Module 5: Incretins

Question 1

What are incretins and when are they secreted

Answer 1

Hormones and gut peptides
-secreted following glucose intake

Question 1

What does incretins do

Answer 1

Stimulate insulin secretion

Question 2

2 examples of incretins

Answer 2

1. glucose-dependant insulinotropic polypeptide (GIP)
   2.glucagon-like peptide-1 (GLP-1)

Question 3

What is the “incretin effect”

Answer 3

More insulin secreted when glucose is consumed rather than when injected into blood (bypassing gut)

Question 4

Is glucose more effectively cleared when consumed orally or injected

Answer 4

-consumed orally (insulin spike)

Question 5

How GIP and GLP-1 activated

Answer 5

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

Question 6

2 enteroendocrine cells and what they do

Answer 6

K-cells and L-cells
Enteroendocrine cells in intestine are polarized cells that sense contents of intestinal lumen

Question 7

Which incretins are released from each enteroendocrine cell

Answer 7

K-cells –> release GIP
L-cells –> release GLP-1
(in response to nutrients in intestinal lumen)

Question 8

2 mechanisms in which glucose stimulates incretins

Answer 8

1. SGLT-1 (sodium/glucose co-transporter 1)
   2.Sweet taste receptor

Question 9

HOW do the 2 mechanisms stimulate incretins

Answer 9

depolarization within the celll –> increase calcium levels –>incretin-containing vesicles release contents into circulation

Question 10

SGLT1+/+ WT) mice vs SGLT-/- (KO) mice (3 points, experiments)

Answer 10

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

Question 11

Blood GIP in SGLT+/+ (WT) and SGLT-/-(KO) when given G (glucose) or oil (lipid) bolus

Answer 11

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)

Question 11

Blood GLP-1 in SGLT+/+ (WT) and SGLT when fed B (control) and G (glucose) bolus

Answer 11

G bolus only cause increase of GLP-1 in WT animals

Question 12

How are incretins inactivated

Answer 12

Half life!
Cleaved by DPP-4 enzyme

Question 13

Half-life of GLP-1 and GIP

Answer 13

GLP-1 = 1-2 min
GIP = 7 min

Question 14

What does intact (active) incretin represent

Answer 14

Active form

Question 15

What does total (active+inactive) incretin represent

Answer 15

Secretion

Question 16

Obesity and GIP secretion and active levels

Answer 16

Obesity does not affect GIP secretion, reduced active levels

Question 17

Obesity and GLP-1 secretion and active levels

Answer 17

Obesity reduces both GLP-1 active AND secretion levels

Question 18

Role of incretins in pancreas

Answer 18

-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

Question 19

Can glucose increase intracellular calcium or just incretins?

Answer 19

Glucose can increase intracellular calcium, combined with incretins cause massive insulin release

Question 20

Incretins and beta cell apoptosis relationship

Answer 20

Incretins reduce beta-cell apoptosis

Question 21

Incretins and glucagon/insulin secretion from pancreatic a-cells relationship

Answer 21

Decrease glucagon secretion
Increase insulin secretion

Question 22

Incretins and glucose production relationship

Answer 22

Decrease glucose production

Question 23

Obesity and incretin response relationship

Answer 23

Obesity decreases incretin response

Question 24

2 strategies to enhance incretin response

Answer 24

1) Incretin mimetics
2 Incretin enhancers

Question 25

How do incretin mimetics work

Answer 25

-Same structure as incretins, resists DPP-4 inactivation
-Creates incretin with higher half-life

Question 26

How do incretin enhancers work

Answer 26

-Block DPP-4 enzyme directly - preserve “natural” incretin levels for longer

Question 27

Treating with incretin mimetics affects

Answer 27

-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

Question 28

Metformin

Answer 28

anti-diabetic drug
-suppresses hepatic glucose production