What is the action of insulin?
- Activates GLUT4 to relocate to cell membrane and increase uptake of glucose into cells
- inhibits glycogen breakdown and increases glucose uptake by liver and adipose
- stimulates FA synthesis for transport as lipoproteins and inhibits lipolysis in adipocytes
- Inhibitis proteolysis
What are the normal values in which glucose are kept in plasma?
3.8 - 6.5 mmol.L
What is the effect of diabetes mellitus ie hyperglycaemia?
In the short term - not much
In long term - macrovascular (increases risk of IHD, stroke, and PVD) and microvascular damage (increases risk of retinopathies, neuropathies, and nephropathies)
What is type 1 and type 2 diabetes?
type 1 - autoimmune destruction of beta islet cells
type 2 - insulin resistance and decreased insulin output from beta cells
How are type 1 diabetics treated? What are the varieties of treatment offered and how are these utilised to mimic physiological functioning?
insulin subcutaneous injections
Can be short, intermediate or long acting
Basal bolus regimen - uses long acting insulin in background and then a fast acting insulin with meals - 5 injections per day
Pre-mixed insulin regime - mix of fast and slow acting insulin - 2 times per day
What are the 5 classes of drugs on offer for type 2 diabetics?
Biguanides, thiazolidinediones, sulphonylureas, meglitidine, incretin based therapies
What is the mechanism of action of biguanides and give an example drug. How much can it reduce HbA1c by?
Works by increasing cell sensitivity to insulin and inhibits hepatic gluconeogenesis.
What are the pros and contraindications of metformin?
Pros - well tolerated, weight neutral, cheap, good at lowering glucose
Contraindications - compromised renal function or resp disease
What is the mechanism of action of thiazolidinediones (TZDs) and give an example drug. How much does it lower HbA1c by?
e.g. rosiglitazone or pioglitazone
Works by reducing gluconeogenesis and increasing glucose uptake in muscles. This is done by binding to a nuclear hormone receptor site which activates the RXR receptor, upregulating genes that affect glucose and lipid metabolsim
What are the pros and cons of TZDs? What are the contraindications?
pros - long half life, cannot cause hypoglycaemia
cons - may cause oedema, increase LDL and HDL, binds to albumin causing PK and PD consequences, weight gain
Contraindication - heart failure patients
What is the mechanism of action of sulphonylureas and give an example drug. How much do they reduce HbA1c by?
Act by binding to beta cells K+-ATP channel activity and increasing K+ conc within the cell and cause depolarisation. This results in increases of calcium ion entry into the cell and increases the insulin release from beta cells.
What are the pros and cons of sulphonylureas? Contraindications?
pros - once a day
cons - can cause hypoglycaemia, bidns to albumin causing pk and pd consequences, weight gain and GI disturbances
Give an example meglitidine and mechanism of action. How much does it reduce HbA1c
Same as sulphonylureas - Act by binding to beta cells K+-ATP channel activity and increasing K+ conc within the cell and cause depolarisation. This results in increases of calcium ion entry into the cell and increases the insulin release from beta cells.
pros of meglitidine?
pros - low risk of hypo, no weight gain
What is the order of therapy for type 2 diabetes?
lifestyle advice, metfomin, sulphonylureas, TZDs
If HbA1c levels not brough to 7% or below, move on to metformin and then sulphonylureas
if sulphonylureas doesnt bring down HbA1c to below 7.5% then go on to add a TZD, or start insulin therapy
Name 3 anti obesity drugs and how they work
orlistate - gastric and pancreatic lipase inhibitor
sibutramine - noradrenaline and serotonin reuptake inhibitor = appetite suppression
Rimontadine - endocannabinoid antagonist
What are the 2 incretin based therapies?
DPP-4 inhibitors (gliptins), and GLP-1 receptor agonists
Give an example drug of a DPP-4 inhibitor
Give an example GLP-1 receptor agonist
What are the physiological effects of GLP-1?
- Brain - decrease hunger
- Stomach - decrease gastric emptying
- pancreas - increased insulin secretion, decreased glucagon secretion
- liver - decreased glucose production
- muscle - increase glucose uptake
What is the mechanism of action of gliptins?
DPP-4 inhibitor inhibits breakdowns of incretins. Increatins stimulate increased insulin from beta cells and decreased glucagon from alpha cells.
What are the pros and cons of incretin related therapies?
pros - weight neutral, modest HbA1c reduction
cons - high cost, some GI symptoms
How do SGLT2 inhibitors work?
work by blocking SGLT2 in the proximal tubule which prevents glucose reabsorption
Give an example SGLT2 inhibitor and the major con to using them.
increased risk of lower UTIs
What is normal HbA1c levels?