type 2 diabetes

Question 1

what is the mechanism of action of metformin

Answer 1

increases glucose uptake into tissues and inhibits gluconeogenesis

binds to organic cation transporter 1 and inhibits the mitocohndrial electron complex to produce less atp. this increases the ADP to ATP and AMP to ATP ratio which activates AMP kinase
AMPk decreases expression of enzymes involved in gluconeogenesis, and decreases lipogenesis to improve hepatic insulin sensitivity. ampk also increases glucose uptake into liver and skeletal muscle.

Lactate concentrations increase as a side effect which is negative if patient has chronic kidney disease

Question 2

what is the mechanism of action of sulphonylureas

Answer 2

stimuates insulin secretion from Beta cells (require functional beta cells)

closes Katp channels by binding to SUR. this blocks potassium efflux and activates voltage gated calcium channels to influx calcium. intracellular calcium is also mobilized to lead to insulin release
ex: glibenclamide, tolbutamide and glicazide

this effect is independant of plasma glucose levels (KATP channels blocked even if there is no glucose present)
this can lead to hypoglycaemia.
this medication also can lead to weight gain and increased appetite which can make diabetes symptoms worse

Question 3

what is the mechanism of action of meglitinides

Answer 3

Nateglinide, repaglinide

stimulates insulin secretion from Beta cells (require functional beta cells)

inhibits Katp channels by binding to another binding site. this blocks potassium efflux and activates voltage gated calcium channels to influx calcium. intracellular calcium is also mobilized to lead to insulin release
has rapid onset and short duration of action (taken before meals)
less likely to cause hypoglycaemia compared to sulphonylureas

Question 4

what is the mechanism of action of thiazolinediones

Answer 4

increases glucose uptake into tissues

agonist at PPAR gamma receptor which is a nuclear hormone receptor. alters gene transcription in nucleus to increase levels of GLUT-4 glucose transporter gene expression. forms heterodimer with RXR.
has a slow action (1-2 months for max effect)

ex: pioglitazone

Question 5

what is the mechanism of action of GLP-1 targeted drugs

Answer 5

stimulates insulin secretion from beta cells

incretin (GLP1) /analogue (exenatide)/ Agonists ex: liraglutide
acts at glp-1 receptor on b cells to stimualte insulin secretion in a glucose-dependent way.
also inhibits glucagon release from a cells.
incretin broken down by dipeptidypeptidase 4 which limits rate exenatide is resistant to this
liraglutide also inhibits appetite and is used in obesity

incretin enhancers:
DPP4 inhibitors ex: sitagliptin, linagliptin, vildagliptin
competitive inhibitors that prolong GLP-1 effects by preventing their breakdown

Question 6

what is the mechanism of action of sodium glucose cotransporter 2 inhibitors

Answer 6

reduces glucose reabsorption from kidney by inhibiting SGLT-2
ex: dapagliflozin, canagliflozin

Question 7

what is the mechanism of action of acarbose

Answer 7

reduces glucose uptake from GI tract
by preventing the digestion of carbs.
reduced glucose absorption from diet
side effect: diarrhoea from decrease in fibre

Question 8

what is the strategy of treatment for DM2 (order of treatment, e.g., first line)

Answer 8

1. diet and lifestyle interventions when pre-diabetic
2. metformin or sulphonylurea/ DPPP4 inhibitors/pioglitazone
3. dual therapy (secondary drug picked based on patient, CV effects, weight effects, hypoglycaemia, cost and renal effects)
4. triple therapy
5. insulin