pharmacology of drugs used in the management of diabetes: drugs affecting insulin secretion

what are the different classes of anti diabetic drugs that act by increasing the secretion of insulin form pancreatic beta cells

• the sulphonylureas e.g. gliclazide

• the meglitinides e.g. nateglinide

• GLP-1 agonists e.g. exenatide

• DPP-4 inhibitors e.g. alogliptin

what do all the anti diabetic drugs acting by increasing the secretion of insulin require in order to work

functioning beta cells

what is the pharmacological target of sulphonylureas

the ATP-sensitive K+ channel (KATP)

what is there a high affinity of on the KATP channel 

sulphonylurea binding sites

mechanism of sulphonylureas

block KATP channel causing depolarisation of the membrane potential and consequent downstream actions 

what can sulphonylureas cause

hypoglycaemia as insulin secretion is increased even in the absence of glucose

how do meglinitides work

via the same mechanism as sulphonylureas

what do sulphonylureas and meglinitides inhibit directly

• the KATP channel

• therefore closing the channel and less K+ out of cell 

• even in the absence of glucose we can get insulin secretion 

what is the pharmacological target of GLP-1 agonists

the glucagon-like peptide-1 (GLP-1) receptor

what does the GLP-1 increase

increases the glucose-dependent secretion of insulin 

what type of hormone is GLP-1, where is it released from, and what does it act on

• peptide hormone

• released from ileum 

• acts on GLP-1 GPCRs in pancreatic beta cells

what can GLP-1 also do regarding gastric emptying, glucagon secretor, and satiety

• decreases gastric emptying

• decreases glucagon secretion

• increases satiety 

what do GLP-1 agonists do

• activate the GLP-1 receptor

• increase glucose-dependent insulin release

what will a GLP-1 agonist do intracellularly 

• activates adenylate cyclase making cAMP

• further increases intracellular Ca2+ 

• facilitates/augments the increase in intracellular Ca2+ for a given conc. of glucose and we get a greater release/secretion of insulin

why is a decrease in gastric emptying good for diabetics

slows down absorption of glucose from gut

why is a decrease in glucagon release good for diabetics

beings down glucose conc. in blood

why is increasing satiety good for diabetics

• eat less

• particularly good for type 2 diabetics who are more prone to obesity 

what is the pharmacological target of DPP-4 inhibitors 

dipeptidyl peptidase-4 (DPP-4)

what is DPP-4 

enzyme that helps in the breakdown of GLP-1 

what does DPP-4 do

• GLP-1 has a very short half life (<2 mins)

• DPP-4 therefore rapidly inactivates GLP-1 in the plasma 

what do DPP-4 inhibitors increase

glucose-dependent insulin secretion

what is the name for DPP-4 inhibitors

• the gliptins

• alogliptin

what does inhibition of DPP-4 decrease and what does this mean for GLP-1

• decreases the breakdown of GLP-1

• GLP-1 can therefore perform its biological actions for longer