Type 2 Diabetes Mellitus Flashcards
What is diabetes?
A state of chronic hyperglycaemia sufficient to cause long-term damage to specific tissues.
Diabetes = fasting glucose above 7mmol/L.
*The space between diabetic and non-diabetic is considered – Impaired fasting glucose (fasting test) and impaired glucose tolerance (2hr response).
What is MODY?
Maturity Onset Diabetes of the Young
There are several hereditary forms of MODY (1-8) and it is autosomal dominant.
Mutations in transcription factor glucokinase gene produce ineffective beta cell insulin secretion.
MODY causes no obesity and there is a specific treatment for each type of MODY
What influences the pathophysiology of T2DM?
genetics
intrauterine environment
adult environment
Genes can contribute to risk (insulin resistance).
IUGR – Intrauterine Growth Restriction – can greatly increase chances of developing T2DM
Insulin resistance -> dyslipidaemia -> increased mitogenic pathway -> hypertrophy and increase in BP -> macrovascular disease (all while blood sugar is normal)
- Dyslipidaemia -> macrovascular
Hyperglycaemia -> microvascular
*Twin studies have shown T2DM follows an almost autosomal dominant pattern whereas T1DM has less genetic input
**Low birth weight also increases the risk
How does T2DM present?
Heterogeneous – there are many forms/causes of T2DM; there isn’t just one T2DM
Obesity
Insulin resistant and secretion deficient
Hyperglycaemia and dyslipidaemia -> acute and chronic complications
What is the hyperglycaemic clamp?
in people that are developing T2DM, they will have some insulin production but there will lose their first phase response to glucose – they make insulin eventually but it takes longer.
First phase response – stored insulin that is ready to be released when stimulated.
Second phase response – produced and secreted insulin over time
What causes increased blood glucose in T2DM?
deficient insulin means the HGO continues after eating food and the deficient insulin also means the glucose cannot move into muscles and fat.
As you age and insulin sensitivity decreases, the secretions must increase to compensate but those with diabetes don’t compensate enough
Fatty acids cannot be used to make glucose so instead are made into VLDLs which are atherogenic
Liver is not inhibited to make new glucose in gluconeogenesis or breakdown glycerol into glucose in glycolysis
What is the association between T2DM and the gut microbiota?
The gut microbiota appears to be associated with obesity, insulin resistance, T2DM, inflammation and adipocytokine pathways
Possibly via host signalling
Various lipopolysaccharides are fermented by gut bacteria to short chain FFAs which enter the host circulation and modulate bile acids
Possible treatments in the future involve microbiota transplants
How does T2DM present?
Osmotic symptoms
Infections – hyperglycaemia is favourable for bacteria
Screening tests
Often found at presentation of complications – acute (hyperosmolar coma) or chronic (IHD, retinopathy)
- Complications can be microvascular, macrovascular, metabolic (much rarer than for T1DM and ketoacidosis) or from treatment (hypo attack)
How is T2DM managed and monitored?
education, diet, pharmacological treatment and complication screening
Diet:
- Control total calorie intake/increase exercise
- Reduce fat as proportion of calories and reduce refined carbohydrate (sugar)
- Increase complex carbohydrate, unsaturated fat as proportion of fat and soluble fibre
Monitoring T2DM:
- Weight
- Glycaemia
- BP
- dyslipidaemia
What treatments are available?
Orlistat - pancreatic lipase inhibitor
Metformin - biguanide -insulin sensitizer
Sulphonylureas - makes existing pancreas secrete more insulin
Alpha glucosidase inhibitors - delays glucose absorption
Thiazolidinediones - acts on adipocytes and insulin sensitizer peripherally in fat and muscles.
What is metformin?
Biguanide class – oral anti-hyperglycaemic drugs
Insulin sensitizer
Used in overweight T2DM patients where diet alone has not succeeded
In reducing insulin resistance – reduces HGO and increases peripheral glucose disposal
Side effects – GI side effects and do not use if severe liver/cardiac failure and mild renal failure.
What are sulphonylureas?
e.g. Glibenclamide/ glyclazide
Sulphonylureas act on the beta cell and act to increase insulin secretion by blocking the ATP-sensitive potassium channel and cause influx of calcium.
This is used in lean patients with T2DM.
Side effects – hypoglycaemia and weight gain
What are alpha glucosidase inhibitors?
e.g. Acarbose.
Prolongs absorption of oligosaccharides
Allows insulin secretion to cope following defective first phase insulin
Is as effective as metformin but side effects include flatulence
What are thiazolidenediones?
e.g. Pioglitazone.
Peroxisome proliferator-activated receptor agonist (PPAR-g agonist)
Insulin sensitizer peripherally
Adipocytes are rearranged so weight gain is peripheral and not central
Improvement in glycaemia and dyslipidaemia
Side effects include – hepatitis and heart failure
What are GLP-1 and gliptins?
e.g. Exenatide, liraglutide, Gliptins
GLP-1 is secreted (from L-cells) in response to nutrients in the gut (incretin effect) - it stimulates insulin and supresses glucagon and increases satiety
GLP-1 has a short half-life though and is broken down by DPPG-4
Drugs:
- GLP-1 – injectable, long acting GLP-1 agonist, decreases glucagon and glucose and leads to weight loss
- Gliptins – DPPG-4 inhibitor, increases half-life of exogenous GLP-1 but has neutral effect on weight
