LT3 Incretins & Drugs Flashcards by HuiXin Chen

What is the incretin effect?

When given oral glucose it produces a higher insulin secreiton than intravenous glucose at the same concentration

How well did you know this?

Not at all

Perfectly

What conditions allow oral and intravenous insulin secretion to be compared?

Isoglycaemic concentrations

How well did you know this?

Not at all

Perfectly

How is the incretin effect affected by T2D?

Incretin effect is lost

How well did you know this?

Not at all

Perfectly

Why is the incretin effect lost in T2D?

Reduced GLP-1 and GIP (incretins) secretion after nutrient stimulus

Reduced action of incretins as the beta-cells

How well did you know this?

Not at all

Perfectly

What does incretins stand for?

Intestinal secreiton of insulin

How well did you know this?

Not at all

Perfectly

Where are GIP and GLP-1 secreted from?

GIP from K cells
GLP-1 from L cells

How well did you know this?

Not at all

Perfectly

How are incretins broken down?

DPP4 breaks them down into inative metabolites

These metabolites are then cleared by the kidney

How well did you know this?

Not at all

Perfectly

How are GIP and GLP-1 related?

Both derived form the same gene = preproglucagon

Then cleaved in their respective cells

How well did you know this?

Not at all

Perfectly

Where are L-cells mostly found?

Primarily distal ileum & colon

(some in duodenum and jejunum)

How well did you know this?

Not at all

Perfectly

How do nutrients trigger gut hormones to be secreted into bloodstream?

Ingested food it digested into its nutrient components in GUT LUMEN of small intestine

Enterocytes act as nutrient sensors, detecting the presence of digested food components which then trigger the enteroendocrine cells (EECs) to secrete appropriate gut hormones to regulate digestion and absorption processes like appetite, satiety, and insulin secretion

How well did you know this?

Not at all

Perfectly

How are incretins released by glucose sensing?

Glucose is taken up into enteroendorcine cells by SGLT1 transporter

Na+ is coupled to this and enters cells causing memrbane depolarization

V.g Ca2+ is sitmulated and Ca2+ influxes

GLUT2 also transports glucose into EECs

How well did you know this?

Not at all

Perfectly

How are incretins released by AA and Fat sensing?

Enteroendicrine cells sense AA and fats using G-coupled protein receptors

How well did you know this?

Not at all

Perfectly

What happens after GLP-1 secretion in to the bloodstream?

Taken up by portal vein and is transported to pancreatic beta-cells (and possible alpha-cells) = endocrine signalling
Acts on enterocytes = paracrine
Acts on other EECs = paracrine action
Activates vagal afferents = neurone effects
Activates enteric NS

How well did you know this?

Not at all

Perfectly

What organs does GLP-1 act on?

Pancreas
Stomach
Brain
Heart

Indirectly acts on adipose tissue and muscle via insulin action

How well did you know this?

Not at all

Perfectly

What affect does GPL-1 have on pancreas?

Increased insulin secretion and biosynthesis
Decreased glucagon secretion

Potential increased beta-cell proliferation and decrease apoptosis

How well did you know this?

Not at all

Perfectly

What affect does GLP-1 have on stomach?

Decreased gastric emptying = feel full for longer

How well did you know this?

Not at all

Perfectly

What affect does GLP-1 have on the brain?

Decreased appetite

Increased neuroprotection

How well did you know this?

Not at all

Perfectly

What affect does GPL-1 have on the heart?

Increased heart rate, cardiac function and cardioprotection

How well did you know this?

Not at all

Perfectly

What affect does GPL-1 have on the liver?

Decreased glucose production

How well did you know this?

Not at all

Perfectly

What does GLP-1 increase the risk of developing?

Pancreatitis

How well did you know this?

Not at all

Perfectly

What is the mechanism of action of sulphonylureas?

Sulphonylureas bind to SUR1

Close K_ATP channels

Causing membrane depolarization & calcium influx

This triggers insulin release

What is the mechanism of action of incretins?

Act via GIP/GLP-1 receptors = both GCPR
Activates Gs = activates adenylate cyclase
Increase in cAMP

cAMP activates PKA = phosphorylates Ca2+ channels

cAMP activates EPAC2 = facilitates granule docking

What drugs act on the triggering and amplifying pathways?

Sulphonylureas act on triggering pathway

Incretins act on amplifying pathway

What is the downside of sulphoylureas that incretin agonists don’t have and why?

Sulphonylureas act on the triggering pathway = causing insulin release regardless of glucose levels

This can cause hypoglycaemia

But incretins act on amplifying pathway, so only work when pathway is triggered (normally under high glucose levels)

Is there actually reduced increting secretion after nutrient stimulus in T2D?

We don't know but probably

How does T2D affect fasting GLP-1?

Increased fasting GLP-1 with increasing glucose levels

Why are GLP-1 agonists so popular and not GIP?

In T2D, insulin did not respond to low doses of either incretin But with high doses insulin secretion was increased ONLY with GLP-1 agonists and not GIP. So GIP does not increase insulin response in T2D

What are the drugs acting on the incretin axis?

Metformin DPP4 inhibitors GLP1 receptor agonists Sulphoylureas

Why are DPP4 inhibitors not as effective as GLP-1RA?

Because inhibiting the breakdown of GLP-1 and GIP = can only modestly increase the increting based on the low endogenous concentrations anyway But adding GLP-1RA increases the concentration because applied externally

How were bile acids used to help with diabetes?

Administered rectally because L cells are found distally

How does metformin help T2D?

Inhibits hepatic glucose production, which is high in T2D

What is the mechanism of action of metformin?

Metformin activates AMPK, which enhances insulin sensitivity

How does metformin affect GLP-1?

A few studies have suggested it increases FASTING GLP-1 secretion

How does metformin affect bile acids?

Metformin inhibits ASBT = stops reabsorption of bile acids Accumulation of bile acids in the ileum = bind TGR5 (GPC) Increase in adenylates cyclase = increase cAMP = PKA and EPAC Increased GLP-1 secretion

How can lower doses of sulphonylurea prevent hypoglycaemia?***

Low doses mean only some K_ATP channels close This increases insulin Making beta-cells more sensitive to GLP-1

Why do low doses of sulphonylurea augment the incretin effect better than higher doses?

Sulphonylureas cause insulin secretion regardless of glucose levels If you have a high dose of SU = can cause hypoglycaemia Low levels of glucose causes a decrease in release of incretins or inhibit its effectiveness

What are DPP4 inhibitors also called?

Gliptins

Why are there different classes of DPP4i?

They are grouped by molecular structure How they cover the DPP4 active site

Are DPP4i good at lowering glucose levels?

No they are weak at it 48mmol/mol is where diabetes is diagnosted DPP4i decrease HbA1c by 5-8mmol/mol Metformin decreases it be 12mmol/mol

How do DPP4 inhibitors affect weight?

They keep weight nrutral Unlike, sulphonylureas which increase weight

What are the side effects of DPP4 inhibitors?

Minimal = generally well tolerated Possible increased risk of pancreatitis (some but not all studies suggest risk) Some cause increased risk of heart failure hospitalization

Where is Exendin-4 found?

Saliva of Gila Monster

What is exendin-4?

GLP-1 like molecule

What does exendin-4 have to do with GLP-1RA?

First GLP-1 receptor agonist developed for human use = EXENATIDE Synthetic version of exendin-4

How are GLP-1 molecules modified to avoid breakdown by DPP4?

Albumin and fatty acid chains (C18) are added

How did they create a GLP-1RA able to be ingested orally?

SNAC is a FA derivate By facilitating absorption in the stomach, SNAC enables the GLP-1RA to reach the bloodstream when taken orally SNAC raises the pH in the stomach, creating a less acidic environment that protects the GLP-1RA from being broken down by stomach enzymes.

What are the overall effects of GLP-1RAs?

Act directly on GLP-1R Promote insulin secretion in glucose-dependent mechanism Lowers glucagon (which is increased in T2D) Acts in hypothalamus to reduce appeitte Acts in intestine to reduce gastric emptying IMPROVES KIDNEY FUNCTION

How do GLP-1RAs act on HbA1c reduction, weight loss and CV?

Potent = reducing HbA1c 11-15mmol/mol WEight loss = 2-3kg on average Decreased systolic blood pressure; increased heart rate

Issues and side effects of GLP-1RAs?

Expensive Nausea and vomiting Small increase in risk of gallstones Sustained increase in pancreatic lipase and amylase

What is tirzepatide?

Dual GLP-1 and GIP receptor agonist