Drugs affecting insulin secretion- pharmacology Flashcards
What are the 4 classes of drugs (with an example) that increase insulin secretion from beta cells?
- Sulphonylurea- Gliclazide
- Meglitinides- Nateflinidine
- GLP-1 agonists (Glucagon-like peptide 1)- Exenatide
- DPP-4 inhibitors (Dipeptidyl peptidase-4 inhibitors- Alogliptin
What is the overall mechanism of these groups of drugs ?
They increase secretion of insulin which decreases blood glucose.
- Therefore, they require functioning beta cells, so can only be used in type 2 DM
What is the process of insulin secretion in the body?
When concentration of glucose is increased, it enters the beta cells via GLUT-2 transporters (glucose 2)
The glucose is then metabolised by glycolysis, citric acid cycle etc
These processes cause the generation of ATP
ATP binds to the potassium gated ion channels on the membrane of beta cells.
The binding of ATP causes the K+ channels to be closed
As the K+ ions can no longer leave the cell, the membrane becomes depolarised.
Depolarization of the membrane causes the opening of voltage-gated Ca2+ channels. This causes an increase in intracellular calcium
Additionally, this causes calcium induced calcium release from the endoplasmic reticulum to further increase concentrations
Calcium causes the fusing of vesicles containing insulin with the plasma membrane to release the insulin via exocytosis
What is the mechanism of action sulphonylureas to increase insulin production?
- The pharmacological target of the sulphonylureas e.g. Gliclazide are the ATP-sensitive K+ channel (Katp). These have a high affinity binding site for sulphonylureas
- When sulphonylureas bind to these channels, they block the ATP channels, causing them to be closed
- This causes less K+ ions being allowed out of the cell
- This causes depolarisation of the membrane
- This causes opening of the voltage-gated Ca2+ channels, causing an increase in intracellular calcium
- Additionally, this causes calcium induced calcium release from the endoplasmic reticulum to further increase concentrations
- Calcium causes the fusing of vesicles containing insulin with the plasma membrane to release the insulin via exocytosis
What is the mechanism of action of meglitinides?
The method of action is the same as that of Sulphonylureas
- The pharmacological target of the Meglitinides e.g. Nateglinide are the ATP-sensitive K+ channel (Katp). These have a high affinity binding site for sulphonylureas
- When sulphonylureas bind to these channels, they block the ATP channels, causing them to be closed
- This causes less K+ ions being allowed out of the cell
- This causes depolarisation of the membrane
- This causes opening of the voltage-gated Ca2+ channels, causing an increase in intracellular calcium
- Additionally, this causes calcium induced calcium release from the endoplasmic reticulum to further increase concentrations
- Calcium causes the fusing of vesicles containing insulin with the plasma membrane to release the insulin via exocytosis
What is the mechanism of action of GLP-1 agonists to increase insulin production?
- The pharmacological target of GLP-1 agonists are the Glucagon-like peptide-1 (GLP-1) receptors found on beta cells
- GLP-1 is a peptide hormone that is released from the ileum when we eat and acts on GLP-1 receptors on pancreatic cells
- They bind to GLP-1 receptors which activates G alpha s
- This activates adenyl cyclase
- Adenyl cyclase causes the conversion of ATP to cAMP
- cAMP signals via protein kinase A (pka) and EPAC (Exchange protein activated by cyclic AMP)
- These signals can increase concentrations of intracellular Ca2+
- This causes the fusion of insulin-containing vesicles to the plasma membrane to release insulin via exocytosis
Can also:
- Decrease gastric emptying causing the stomach longer to empty and decreasing rate of absorption from the gut- causes slower glucose increase
- can decrease the secretion of glucagon which would increase glucose concentration via gluconeogenesis= decrease glucose conc
- Can increase satiety (fullness)- GLP-1 in the bloodstream tells us we are full- eat less, good where obesity is common in type 2 DM
What is the mechanism of action of Dipeptidyl peptidase-4 inhibitors (DPP-4)?
- Dipeptidyl peptidase is an enzyme involved in the breakdown of GLP-1.
- GLP-1 has a short half life (less than 2 minutes) because it is inactivated rapidly in the plasma by DPP-4- breaks down the GLP-1 and terminates its action of increasing insulin secretion
- If DPP-4 is blocked with these drugs, it cant breakdown the GLP-1 and therefore GLP-1 can perform its action for longer to increase insulin secretion
Why doesn’t metformin cause hypoglycaemia?
Because metformin doesn’t involve the increase in insulin secretion.
It lowers the basal and post-prandial (after meal) glucose levels
Why does the liver continue to perform gluconeogenesis even when glucose levels are high?
Because due to the loss of insulin sensitivity, the cells are still being starved of glucose so are signalling for more glucose
What is the pharmacological mechanism of metformin?
- Metformin activates the AMP kinase (AMPK), this kinase is important in monitoring cellular energy status
- AMPK is activated by the amp:atp ratio- When AMP increases, Atp decreases.
- Metformin enters the cell via the organic cation transporter (OCT) and enters the mitochondria, where it inhibits the activity of complex 1 in the respiratory chain
- Reduces gluconeogenesis in the liver - by decreasing atp= decrease cAMP= reduce gluconeogenesis
- Increases uptake and ant utilisation of glucose in skeletal muscle and adipose tissue
- Reduces carbohydrate absorption from GIT- decrease levels of blood glucose
- Decreases lipid synthesis- less gaining of weight which is good when most type 2 patients are obese. Also, reduces LDLs and VLDLs ( very low and low density lipoproteins) in the blood- decreased risk of cardiovascular disease
- AMPK inhibits triglyceride synthesis and promotes lipolysis- decreases CVD risk
- AMPK effects gene transcription of enzymes needed for gluconeogenesis
What does PPAR𝛾 stand for and what is it?
Peroxisome proliferator activated receptor gamma
- This is a nuclear receptor, meaning acts as a transcription factor to influence gene transcription
What is the mechanism of action of PPAR𝛾 s?
- An agonist such as a fatty acid binds to the PPAR𝛾 receptor
- This receptor associates with another receptor called the Retinoid X receptor. The endogenous ligand for this receptor is a retinoid
- Once both receptors are occupied, they come together and translocate to the cell nucleus to have an effect on gene transcription
- This will influence the genes involved in lipid metabolism and also those that are downstream in insulin signalling to increase insulin sensitivity
What is an example of Sodium-glucose co-transporter 2 (SGLT-2)?
Dapagliflozin
What is an example of an 𝛼-glucosidase inhibitor?
Acarbose
What is the mechanism of action of SGLT-2 inhibitors?
SGLT-2 co-transporters mediate the reabsorption of glucose in the kidney tubule- proximal convoluted tubule
- SGLT-2 inhibitors reduce the reabsorption of glucose in the kidney, causing more glucose to be lost in the urine and decreasing plasma glucose concentration
- Na+/K+ ATPase cause na+ ions out and K+ in, this causes a good concentration gradient for Na+ to come in via Na+: glucose transporter, and glucose down the passive transporter and reabsorbed into blood- IDK CHECK THIS
