Incretin Islet Axis Flashcards
What is the incretin effect?
Beta cells don’t produce as much insulin when given IV glucose as when given oral glucose
The incretin effect is lost early/late in T2DM?
Early
What are incretins?
Intestinal secretion of insulin
What are incretins secreted in response to?
Nutrient stimuli
Name the two incretins and where they are secreted from
GIP - secreted from K cells
GLP-1 - secreted from L cells
Incretins are broken down quickly/slowly
Quickly
What breaks down incretins?
DPP-4
GIP is more/less potent than GLP-1
Far less potent
What is the function of GIP?
To promote glucose dependent insulin secretion
What is GLP-1?
Glucagon-like peptide I
1
What is GLP-1 cleaved from?
Proglucagon in the intestinal L cels
Where are L cells found?
Distal ileum and colon (some in jejunum and duodenum)
How does glucose stimulate GLP-1 secretion?
Co-transported with sodium which causes sodium influx and depolarisation, calcium influx and hormonal release
Names of some non-glucose nutrients that stimulate GLP-1
Amino acids
Short chain fatty acids
Long chain fatty acids
What happens to GLP-1 after it is secreted?
It is taken up by portal vein and acts on pancreatic beta cells
Acts on enterocytes and other enteroendocrine cells
Activates vagal afferents and the enteric nervous system
Effects of GLP-1 on different organs
Pancreas (can cause pancreatitis)
Brain - appetite regulation
Stomach - reduction in gastric emptying
The heart - increases heart rate
What type of receptor is the GLP-1 receptor?
G-protein coupled receptor
What pathway do incretin drugs act on?
The amplifying pathway - which augments insulin secretion
What pathway do sulphonylurea drugs and glucose act on?
Triggering pathway
What do sulphonylureas do?
Close the KATP channel which is the master switch for insulin secretion.
The membrane depolarises and calcium influx triggers insulin release
Is the insulin release caused by sulphonylureas dependent on glucose?
No - it triggers insulin release no matter the glucose level and so can cause hypoglycaemia
Is the insulin release caused by incretin drugs dependent on glucose?
Yes - they result in augmentation of insulin secretion when the pathway is triggered by glucose and so there is no hypoglycaemia
What do DPP-4 inhibitors do?
Prevent the breakdown of GLP-1 and GIP, resulting in modest rise of GLP-1 and GIP.
But reliant on levels of GLP-1 and GIP so can only boost levels a little
What are GLP-1 receptor agonists?
Modified GLP-1 molecules that avoid breakdown by DPP-4, resulting in supraphysiological GLP-1 action
