Module 5: Incretins Flashcards
What are incretins and when are they secreted
Hormones and gut peptides
-secreted following glucose intake
What does incretins do
Stimulate insulin secretion
2 examples of incretins
- glucose-dependant insulinotropic polypeptide (GIP)
2.glucagon-like peptide-1 (GLP-1)
What is the “incretin effect”
More insulin secreted when glucose is consumed rather than when injected into blood (bypassing gut)
Is glucose more effectively cleared when consumed orally or injected
-consumed orally (insulin spike)
How GIP and GLP-1 activated
GIP: Pro-GIP processed in intestinal cells by PC2 to form active GI
GLP-1: Pro-GLP-1 activated in intestinal cells by PC1 to form active GLP-1
2 enteroendocrine cells and what they do
K-cells and L-cells
Enteroendocrine cells in intestine are polarized cells that sense contents of intestinal lumen
Which incretins are released from each enteroendocrine cell
K-cells –> release GIP
L-cells –> release GLP-1
(in response to nutrients in intestinal lumen)
2 mechanisms in which glucose stimulates incretins
- SGLT-1 (sodium/glucose co-transporter 1)
2.Sweet taste receptor
HOW do the 2 mechanisms stimulate incretins
depolarization within the celll –> increase calcium levels –>incretin-containing vesicles release contents into circulation
SGLT1+/+ WT) mice vs SGLT-/- (KO) mice (3 points, experiments)
1) stronger increase in blood insulin in WT mice than KO
2) Fed G bolus (glucose) or oil bolus (lipid)
-G bolus = large increase in GIP levels in WT not KO
-lipid bolus increased but same between both (SGLT1 independent)
3) Fed B bolus (control) or G bolus (glucose)
-glucose only increased GLP-1 levels in WT
Blood GIP in SGLT+/+ (WT) and SGLT-/-(KO) when given G (glucose) or oil (lipid) bolus
Large increase in GIP when given G bolus in WT mice, not KO
GIP increase in both WT and KO with lipid bolus, (independent of SLGT1)
Blood GLP-1 in SGLT+/+ (WT) and SGLT when fed B (control) and G (glucose) bolus
G bolus only cause increase of GLP-1 in WT animals
How are incretins inactivated
Half life!
Cleaved by DPP-4 enzyme
Half-life of GLP-1 and GIP
GLP-1 = 1-2 min
GIP = 7 min
What does intact (active) incretin represent
Active form
What does total (active+inactive) incretin represent
Secretion
Obesity and GIP secretion and active levels
Obesity does not affect GIP secretion, reduced active levels
Obesity and GLP-1 secretion and active levels
Obesity reduces both GLP-1 active AND secretion levels
Role of incretins in pancreas
-Bind to specific receptors in pancreas
-Rec activation forms CAMP - triggers increase in intracellular calcium (depol)
-depol causes exocytosis of insulin granules - insulin release into blood
Can glucose increase intracellular calcium or just incretins?
Glucose can increase intracellular calcium, combined with incretins cause massive insulin release
Incretins and beta cell apoptosis relationship
Incretins reduce beta-cell apoptosis
Incretins and glucagon/insulin secretion from pancreatic a-cells relationship
Decrease glucagon secretion
Increase insulin secretion
Incretins and glucose production relationship
Decrease glucose production
Obesity and incretin response relationship
Obesity decreases incretin response
2 strategies to enhance incretin response
1) Incretin mimetics
2 Incretin enhancers
How do incretin mimetics work
-Same structure as incretins, resists DPP-4 inactivation
-Creates incretin with higher half-life
How do incretin enhancers work
-Block DPP-4 enzyme directly - preserve “natural” incretin levels for longer
Treating with incretin mimetics affects
-lower body weight
-lower ALT (marker assess liver dysfunction)
-lower HbA1c (marker of long-term whole body glu homeostasis)
-increase in HDL-cholesterol
-lower blood TAG, cholesterol, LDL-cholersterol and BP
Metformin
anti-diabetic drug
-suppresses hepatic glucose production
