2 - Incretin hormones

What are incretins?

small peptide hormones released from the GI tract in response to food intake.

what do incretins enhance?

They enhance the insulin secretory response to glucose.

what are the 2 types?

• glucose-dependent insulinotropic polypeptide (GIP)

• glucagon-like peptide-1 (GLP-1)

what are plasma levels of GIP and GLP-1 like in fasting state plasma levels of GIP and GLP-1?

Low.

what is GIP + how is it synthesised?

42 amino acid peptide, synthesised from proGIP in K-cells of the proximal GI tract.

where are K-cells found?

In the upper GI tract, in the duodenum and proximal jejunum.

how do levels of GIP increase?

in response to nutrient absorption.

when are GIP peak levels?

30 minutes after food intake.

where is GIP carried to and through what?

GIP carried to islets through circulation.

what is GLP-1 + how is it synthesised?

A 30 amino acid peptide+ it is synthesised from proglucagon in L-cells of the distal GI tract.

what is proglucagon + name 2 examples of hormones it can be produced into?

A precursor protein that is cut to produce different hormones, including glucagon + GLP-1.

Proglucagon is cleaved differently to give different products, what is it cleaved into in islet alpha-cells?

GLUCAGON

what is it cleaved into in gut L-cells?

GLP-1

where are L-cells found?

in the lower GI tract, in the ileum and colon.

what causes GLP-1 to be released?

in response to nutrient absorption in the GI tract.

when are GLP-1 peak levels?

30 minutes after food intake.

what are the beneficial effects of GLP-1?

• stimulates insulin secretion

• decreases glucagon secretion

• delays gastric emptying

• decreases appetite/reduces food intake (central effects)

• increases beta-cell mass ➢ decreased apoptosis/increased proliferation

what affect does type 2 diabetes have on the effectiveness of incretin?

significantly reduces it.

Are there changes in GIP in T2D?

• GIP levels are not substantially decreased

• GIP has a reduced effect to stimulate insulin secretion - This may be a consequence of GIP receptor down-regulation due to hyperglycaemia

Are there changes in GLP-1 in T2D?

GLP-1 secretion in response to nutrients may be decreased but GLP-1 that is present works properly.

• Therefore GLP-1 replacement might be a good treatment for T2DM

how usefull is GLP-1 in treating T2DM?

it has limited usefulness.

why?

as GLP-1 is a short-lived peptide.

what breaks it down?

it is degraded by dipeptidyl peptidase-4 (DPP-4).

what does half life (T1/2) mean?

The time taken for the amount of a substance to decrease by half.

what is the half-life of GIP + GLP-1

GLP-1 half-life = 2 minutes

GIP half-life = 5 minutes

how does DPP-4 degrade GLP-1 and GIP?

it removes 2 amino acids from their N-terminus and inactivates them.

what would a DPP-4 inhibitor do?

It would increase GLP-1 + GIP levels in the body.

what affect does this have on blood glucose levels?

causes them to decrease.

how does a DPP-4 inhibitor work?

it prevents the removal of the n-terminal dipeptide which inactivates it. This doesn’t degrade GIP + GLP-1 and elevates insulin levels, as well as reducing glucagon release.

what are DPP-4 inhibitors used to treat?

Type 2 diabetes.

what was the GLP-1-like peptide which was found in glia monsters’ saliva called?

Exendin-4

why did it have a longer half-life?

because it is not a substrate for the enzyme DPP-4 as it lacks the N-terminus sequence.

what was a synthetic version of exendin-4 developed for?

to treat type 2 diabetes.

why does exendin-4 act like GLP-1?

it has 50% amino acids in common and BINDS TO GLP-1 RECEPTORS.

what is it’s half life?

roughly 2 hours.

What does exendin-4 do?

stimulates insulin secretion in a glucose-dependent manner.

what is an agonist?

a substance that binds to a receptor and activates it, producing a response.

why is having GIP + GLP-1 injected more effective than GLIP-1 alone?

they activate 2 different receptors + produce a stronger overall effect.

what is Tirzepatide?

It is a peptide that activates both GIP and GLP-1 receptors.

how often is it injected?

weekly.

what is HbA1c?

a measure of your average blood glucose levels over past 2-3 months?

what does lowering the HbA1c do?

it means better long-term blood glucose control.

so what does the Tirzepatide do?

reduces HbA1c and weight more effectively than GLP-1 agonists alone. (it is used to treat type 2 diabetes in USA).

what do pancreatic beta-cells do?

produce and release insulin.

what are analogues?

man-made substances that are designed to act like a natural substance in the body.

Can GLP-1 analogues treat type 1 diabetes?

as the beta-cells are destroyed in type 1, GLP-1 analogues can’t stimulate insulin secretion. but they can inhibit glucagon secretion, which reduces the liver’s glucose production and overall lowers blood glucose levels.

what affect do analogues have on gastric emptying in type 1 + 2?

They slow the movement of food from the stomach into the small intestine, so glucose enters the blood more slowly and blood glucose levels rise more gradually after eating.

what must be used alongside GLP-1 analogues in type 1 diabetes and why?

must also be treated with insulin as the beta-cells are destroyed and insulin is still required.