PBL 2: T2DM and Microvascular complications Flashcards
what are the risk factors of T2DM
obesity (abdominal/truncal obesity)
increasing age
sedentary lifestyle
use of drugs- especially glucocorticoids and Thiazides
genetics
ethnicity- more common in south asian, caribbean and african people
what are the clinical features of T2DM
- polyuria
- polydipsia
- polyphagia
- overweight patients (BMI >30)
- presents with a longer history, with slowly progressing symptoms
- islet cell antibodies not present
- hyperglycaemia less marked than T1DM
- infections
- fatigue
- blurred vision
- parasthesia (abnormal dermal sensation)
describe the pathological mechanism underlying T2DM
- Increased BG levels, Beta cells secrete insulin.
- Insulin binds to its receptors on adipose tissue and skeletal muscle to promote glucose transport from blood to cells
- In Diabetes- insulin receptors don’t respond well to insulin- Insulin resistance = increased BG levels
- In response, Beta cells try secrete more insulin to lower BG levels.
- -> Beta cells hyperplasia + hypertrophy to secrete more insulin
- Beta cell compensation isn’t sustainable
- -> Beta cells undergo hypoplasia and hypotrophy- Beta cells die
- -> Insulin levels decrease and BG levels increase
- -> Hyperglycaemia
Describe the mechanism, example and side-effect of BIGUANIDES
Mechanism:
- Not fully understood but improves insulin sensitivity so causes suppression of hepatic glucose output and enhances insulin-stimulated glucose uptake into muscle
- 1st line therapy in T2DM
Example:
- Metformin
Side-Effects:
- GI upset (20%)
- Lactic acidosis (rare)
- does not cause weight gain or hypoglycaemia
Describe the mechanism, example and side-effect of SULFONYLUREAS
Mechanism:
- Inhibits ATP sensitive Potassium channels in the beta cell membrane
- influx of calcium –> insulin release
Example:
- Glibenclamide
- Gliclazide
- Glimepiride
- Glipizide
- Tolbutamide
Side-effects:
- weight gain
- hypoglycaemia
- rash
- nausea
Describe the mechanism, example and side-effect of GLITAZONES/ THIAZOLINEDIONE
Mechanism:
- Binds to nuclear receptors in adipocytes to increase transcription of insulin sensitive genes
Example:
- Rosiglitazone
- Pioglitazone
Describe the mechanism, example and side-effect of SGLT2 inhibitors
Mechanism:
- inhibits the reuptake of glucose by blocking action of SGLT2 transporters in kidney PCT
- decreased hyperglycaemia
Example:
- Dapagliflozin
Side-effects;
- glycosuria
What are incretins and give examples
Peptide hormones that are released in the GI tract in response to food and potentiates insulin secretion:
- Glucagon like peptide (GLP-1)
- Gastro intestinal peptide (GIP)
what normally breaks down incretins
rapidly broken down by DPP-4
Describe the mechanism, example and side-effect of DDP-4 inhibitors
Mechanism:
- Inhibits DDP-4 and so prevents the breakdown of incretins
- Enhances action of GIP and GLP-1
Example:
- Exanatide
- Sitagliptin
what are the MICROvascular complications of diabetes
Retinopathy
Neuropathy
Nephropathy
what are the MACROvascular complications of diabetes
Ischaemic heart disease
Peripheral Vascular disease
Cerebrovascular disease
Does reversal/ improving hyperglycaemia prevent microvascular disease
YES
Does reversal/ improving hyperglycaemia prevent macrovascular disease
TO AN EXTENT
- preventing macrovascular disease- control of BP, cholesterol and smoking is more important
Describe the pathogenesis of microvascular disease
- Capillary damage
- Metabolic damage
Describe capillary damage in the pathogenesis of microvascular disease
- Prolonged Hyperglycaemia
- Increased blood flow
- Increased Capillary pressure
- Thickened and damaged blood vessels
- Endothelial damage (leakage of albumin and other proteins)
what tissues need insulin to take up glucose
retina
kidney
nerves do not
Glucose is metabolised to sorbitol by ___________
aldose reductase
In diabetes, glucose levels rises. What happens when excessive glucose enter polyol pathway
- sorbitol accumulates
- less NADPH available for cell metabolism
- build up of ROS and oxidative stress
- cell damage
what is the leading cause of impaired vision in ages 20-74
diabetic retinopathy
what are the early stages (non-proliferative) of diabetic retinopathy
Hyperglycaemia
- damage to small vessel wall
- micoraneurysms
When vessel wall is breached
- Dot haemorrhages
Protein and fluid left behind
- Hard exudates
Micro-infarcts
- cotton wool spots
look at pics
what are the later stages (non-proliferative) of diabetic retinopathy
Damage to veins
- Venous budding
- Blockage of blood supply
Ischaemia –> VEGF and other growth factors
- neovascularisation
- proliferative retinopathy
- vitreous haemorrhage
Fluid not cleared from macular area
- Macular oedema
what is the prevention of diabetic retinopathy
Good glycaemic control
Stop smoking
good blood pressure control
what is the treatment of diabetic retinopathy
Address risk factors Opthalmic review (retinal screening of diabetics aged >12) - laser - VEGF inhibitors (bevacizumab) - vitrectomy
