Drug Management of Diabetes Flashcards
2 major cell types of pancreatic islets
- Alpha cells (glucagon)
- Beta cells (insulin)
What type of agent is glucagon?
Potent hyperglycaemic agent
What is the major target of glucagon and what does it promote?
- Target = liver
- Glycogenolysis
- Gluconeogenesis
- Release of glucose into blood
What type of agent is insulin?
Potent hypoglycaemic agent
What does insulin binding trigger?
- Oxidation of glucose for ATP production
- Polymerisation of glucose to glycogen
- Conversion of glucose to fat
How does glucose regulate insulin?
- Glucose enters beta cells
- ATP concentration increases
- ATP-sensitive K+ channel activity decreases
- K+ efflux decreases, cell depolarised
- Voltage-gated Ca2+ channels open
- Ca2+ causes secretion of insulin (exocytosis)
What tissues contain insulin receptors?
- Liver
- Muscle
- Fat
What subunits make up the insulin receptor (and what bit do they form)?
- 2 alpha subunits (extracellular binding site)
- 2 beta subunits (transmembrane tyrosine kinase)
What does the insulin receptor do upon binding?
- Phosphorylates insulin receptor substrate (IRS) proteins
What does phosphorylation of IRS proteins cause (and what is subsequently caused)?
- Enzyme activation and gene expression
> Causes expression of Glut-4 transporter so increased glucose uptake
> Causes increased glycogen synthesis
What are the injected drugs given?
- Insulin
- Incretin mimetics
What are the oral drugs given (for type 2)?
- Biguanides
- Sulfonylureas
- Thiazolidinediones
- Gliptins
- Glucose transport inhibitors
2 types of insulin
- Short acting
- Long acting
Onset and peak of the 2 types of insulin
- SA = 30min onset, 2-4h peak
- LA = onset 1-2h, peak 4-12h
Different dose regimes of insulin
- SA 3x before meals, LA 1-2x
- Pre-mixed SA + LA 1-2x
- Continuous infusion
Primary management methods for type 2
- Diet/exercise/lifestyle modifications
- Intermittent fasting
- VLCD
What happens if primary management fails?
- Drugs
- Insulin (1/3 people)
Where do biguanides produce their effects?
- Liver
- Muscle
What do biguanides do?
- Decrease gluconeogenesis (liver)
- Increase fatty acid oxidation
- Decrease carb absorption (intestine)
- Increase glucose uptake by skeletal muscle
Side effects of biguanides
- Lactic acidosis
- GI disturbances
When and with what are biguanides combined (and what does that do)
- For obese patients
- Combined with acarbose (decreases carb absorption)
Mechanism of sulfonylurea action
- Drug binds part of ATP-sensitive K+ channel
- Channel closes
- Beta cell depolarises
- Ca2+ enters and increases insulin secretion
- Increases tissue sensitivity to insulin
Different durations of action of sulfonylureas
- Long –> t1/2 = 10h
- Short –> t1/2 = 4h
Side effects of sulfonylureas
- Hypoglycaemia
- Diuretic actions
How are other sulphonylurea receptor modulators similar to sulphonylureas?
Decrease ATP-sensitive K+ channel activity by binding SUR
How do other sulphonylurea receptor modulators differ from sulphonylureas?
- Shorter duration of action
- More selective for ATP-sensitive K+ channels in beta cells
Side effects of other sulphonylurea receptor modulators
- Hypoglycaemia
- Stimulate appetite
- Contraindicated in pregnancy/breastfeeding
What receptor do thiazolidinediones bind to and what is the effect?
Binds nuclear receptor PPARγ - affects gene expression
Primary action of thiazolidinediones
- Increase fatty acid uptake in adipose tissue
- Increase lipogenesis in adipose tissue
Secondary effect of decreased plasma fatty acids from thiazolidinediones
- Increased glucose uptake
- Decreased gluconeogenesis
What are thiazolidinediones used with?
Sulfonylureas or metformin
Side effects of thiazolidinediones
- Weight gain
- Liver toxicity
- Heart failure
What are incretins?
GI hormones that cause insulin secretion
What do GLP-1 agonists do?
- Increase insulin production in the pancreas
- Slow gastric emptying
- Lower blood glucose after a meal
- Induce satiety
How are GLP-1 agonists administered?
Injection
What is the function of gliptins?
Inhibit dipeptidyl peptidase-4 (DPP-4)
What does DPP-4 do?
Metabolises incretins
Mechanism of glucose transport inhibitors
- Increase glucose and Na+ loss in proximal convoluted tube of kidney
- Promotes osmotic diuresis
Side effects of glucose transport inhibitors
- Peripheral vascular disease
- Hypotension
- Dehydration
- Ketoacidosis
- UTIs
