8. Diabetes Mellitus

Question 1

What is diabetes mellitus?

Answer 1

Chronic non-communicable disease characterised by hyperglycaemia

Question 2

What causes diabetes mellitus and what are the consequences (brief)?

Answer 2

Caused by relative insulin deficiency or resistance or both

Usually irreversible
Late complications of diabetes mellitus result in reduced life expectancy and major health costs

Question 3

What is the prevalence of diabetes in the UK?

Answer 3

Currently 3.5 million people diagnosed with this in the UK

Numbers are continually increasing each year

Question 4

What is type 1 diabetes and how is it caused?

Answer 4

Chronic autoimmune disease

Characterised by immune (t-cell) mediated disruption of the pancreatic Beta cells within the islets of Langerhans

Autoantibodies act against the Beta cells in the islets and there is infiltration of the pancreas islets by mononuclear cells

This results in an insulin deficiency as the Beta cells cannot produce insulin

Question 5

Describe the hereditary aspect of type 1 diabetes and the age of presentation

Answer 5

Prominent disease in childhood and generally in younger patients (<30 years old) but can present at any age

The genetic basis of the disease is not fully understood - not genetically predetermined but increased susceptibility to the disease can be inherited

Question 6

How is type 1 diabetes treated?

Answer 6

There is a constant need for insulin injections

Immunosuppression may be administered as this acts to delay the Beta cell disruption

Question 7

What is type 2 diabetes?

Answer 7

Chronic, progressive disease characterised by abnormal insulin action and secretion as well as elevated insulin resistance

Most common form of diabetes (85-90% of all cases of diabetes)

Question 8

SO compare the cause of type 1 diabetes to type 2 diabetes

Answer 8

Type 1 - due to destruction of beta cells and lack of secretion of insulin

Type 2 - Beta cells are still functioning and insulin is being secreted but it is not sensed by the receptors and so the actions mediated by insulin is not correctly elicited BUT there is also some level of a lack of insulin secretion by the beta cells - this may be due to exhaustion of the beta cells after trying to compensate via increased production of insulin

Question 9

Describe the hereditary aspect of type 2 diabetes and the age of presentation

Answer 9

Used to be more prominent in older patients - greater than 30 years
BUT is now becoming more and more common in younger populations due to increased levels of obesity (one of the major risk factors)

There is a strong genetic component but again this is not fully understood - currently a lot of research being carried out relating to this

Question 10

What are the risk factors for type 2 diabetes?

Answer 10

Obesity - BMI greater than 31 leads to a 40-fold increased risk
Family history
Increasing age
Ethnicity

Question 11

What is meant by insulin resistance?

Answer 11

This is when there are reduced responses to the hormone insulin
SO the hormone is circulating but the target tissues are not responding to it properly e.g. due to a reduction of insulin receptors

Essentially what is occurring in type 2 diabetes

Question 12

Give a suggested mechanism of insulin resistance

Answer 12

Insulin binds to it’s receptor insulin receptor substrate (IRS)
This must then be phosphorylated by tyrosine to activate the pathway of events for insulin signalling i.e. for the translocation of the receptor
BUT in insulin resistance, has been found that the IRS isn’t phosphorylated by the tyrosine kinase as it should be and so the pathway is stopped

Question 13

What role do macrophages play on insulin resistance?

Answer 13

Infiltrating macrophages into adipose tissue - these can release cytokines which can contribute to insulin resistance

Question 14

What are the causes of insulin resistance?

Explain these

Answer 14

Obesity:
Accumulation of lipids and their metabolites or increased circulation of free fatty acids
Chronic inflammation
Altered adipokine levels

Hyperinsulinaemia:
Increases lipid synthesis and exacerbates insulin release

Question 15

Does insulin resistance always lead to diabetes?

Answer 15

NO - diabetes does not always develop because generally there will be islet compensation

E.g. if the insulin resistance is because of e.g. pregnancy or body weight gain then islet compensation will occur to counter this

Question 16

What is islet compensation ?

Answer 16

This is where new beta cells can be generated in response to insulin resistance
They may also increase in size and can increase their ability to secrete insulin

This will generally allow the body to maintain the normal glucose level (3-5mm/L) in instances of e.g. pregnancy or increased body weight

Question 17

What is the role of islet compensation in diabetics?

Answer 17

Diabetics do not have islet compensation

In contrast, they will actually produce fewer levels and smaller beta cells due to abnormalities and hence fewer levels of insulin synthesised/secreted

This is why some obese people will not develop diebetes - they have islet compensation but those who do not have islet compensation have a predisposition to developing diabetes

Type 2 diabetes –> dysfunction of the beta cells

Question 18

Apart from type 1 and type 2, what are the other forms of diabetes mellitus?

Answer 18

Maturity onset diabetes of the young (MODY) - autosomal dominant inheritance of mutated gene resulting in disrupted insulin production - but this is very rare

Gestational diabetes - occurs in 2-6% of pregnancies - insulin resistance is not compensated - increased risk of subsequent type 2 diabetes

Latent autoimmune diabetes of adults (LADA) - have markers of autoimmunity and there is a progression to insulin dependency faster than type 2 diabetes

Question 19

How is type 2 diabetes diagnosed?

Answer 19

One abnormal plasma glucose concentration in the presence of symptoms OR in asymptomatic people, two fasting venous plasma glucose samples in the abnormal range

Question 20

What investigation can be used to diagnose type 2 diabetes?

Answer 20

HbA1c - haemoglobin is affected in people that have diabetes - becomes glycosylated so can measure the levels of glycosylated haemoglobin in the blood

This is a reliable measure but it can be expensive in some parts of the world - this is reliable because the glcoysylated haemoglobin is more stable than the blood glucose

Gives you information on the levels of blood glucose for the past three months

Question 21

What is the treatment for type 2 diabetes?

Answer 21

Target the insulin resistance of the beta cell dysfunction - certain drugs act to do this DPP-4 inhibitors or SGLT2 inhibitors
e.g. can enhance the sensitivity so that target tissues are more likely yo so they e.g. increase glucose uptake

Inhibit gluconeogensis in the liver e.g. metformin - results in increased glucose uptake in the muscles

Drugs to stimulate insulin secretion e.g. act on the K+ channels of the beta cells

OR may have drugs that act on the GLP-1 hormone - this is a hormone which can increase insulin secretion and also reduces glucagon secretion

Question 22

What are the acute complications of diabetes?

Answer 22

Ketoacidosis - most common in type 2 but can occcur in type 1

Hypoglycaemia

Question 23

What is ketoacidosis?

Answer 23

Due to a lack of insulin, the metabolism will be shifted to fatty acid consumption

Continual use of fatty acids for fuel will result in the production of ketone bodies from acetyl coA - the ketone bodies then dissociate into anions and H+ and this leads to ketoacidosis in the body

This can lead to increased levels of blood and urine acid, can lead to dehydration, coma and death

Question 24

Why can hypoglycaemia occur?

Answer 24

When treating the hyperglycaemia in diabetes, may result in the utilisation of too much glucose relative to the inhibition of glucose release

Other causes include:
Alcohol excess - gluconeogenesis is inhibited at the level of lactate dehydrogenase
Insulinoma - tumour of pancreatic beta cells
Excessive exercise leading to the increased utilisation of glucose

Question 25

What are the consequences of prolonged hypoglycaemia?

Answer 25

Growth hormone and cortisol are secreted and these decrease the rate of glucose utilisation

Can lead to neuroglycopaenia due to shortage of glucose for the brain and can lead to brain damage
Loss of cognitive function, seizures and coma

Question 26

What are the chronic complications of diabetes?

Answer 26

Hyperglycaemia

Dyslipidaemia - increased level of lipids in the blood

Increased levels of protein kinase C which can then cause damage and occlusion of blood vessels, mitochondrial dysfunction and increased levels of inflammation

Post-translational modifications - excess glucose can be converted to sugar molecules - these can then attach to proteins and can cause post-translational modifications to them - so the function of the proteins are altered - and these can result in the activation of other processes and pathways which can cause damage

Question 27

What is diabetes retinopathy?

Answer 27

This is a disease of the retina involving damage to the blood vessels in the back of the eye due to protein modification by sugars

Question 28

What is diabetes nephropathy?

Answer 28

Disease of the kidney involving damage to the blood vessels in the glomerulus

Decreased filtration - proteinuria
Glomerular hypertrophy
Renal fibrosis

Question 29

What is diabetes neuropathy?

Answer 29

Damage to the blood vessels supplying nerves

Can be peripheral, autonomic, proximal or focal

Question 30

What can diabetes lead to on the surface of blood vessels?

Answer 30

Can lead to atherosclerotic plaque formation

The low density lipoprotein receptors can be modified leading to an increased uptake of the LDL

Question 31

What are the different methods by which metformin can work?

Answer 31

Counteracts insulin resistance - increases sensitivity of e.g. muscle cells to the insulin - take up more glucose

Inhibits the levels of gluconeogenesis at the liver

Question 32

What are the physiological and behavioural responses to hypoglycaemia?

Answer 32

Decreased insulin secretion
Increased glucagon secretion
Increased adrenalin secretion

Increased carbohudrate ingestion

Question 33

What are the responses to prolonged hypoglycaemia?

Answer 33

Secretion of growth hormone and cortisol

Question 34

What are the symptoms of hypoglycaemia?

Answer 34

Autonomic - trembling, palpation, sweating, hunger, anxiety

Neuro - weakness, drowsiness, lack of concentration, dizziness

Question 35

What is the significance of severe hypoglycaemia?

Answer 35

This is a diabetic emergency

Question 36

What are the chronic complications of diabetes?

Answer 36

Atherosclerosis 
Nephropathy
Neuropathy
Retinopathy
Ampytation
Dyslipidaemia

Question 37

Why do protein kinase levels increase in someone with diabetes?

Answer 37

Excess of glucose in the blood - too much to store in the liver, muscles, adipocytes so it is converted to a different form of glycerol which then activates protein kinase C

Question 38

What is the significance of raised protein kinase C levels?

Answer 38

Increased permeability of blood vessels - leaky
Increased occlusion of blood vessels and vasoconstriction
Increased mitochondral dysfunction

Question 39

Why does hyperglycaemia cause post-translational modification?

Answer 39

Excess of glucose in the blood - too much to store in the liver, muscles, adipocytes so some is converted to sugar molecules - can post-translationally modify proteins - altered function

Question 40

What is the function of GLP-1?

Answer 40

Hormone that increases insulin secretion and reduces glucagon secretion
Also increases insulin sensitivity
Increases beta-cell mass

Question 41

Why are so many blood vessels impacted in T2DM?

Answer 41

Post-translational protein modification - altered function - can damage vessels and also leaky vessels from protein kinase C