Blood Glucose Flashcards
What are the 12 steps of glucose regulation
CNS triggers desire to eat
Food consumed and glucose absorbed
Plasma glucose increases
Insulin release stimulated
GLUT externalisation
Glucose uptake by fat and muscle
Glycogen synthesis
Plasma glucose levels fall
Production of glucagon triggered
Triggers breakdown of glycogen
Plasma glucose levels increase
Euglycaemia restored
What two organs play a key role in maintaining blood glucose and how?
(2)
Live and kidney
Express glycogen phosphorylase which can supple glucose to bloodstream from glycogen
Liver can also convert many small molecules into glucose via gluconeogenesie
What are the five main GLUT transporters
GLUT 1
Glut 2
Glut 3
GLUT 4
GLUT 5
What is the most important GLUT
GLUT 4
What does GLUT 4 do?
Insulin responsive glucose transporter
For skeletal muscle, cardiac muscle and adipose tissue
What are the hormonal components of glycaemic control?
(3)
Oscillation between catabolic and anabolic states
Driven by nutrient supply (post-prandial increase in anabolic processes)
Pituitary also involved (senses low glucose and triggers hormone production)
What are the four catabolic controls for glucose
Cortisol
Epinephrine (adrenaline)
Growth hormone (IGF1)
Glucagon
What is the only anabolic control for glucose
Insulin
Comment on the type of energy used by most cells
(3)
Glucose is the main source of energy during the absorptive (fed state)
Fatty acids are the main source of energy during the long fasting state
Brain is the only exception which uses glucose
What cells secrete insulin
Beta cells
What causes insulin to be secreted
Rising blood glucose levels
Write about the structure of insulin
Polypeptide hormone - 51 amino acids
Synthesised as a precursor (preproinsulin -> proinsulin -> insulin + C-peptide)
Why can’t insulin be taken orally
Considered unstable if taken orally
How does insulin act in cells
Acts via insulin receptor
Phosphorylation triggers intracellular signalling pathway
What is the function of glucose facilitators and how do they work?
(4)
They equalise concentrations across membranes
They transport down concentration gradients
GLUTs are stored in intracellular granules
Insulin signalling promotes externalisation of preformed GLUT
What happens when insulin binds to the insulin receptor
This induces a signal transduction cascade which allows the glucose transporter (GLUT 4) to transport glucose into the cell
Results in gene expression and growth regulation and glucose utilisation
Why can the BBB only use glucose
The blood-brain barrier excludes fatty acids from the brain
High FFA can act as detergents to the brain
Write about the glucose metabolism in the brain
(5)
Brain depends on glucose
Needs a constant supply of about 110g a day
Older brains need more glucose to carry out the same tasks
GLUT1 expressed on the BBB which facilitates blood-brain movement of glucose
GLUT3 expressed on neurons
What happens when blood glucose rises
Stimulates the pancreas to release insulin
Insulin stimulates the uptake of glucose and storage as glycogen in the liver and muscles
Insulin also stimulates the conversion of excess glucose into fat for storage
Blood levels begin to decline
What happens when there is low blood glucose
This stimulates the pancreas to release glucagon into the bloodstream
Glucagon stimulates liver cells to break down glycogen and release glucose into the blood
Blood glucose begins to rise again
Why is glucose in urine seen in diabetes
(3)
If blood glucose is too high some will spill into the urine
Kidney filters glucose into tubules and then reabsorbs it (100% in normal people)
If glucose concentration is too high reabsorption cannot keep up with filtration and some glucose stays in tubule and becomes part of urine
Glucose in the urine will suck more water into the urine via osmosis and cause excess urine production in diabetes -> causes dehydration and thirst
What is the role of the kidney
(4)
Its a minor glycogen store
Filtered glucose is reabsorbed by the kidney
For normal concentrations it is 100% effective are reabsorption
If concentration too high it will exceed capacity and will spill over which leads to glucose rich urine (glucosuria)
What is the role of the liver
After meals blood glucose comes from carbohydrates in meal
Between meals blood glucose comes from the liver and kidneys
Liver provides 80% of blood glucose supply via
- glycogenolysis
- gluconeogenesis
What is glycogenolysis?
Breakdown of liver glycogen
What is gluconeogenesis?
Conversion of small molecules into glucose
Reversal of some reactions of glycolysis
What is gluconeogenesis?
Conversion of small molecules into glucose
Reversal of some reactions of glycolysis
Give four examples of small molecules that can be converted to glucose
Lactate and pyruvate
Glycerol
AcetylCoA
Amino acids
What three tissues require insulin to transport glucose into the cells
Muscle
Fat
Liver tissue
What is the endocrine part of the pancrease
Small clumps of cells called islets of Langerhans (consists of alpha cells (glucagon) and beta cells (insulin))
What is the exocrine part of the pancrease
This makes digestive enzymes and delivers them to the duodenum through ducts
What four main hormones can increase blood glucose
Glucagon
Cortisol
Epinephrine (adrenaline)
Growth hormone
When would all four major hormones to raise blood glucose be seen raised together
Vigorous exercise
When does diabetes mellitus result
When insulin is deficient or ineffective
What does high levels of glucose in blood stimulate
(4)
Increased glycogen production from glucose (glycogenesis)
Increased fatty acid synthesis and triglyceride production from glucose
Decreased production of glucose from glycogen (glycogenolysis)
Decreased glucose production from protein (gluconeogenesis)
What does low levels of insulin stimulate but increased glucagon (starvation)
Glycogen depletion
Triglyceride catabolism and ketone formation
Protein breakdown and gluconeogenesis
Define diabetes mellitus
The term diabetes mellitus describes a metabolic disorder of multiple aetiology characterised by chronic hyperglycaemia with disturbances of carbohydrate, fat and protein metabolism. Resulting from defects in insulin secretion, insulin action or both.
Write about HbA1c
(4)
‘Long term bloods’
Formed by non-enzymatic attachment of glucose to haemoglobin A
Formed slowly and continuously
Normally less than 42 (6%) but in diabetics it can increase 2-3 times
Comment on the measurement of HbA1c
(4)
Used to be reported as a % of the total HbA which is glycated
Different methods gave different results
All assays must now be calibrated against the international reference method
Results will be reported as a ratio: mmol of glycated HbA: mol of non-glycated HbA
Is HbA1c diagnostic
(4)
Could be used as a diagnostic test provided the assay is standardised and stringent QA in place
A HbA1c value of 6.5% (48mmol/mol) is the diagnostic cut point
HbA1c value less than 6.5% does not exclude diabetes
Assay not available throughout the world
What would indicate impaired fasting glycaemia
Fasting glucose equal to or between 6.1 and 7
What would indicate impaired glucose tolerance
OGTT between 7.8 and 11.1
What HbA1c would indicate intermediate hyperglycaemia
Between 5.7 and 6.5%
Between 39 and 48 mmol/mol
What are the four types of diabetes
Type 1 (previously IDDM)
Type 2 (previously NIDDM)
Gestational diabetes
“other specific types” e.g. endocrinopathies
Define type 1 diabetes mellitus
Autoimmune destruction of pancreatic cells, usually occurs early in life
Characterised by low insulin output, high blood glucose, glucose in urine, excess urine flow, switch to fat metabolism
Treated with insulin injections, careful balance of diet and exercise
10% of diabetics
Define type 2 diabetes mellitus
(3)
Associated with obesity, usually starts later in life.
Insulin may be normal, but is ineffective (insulin resistance)
Many of symptoms the same, but less severe
What is gestational diabetes
Diabetes that lasts for the duration of pregnancy
4% of all pregnancies
Increased risk of type 2
What is type 4 diabetes, give some examples
Genetic defects of beta-cell function
Genetic defects in insulin action
Diseases of the exocrine pancreas (endocrinopathies)
Drug-or chemical induced
Infections
Uncommon forms of immune-mediated diabetes
Other genetic syndromes sometimes associated with diabetes
How does type 1 present
(3)
Acute with symptoms of polyuria, polydipsia, lethargy, weight loss, nausea, vomiting, abdominal cramps, blurred vision and superficial infection
This presentation is the end point of recent and continuing beta cell function resulting in near total loss of insulin production
Hyperglycaemia itself begets further beta cell destruction as treatment with insulin often results in a “honeymoon” period
Describe the pathogenesis of type 2
A group of metabolic diseases characterised by hyperglycaemia resulting from defects in insulin secretion, insulin action or both
The chronic hyperglycaemia of diabetes is associated with long-term damage, dysfunction and failure of various organs, especially the eyes, kidneys, nerves, heart and blood vessels
How does type 2 present?
(4)
Insidious presentation with symptoms of polyuria, polydipsia, lethargy, weight loss, nausea, vomiting, abdominal cramps, blurred vision and superficial infection
Often discovered at routine medical
This presentation is the end point of the gradual loss of beta cell function in the setting of insulin resistance
90-100% concordance in Twins
What are the three macrovascular complications of diabetes
Coronary artery disease (MI)
Cerebrovascular disease (stroke)
Peripheral vascular disease
What are the three microvascular complications of diabetes
Retinopathy
Nephropathy
Neuropathy
What can hyperglycaemia cause?
(2)
Glucose in urine (weight loss and genital thrush)
Osmotic diuresis, water follows (increased urine volume -> thirst and tiredness)
Write about the onset of type 1 diabetes
(8)
typical onset less than 30 but can start at any age
Sudden onset
Sever symptoms
Recent weight loss
Usually thin
Spontaneous ketosis
Absent C-peptide
Markers of autoimmunity
Write about the onset of type 2 diabetes
(8)
Typical onset greater than 20 years but can start at any age
Gradual onset
May be no symptoms
Often no weight loss
Usually obese
Not ketotic
Detectable C-peptide
No autoimmune markers
what five laboratory test are carried out for diabetes
Blood glucose
Fasting glucose
Postprandial glucose
Glycosylated haemoglobin (HbA1c)
Glycosylated albumin
How is diabetes managed
diet
Exercise
Oral anti-diabetes medications
Insulin therapy
How do oral anti-diabetes medications work
Stimulates beta cells to release more insulin
Sensitises the body to the insulin already present
Helps insulin work better in muscle and fat: lowers insulin resistance
Slows or blocks the breakdown of starches and certain sugars: action slows the rise in blood sugar levels following a meal
Write about the burden of diabetes
Affects 3% of the population
Estimated that 5 million people will have diabetes by 2025 (most will be type 2 due to rapidly rising numbers of overweight and obese people)
The cost of diabetes to the NHS is over 1.5million pounds an hour or 10% of NHS budget, 25, 000 pounds are spent on diabetes every minute
people with diabetes account for 5.4% of all completed hospital episodes, 6.4% of outpatient episodes and 9.4$ of impatient stay
Why is diabetes sometimes called starvation in the midst of plenty?
(3)
A diabetic has plenty of glucose in their blood but many of their tissues cannot use it because it can’t get into the cells
Glucose is water soluble and cannot cross cell membranes by simple diffusion
A series of facilitated transport molecules move glucose across membranes
What is a by product of lipid metabolism
Build up of ketoacids
How can you tell someone is experiencing ketoacidosis
Ketoacids can be smelled on breath: odour similar to acetone
Why are ketoacids dangerous
They disturb mental functions and lower blood pH
What are five consequences of poor glycaemic control
Neuropathy (nerve damage) -> impotence is commonly a presenting symptom
Cataracts
Kidney damage (nephropathy)
Arthritis -> damage to collagen in joints
Capillary damage -> circulatory defects and damage to retina
Abnormal plasma lipoprotein metabolism -> increased risk of cardiovascular disease
How can poor glycaemic control cause cataracts?
Damage to the protein a-crystallin in the lens
What are the mechanisms of damage in hyperglycaemia
(3)
Glucose is converted to sorbitol by aldose reductase - Sorbitol accumulates in tissues
Glucose is converted into ketones
Glycation of collagen
What happens when sorbitol accumulates in tissues
This disturbs control of intracellular osmotic pressure
Why is glycation of collagen dangerous
Results in stiffening of the collagen in the blood vessel walls, leading to high blood pressure
why might diabetics have poor circulation
Excess glucose makes the blood syrupy (more viscous) this makes it harder for the heart to pump
Excessive urine flow dehydrates body, reduces blood volume
Both effects reduce the circulation
How is diabetic ketoacidosis considered a medical emergency
If a diabetic lets their blood glucose get too high he may develop ketoacidosis, a life-threatening emergency
Most of the problems in ketoacidosis are due to:
- Dehydration (due to excessive urine production)
- Low pH (due to excessive lipid metabolism)
- Large amounts of ketoacids in the blood (also due to excessive lipid metabolism)
What is Pre-diabetes
(3)
WHO and ADA use this new term to describe those with impaired fasting glucose and impaired glucose tolerance
16 million people have pre-diabetes
Most will develop diabetes within 10 years
How is pre-diabetes prevented
(3)
Screening at risk populations (45+, obese)
Lose 5-10% of weight
Modest exercise 30 minutes a day
Comment on using blood versus plasma
(4)
Glucose is dissolved in water
Plasma has a higher concentration of water compared to red blood cells
Therefore plasma has a higher glucose concentration that that of whole blood
The difference in glucose concentration will also vary with the haematocrit, the lower the haematocrit the smaller the difference, and the higher the haematocrit the larger the difference between the two sample types
How do we compared serum and plasma result(4)
International Federation of Clinical Chemistry (IFCC report 2006)
States that a constant factor of 1.11 is used to convert concentration in whole blood to the equivalent concentration in the pertinent plasma
This factor is based on the relationship between plasma and whole blood glucose at normal haematocrit
The conversion will provide harmonized results, facilitating the classification and care of patients and leading to fewer therapeutic misjudgments
How are most diabetes patients diagnosed?
On the basis of symptoms, examination and random or fasting plasma glucose
What is the oral glucose tolerance test
75g oral glucose taken
Blood samples takes at 0 and 2 hours for blood glucose
Test is only done if the random or fasting glucose result was equivocal or there was still a high index of suspicion
How is the OGTT interpreted
(2)
Patient has diabetes if OGTT 2h greater than 11.0 and or a fasting glucose of greater than/equal to 7.0 mmol/L
Patient has IGT if OGTT 2h between 7.8 and 11.1 and a fasting glucose less than 7.0 mmol/L
Write about blood glucose testing
(3)
Performed mainly on venous plasma
Enzymatic (hexokinase, glucokinase)
Performed mainly on automated analysers
Write about Bedside or self monitoring blood glucose tests
(4)
BM sticks, glucose meters or urine glucose
Performed on whole blood
Can be enzymatic, chemical or photoelectric
Manual techniques
Comment on the monitoring of diabetes
Daily
- Self monitoring of blood glucose
Fortnightly
- Fructosamine (glycated albumin)
Bi-Monthly - Quarterly
- Total glycosylated haemoglobins
- HbA1c
What is fructosamine and why is it measured
Fructosamine is a glycation product that forms when glucose binds to proteins1. It measures average blood glucose levels over the past two to three weeks and is used to help manage diabetes
It is an earlier indicator of diabetes control compared to haemoglobin A1c (HbA1c), which measures average blood sugar over the previous two to four months
Write about HbA1c measurements
(4)
Formed by non-enzymatic attachment of glucose to haemoglobin A
Formed slowly and continuously
Normally less than 42 mmol/mol (6%) but in diabetics can be 2 to 3 times higher
Provides an index to average plasma glucose over the last 2 to 3 months
Write about microalbuminuria
(4)
The excretion of a small amount of albumin in urine
Diabetic nephropathy is a major complication in 35-45% of IDDM which may progress to end stage renal failure
Microalbuminuria is the excretion of 50-200mg albumin in 24 hours
Its detected by sensitive immunoassays (using antibodies directed against human albumin)
How can we use detection of microalbumin to predict future complications?
(2)
Early detection can allow reversal of nephropathy through good glycaemic control, hypotensives and a low protein diet
However once proteinuria has developed then improving glycaemic control may transiently slow down progression but will not reverse it
What are four acute metabolic complications of diabetes mellitus
Diabetic ketoacidosis (DKA)
Hyperosmolar non-ketotic coma (HNC)
Lactic acidosis (LA)
Hypoglycaemia
How does diabetic ketoacidosis develop
(3)
Altered lipid metabolism
Increased concentrations of total lipids, cholesterol, triglycerides and free fatty acids
Free fatty acids are shunted into ketone body formation due to lack of insulin
The rate of formation of these ketone bodies exceeds the capacity for their peripheral utilisation and renal excretion leading to accumulation of ketoacids and therefore metabolic acidosis
What are symptoms of DKA
Dehydration
Acidosis
Hyperosmolality
Diminished cerebral oxygen utilisation
Consciousness becomes impaired
Ultimately patient becomes comatose
What are the laboratory findings of DKA
Hyperglycaemia
Glucosuria
Ketonaemia
Ketonuria
Metabolic acidosis
What might cause DKA in diabetics
Not enough insulin
Skipping insulin
Stress, trauma
Insulin resistance
Why is ketoacidosis considered so important
Ketoacidosis is responsible for the initial presentation of up to 25% of children
How does someone usually present if they have ketoacidosis
(4)
Early manifestations are mild and include vomiting, polyuria and dehydration
More severe cases include Kussmaul respirations (acetone breath)
Abdominal pain or rigidity may be present and mimic acute appendicitis or pancreatitis
Cerebral dehydration and coma ultimately ensure
What is a hyperosmolar non-ketotic coma (HNC)
(2)
Presence of relative insulin deficiency and hyperglycaemia with associated elevated serum osmolality, dehydration and stupor progressing to coma if uncorrected without the presence of ketosis or acidosis
These patients have sufficient circulating insulin to prevent lipolysis and ketosis
What might cause a hyperosmolar non-ketotic coma?
(5)
Dehydration
Medications such as steroids and thiazides
Acute illness
Cerebral vascular disease
Advanced age
What is lactic acidosis
Elevated lactic acid with acidosis and without ketoacidosis
There may be low levels of ketones present
Half of the reported cases of LA have been in diabetics
Rarely seen in diabetic patients particularly since the withdrawal of phenformin from the market
What causes lactic acidosis
Hypoxia
Medications such as phenoformin
What is hypoglycaemia?
(4)
Common in insulin-treated diabetics and occasionally seen in those treated with oral hypoglycemic sulfonylurea agents
Can range from very mild (3.3 to 3.9) with minimal or no symptoms
To severe (<2.2 mmol/L) where there is neurologic impairment
Associated with insulin therapy, may be related to errors in dosage, delayed or skipped meals, exercise and/or intensity of glycaemic control
