Metabolic disease Flashcards
What is Metabolic disease (aka Metabolic syndrome)?
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
Which human diseases are easy to diagnose?
Most commonly transmissible diseases which are caused by a microbial pathogen which either IS or IS NOT present
Molecular tests can confirm this
How are metabolic diseases more complicated?
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
How is it less clear in metabolic diseases who has them and who doesn’t?
Patients may be just above or just below a threshold, so it much less clear who has the disease and who doesn’t
What is the WHO definition of metabolic disease?
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
What is epidemiology?
The study of disease incidence and distribution
What is the incidence of Metabolic syndrome?
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
Is diabetes genetic or caused by environmental factors?
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
Does metabolic disease further increase with age?
Yes, 10% in aged 20-29, 20% in aged 40-49, and 45% in aged 60-69
What are the risks of metabolic disease?
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
How is the severity of metabolic disease described?
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
What is metabolic disease characterised by?
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
How are levels of glucose in the blood tightly controlled?
By feeding, activity, insulin and glucagon
Metabolism influences behaviour
Low blood sugar induces hunger and tiredness reducing activity
How are the fed and fasted states described?
Fed state- Glucose taken into liver and other tissues, storage into glycogen
Fasted state- Glucose released into bloodstream by liver
Glucagon
What is Adipose tissue?
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)
What are leptins and adiponectins?
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
What causes diabetes?
A group of metabolic diseases characterised by hyperglycaemia (elevated blood glucose)
Resulting from defects in insulin secretion, insulin action or both
What is insulin and what does it do?
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
What does insulin convert glucose to?
Conversion to storage macromolecules, glycogen and lipids
Where are insulin receptors expressed?
On most cell types, but at high levels on liver, fat and muscle cells. These tissues are highly insulin sensitive.
What does the stimulation of cells with insulin do?
Moves glucose transporters to the cell membrane
How does healthy insulin signalling work?
Causes the glucose transporter GLUT4 to dock onto the membrane and increase glucose uptake
Also stimulates glycogen synthesis from glucose (energy storage)
Where is insulin produced?
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
What does insulin signalling induce?
Induces anabolic metabolism and increased synthesis of cellular metabolites and components (proteins, lipids etc) as well as overall cell growth
What is a fundamental aspect of metabolic disease and type 2 diabetes?
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
What is the pathogenesis of metabolic syndrome?
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
What are most receptor activated signalling mechanisms influenced by?
Strongly influenced by pathway feedback mechanisms
How is insulin signalling influenced by pathway feedback mechanisms?
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
What do insulin resistant cells usually have?
- Lower levels of insulin receptor
- Lower levels of IRS-1
- Inhibitory changes to IRS proteins especially phosphorylation on serine and threonine residues
What is Diabetes Mellitus?
Metabolic disease is related to ‘Diabetes Mellitus’ a life threatening chronic disease
What is Diabetes Insipidus?
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
What are the 2 types of Diabetes Mellitus?
Type 1 diabetes (10%)
Type 2 diabetes (90%)
What are the signs of type 1 diabetes?
Destruction of insulin producing cells in the pancreas
Lack of insulin
High levels of blood glucose
Leads to diabetes
What are the signs of type 2 diabetes?
Insulin is produced normally by the pancreas
However, tissues become resistant to insulin
High levels of blood glucose
Leads to diabetes
How is Diabetes diagnosed?
Fasting blood glucose > 7mM
Healthy range is 4 - 6mM
Glycated hemoglobin > 6.5%
How does glycated hemoglobin provide a good test for diabetes?
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
How is type 1 diabetes caused?
Caused by autoimmune destruction of pancreatic beta cells
Root cause of autoimmunity uncertain
Disease develops rapidly, usually in childhood
When is type 1 diabetes usually identified?
Usually identified in childhood but is NOT usually a genetic disorder
Managed acceptably well by insulin injection and blood glucose monitoring
What are glucose sensors?
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
When and how was insulin discovered?
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
How is insulin varied?
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
How common is type 2 diabetes?
> 3 million people in the UK have type 2 diabetes
15% of all hospital beds are occupied by diabetics
How does metabolism influence behaviour in diabetics?
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
How is the progression of type 2 diabetes characterised?
- Cells develop insulin resistance eventually resulting in high blood glucose
- Pancreas responds by producing more insulin. Insulin levels increase. Insulin resistance worsens.
- Failure of pancreas and drop in insulin level. Glucose levels further elevated
What are the complex symptoms of diabetes?
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
What are the causes of insulin resistance?
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
What is the reduced expression and inhibition of Ins-R and IRS function driven by?
- Inflammatory cytokines
- Negative feedback desensitisation caused by long term elevated blood insulin levels
- Elevated circulating free fatty acids and triglycerides
- The unfolded protein response
What is the type 2 diabetes therapy?
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
What is metformin?
Most commonly prescribed treatment for obese type 2 diabetics
It reduces glucose production by the liver and increases insulin sensitivity in many tissues
How does metformin work at the cellular level?
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
