Metabolic disease

Question 1

What is Metabolic disease (aka Metabolic syndrome)?

Answer 1

Metabolic syndrome is a clustering of risk factors, such as central obesity, insulin resistance, dyslipidaemia and hypertension that together culminate in the increased risk of type 2 diabetes mellitus and CVD

Question 2

Which human diseases are easy to diagnose?

Answer 2

Most commonly transmissible diseases which are caused by a microbial pathogen which either IS or IS NOT present
Molecular tests can confirm this

Question 3

How are metabolic diseases more complicated?

Answer 3

Most of the symptoms of metabolic diseases are measures of human metabolism or physiology (e.g. blood glucose concentration) which change to be too high or too low. There are sets of measurements that can be made and which together

Question 4

How is it less clear in metabolic diseases who has them and who doesn’t?

Answer 4

Patients may be just above or just below a threshold, so it much less clear who has the disease and who doesn’t

Question 5

What is the WHO definition of metabolic disease?

Answer 5

the presence of any one of:
- Diabetes mellitus
- Impaired glucose tolerance
- Elevated fasting glucose
- Insulin resistance
And two of the following:
- High blood pressure
- Dyslipidaemia
- Central obesity
- Microalbuminuria

Question 6

What is epidemiology?

Answer 6

The study of disease incidence and distribution

Question 7

What is the incidence of Metabolic syndrome?

Answer 7

One quarter of the worlds adult population has metabolic syndrome
Associated with high BMI, lack of exercise, poor diet, age, and high alcohol consumption
Differences in genetics, diet, family history of diabetes all influence it’s prevalence

Question 8

Is diabetes genetic or caused by environmental factors?

Answer 8

In identical twins, if one twin develops diabetes, the probability of diabetes in the other is very high (70-80%) and the probability of some problem with glucose metabolism even higher (>90%)
BUT
Rates of diabetes in populations without calorie rich diets are very low
Diabetes is one of the best examples of a disease with causative factors are both genetic and environmental

Question 9

Does metabolic disease further increase with age?

Answer 9

Yes, 10% in aged 20-29, 20% in aged 40-49, and 45% in aged 60-69

Question 10

What are the risks of metabolic disease?

Answer 10

It confers a 5-fold increase in the risk of type 2 diabetes mellitus and 2 fold the risk of developing CVD over the next 5 to 10 years
Patients are at 2- to 4- fold increased risk of stroke, a 3- to 4- fold increased risk of myocardial infarction and 2- fold the risk of dying from such an event compared with those without the syndrome regardless of a previous history of cardiovascular events

Question 11

How is the severity of metabolic disease described?

Answer 11

Is a complex condition affecting many organ systems
It can be viewed as the precursor to full diabetes
However, not all patients with metabolic disease will progress to diabetes, in particular if lifestyle changes are made

Question 12

What is metabolic disease characterised by?

Answer 12

Characterised by hyperglycaemia- too much glucose in the blood
Fasting plasma glucose >7.0 mmol/l (diabetic level)
And/or plasma glucose 2 hours after a 75g oral glucose load > 11.1 mmol/l

Question 13

How are levels of glucose in the blood tightly controlled?

Answer 13

By feeding, activity, insulin and glucagon
Metabolism influences behaviour
Low blood sugar induces hunger and tiredness reducing activity

Question 14

How are the fed and fasted states described?

Answer 14

Fed state- Glucose taken into liver and other tissues, storage into glycogen
Fasted state- Glucose released into bloodstream by liver
Glucagon

Question 15

What is Adipose tissue?

Answer 15

Excess glucose also promotes the storage of energy in Adipose tissue
Adipose tissue (fat) is not only a store for energy but also influences metabolism and behaviour by releasing hormones, often called adipokines (adipose derived hormones)

Question 16

What are leptins and adiponectins?

Answer 16

Leptin: ‘satiety hormone’ which inhibits appetite by acting on hypothalamus. Reduced by fasting. Increased in obesity but often body becomes insensitive to this leptin

Adiponectin: reduces blood glucose levels and increases insulin sensitivity
May inhibit appetite
Levels LOWER in obesity

Question 17

What causes diabetes?

Answer 17

A group of metabolic diseases characterised by hyperglycaemia (elevated blood glucose)
Resulting from defects in insulin secretion, insulin action or both

Question 18

What is insulin and what does it do?

Answer 18

A hormone released from the pancreas in response to elevated blood glucose (feeding) which causes many different body cell types to take up glucose and other nutrients from the blood

Question 19

What does insulin convert glucose to?

Answer 19

Conversion to storage macromolecules, glycogen and lipids

Question 20

Where are insulin receptors expressed?

Answer 20

On most cell types, but at high levels on liver, fat and muscle cells. These tissues are highly insulin sensitive.

Question 21

What does the stimulation of cells with insulin do?

Answer 21

Moves glucose transporters to the cell membrane

Question 22

How does healthy insulin signalling work?

Answer 22

Causes the glucose transporter GLUT4 to dock onto the membrane and increase glucose uptake
Also stimulates glycogen synthesis from glucose (energy storage)

Question 23

Where is insulin produced?

Answer 23

Almost exclusively in the pancreas when blood glucose is high and enters the circulation
Insulin receptors are present at high levels on cells in the liver, muscle and adipose tissue and at lower levels on many other cell types

Question 24

What does insulin signalling induce?

Answer 24

Induces anabolic metabolism and increased synthesis of cellular metabolites and components (proteins, lipids etc) as well as overall cell growth

Question 25

What is a fundamental aspect of metabolic disease and type 2 diabetes?

Answer 25

Insulin resistance
Physical inactivity and obesity lead to chronic inflammation and increased circulating free fatty acids and triglycerides. These are drivers of insulin resistance
Equally, if cells are continually exposed to high levels of glucose and insulin, they become more resistant to insulin. This reduces uptake of glucose into many tissues and therefore further elevates glucose levels in the blood

Question 26

What is the pathogenesis of metabolic syndrome?

Answer 26

Insulin resistance
Normal insulin concentration does not adequately produce a normal insulin response in tissues like adipose, muscle and liver
An inability of the pancreatic beta cells over time to produce a sufficient insulin to correct the worsening tissue insulin resistance leads to hyperglycemia and overt T2DM

Question 27

What are most receptor activated signalling mechanisms influenced by?

Answer 27

Strongly influenced by pathway feedback mechanisms

Question 28

How is insulin signalling influenced by pathway feedback mechanisms?

Answer 28

Cells reduce their sensitivity to insulin if they are exposed for long periods of time to elevated levels of either insulin itself, or (importantly) to other factors associated with metabolic disease (e.g. high levels of glucose, free fatty acids or inflammatory cytokines)
Cells exposed to these conditions have lower levels of insulin receptors

Question 29

What do insulin resistant cells usually have?

Answer 29

• Lower levels of insulin receptor
• Lower levels of IRS-1
• Inhibitory changes to IRS proteins especially phosphorylation on serine and threonine residues

Question 30

What is Diabetes Mellitus?

Answer 30

Metabolic disease is related to ‘Diabetes Mellitus’ a life threatening chronic disease

Question 31

What is Diabetes Insipidus?

Answer 31

is a rare and an otherwise unrelated disease which causes over-production of urine, caused by a lack of vasopressin from the pituitary gland
It was one of the first diseases described in historical documents records from ancient Egypt and India about 1500 BCE

Question 32

What are the 2 types of Diabetes Mellitus?

Answer 32

Type 1 diabetes (10%)
Type 2 diabetes (90%)

Question 33

What are the signs of type 1 diabetes?

Answer 33

Destruction of insulin producing cells in the pancreas
Lack of insulin
High levels of blood glucose
Leads to diabetes

Question 34

What are the signs of type 2 diabetes?

Answer 34

Insulin is produced normally by the pancreas
However, tissues become resistant to insulin
High levels of blood glucose
Leads to diabetes

Question 35

How is Diabetes diagnosed?

Answer 35

Fasting blood glucose > 7mM
Healthy range is 4 - 6mM
Glycated hemoglobin > 6.5%

Question 36

How does glycated hemoglobin provide a good test for diabetes?

Answer 36

This provides a good test as hemoglobin glycation is driven by blood glucose concentrations but turns over slowly. Therefore the test indicates average blood glucose concentrations over the previous few months (lifetime of red blood cells) so is more reliable

Question 37

How is type 1 diabetes caused?

Answer 37

Caused by autoimmune destruction of pancreatic beta cells
Root cause of autoimmunity uncertain
Disease develops rapidly, usually in childhood

Question 38

When is type 1 diabetes usually identified?

Answer 38

Usually identified in childhood but is NOT usually a genetic disorder
Managed acceptably well by insulin injection and blood glucose monitoring

Question 39

What are glucose sensors?

Answer 39

Implanted glucose sensors (<1cm) and a matching device on the skin are now entering common use
The sensors record glucose concentration and this can be read using a mobile phone app

Question 40

When and how was insulin discovered?

Answer 40

In 1921 Banting and Best showed that an extract from the pancreas could lower blood sugar levels in dogs.
A year later they experimented on a critically ill diabetic child, who recovered to live for 13 years taking insulin extracts

Question 41

How is insulin varied?

Answer 41

Different formulations (e.g modified and crystalised/aggregated forms) of the insulin protein give different results
This can greatly affect the speed of action and the duration of response

Question 42

How common is type 2 diabetes?

Answer 42

> 3 million people in the UK have type 2 diabetes
15% of all hospital beds are occupied by diabetics

Question 43

How does metabolism influence behaviour in diabetics?

Answer 43

Low blood sugar induces hunger and tiredness reducing hunger
In diabetics, poor control over blood glucose can lead to serious consequences due to either:
- Too high blood glucose (hyperglycemia)
Or, too low blood glucose (hypoglycemia) due to injecting too much insulin or eating too little

Question 44

How is the progression of type 2 diabetes characterised?

Answer 44

1. Cells develop insulin resistance eventually resulting in high blood glucose
2. Pancreas responds by producing more insulin. Insulin levels increase. Insulin resistance worsens.
3. Failure of pancreas and drop in insulin level. Glucose levels further elevated

Question 45

What are the complex symptoms of diabetes?

Answer 45

Thirst, hunger, excessive urination, tiredness
Diabetic retinopathy: blindness caused by cell death in the lining of the blood vessels in the retina
Poor circulation and healing
Heat disease and stroke
Hyperosmolar and Hyperglycemic State (HHS) dehydration, tiredness, cramp, loss of consciousness

Question 46

What are the causes of insulin resistance?

Answer 46

Many different cellular signals and changes in the extracellular environment can make cells in the liver, muscle and fat less sensitive to insulin
Many changes seem to impact on the insulin receptor and on the IRS (insulin receptor substrate) proteins

Question 47

What is the reduced expression and inhibition of Ins-R and IRS function driven by?

Answer 47

• Inflammatory cytokines
• Negative feedback desensitisation caused by long term elevated blood insulin levels
• Elevated circulating free fatty acids and triglycerides
• The unfolded protein response

Question 48

What is the type 2 diabetes therapy?

Answer 48

Insulin injections can provide long term health for type 1 diabetics
BUT type 2 diabetes is caused by failures in insulin function and the body becoming resistant
Recommended T2D treatment is usually a combination of lifestyle changes (diet, weight loss, exercise) and drugs
Most common drug = metformin

Question 49

What is metformin?

Answer 49

Most commonly prescribed treatment for obese type 2 diabetics
It reduces glucose production by the liver and increases insulin sensitivity in many tissues

Question 50

How does metformin work at the cellular level?

Answer 50

At the cellular level, metformin is an activator of AMP-activated protein kinase (AMPK) AMPK is a cellular energy sensor which reduces cellular energy expenditure and increases cellular insulin sensitivity when it is activated