, to cope with high glucose load. When glucose levels are high enough it exceeds enzyme activity and sorbitol can build up and exert an osmotic effect. Inhibiting aldose reductase reduces neuropathy in diabetics.

50
Q

How does hyperglycaemia cause damage to membranes?

A

Non-enzymatic glycation occurs, and it is non-specific, this can disrupt the structure and characteristics of proteins in the body, which will cause damage. Such as a-crystallin (a protein on lens of eye), when glycated will reduce solubility, causing cataracts.

51
Q

What is glycated haemoglobin?

A

HbA1c (glycated haemoglobin) is used to assess diabetic condition, as haemoglobin is glycated when in contact with high levels of glucose for long periods of time. Since RBC life cycle is 120 days, this can give a historical view of glucose over the last 2-3 months. RBC life span can affect results.

52
Q

What methods are there for determining glycated haemoglobins?
(HbA1c)

A

Spectrometry, photometry.
Assays and chromatography could also be used.

53
Q

What is the reference range of HbA1c?

A

48 - 59 mmol/mol.

54
Q

What pros and cons does a HbA1C have?

A

Cons:
- Does rely on red cell lifespan.
- Abnormalities in Hb can affect results
- Can’t be used to make a diagnosis alone

Pros:
- Does not require fasting
- Can asses glycaemia over months
- Lower biological variation
- Increased compliance for diabetic patients.

MSE-2016-0 Basic Clinical Biochemistry (7 decks)

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