Lecture 8 Flashcards
1
Q
What does postprandial mean?
A
After eating a meal
2
Q
What effects does insulin have on postprandial glucose control?
A
- Stimulates glucose uptake and storage into adipose and liver tissue - Stimulates glucose uptake into muscles
3
Q
What are the mechanisms of postprandial glucose control that are insulin-independent?
A
- Delaying the delivery of carbohydrates to the small intestine by inhibiting gastric emptying - Inhibition of hepatic gluconeogenesis by suppression of glucagon secretion
4
Q
What drives the majority of insulin release from beta cells?
A
- GI hormones (incretins) drive this - E.g GLP-1, GIP
5
Q
What can be used as a readout for insulin secretion?
A
C-peptide levels
6
Q
Why is the C-peptide level measured instead of insulin levels?
A
C-peptide has a longer half-life so is more stable than insulin and can be measured more accurately
7
Q
What are some of the functions of C-peptide?
A
- Improves blood flow - Improves endothelial function - Improves nerve function - Improves kidney function - Improves heart function - Improves vision
8
Q
What do we believe the receptor for C-peptide to be?
A
A GPCR
9
Q
In healthy patients, how do the C-peptide levels differ between oral glucose stimulation and intravenous glucose stimulation?
A
- When they eat a chocolate bar (oral stimulation), their C peptide levels rise because the blood glucose levels rise (so insulin levels rise) - If you apply glucose stimulus directly to bloodstream, C peptide level rise is not as big - Differential effect here is called the incretin effect
10
Q
What is the incretin effect?
A
- Something is coming from the gut that adds to the stimulatory effect of insulin - Oral glucose stimulation leads to a higher production of insulin than intravenous stimulation
11
Q
In T2DM, how do the C peptide levels differ between oral glucose stimulation and intravenous glucose stimulation?
A
- Still an intravenous response to glucose stimulus - The incretin effect from GI tract is very much diminished
12
Q
What is GLP-1? Where is it produced?
A
- GLP-1 = Glucagon-like peptide (GLP-1) - Produced through tissue-specific processing of the glucagon prohormone - Production in ‘L-cells’ of the small/large intestines - Similarity to taste receptor signalling
13
Q
What are the effects of GLP-1 in the brain?
A
- GLP-1 receptors are expressed in particular neurons of brain in region that has a primary focus in regulating food intake - Also has important role in neural stimulation of gut motility and stomach emptying
14
Q
What are the effects of GLP-1 in the pancreas?
A
- Tropic function in pancreas: - Increased insulin secretion - Decreased glucagon secretion - Trophic function in pancreas: - Stimulates increase in beta-cell mass
15
Q
Give an example of a GLP-1 receptor agonist
A
Ozempic - Suppresses appetite
16
Q
What can we see by staining different regions of enteroendocrine cells with antibodies?
A
- See intracellular separation of GLP-1-containing vesicles from the receptor signalling complex - Have GLP-1 producing cells within mucosal layer of intestine - Graphs show separation of signalling within the cell - See enteroendocrine cells stained with antibody that is targeted against part of receptor signalling complex (RSC) - See that this RSC is localised to one side of the cell - See vesicles containing GLP-1 being stained by antibody on the other side of the cell - Put the 2 together and see intracellular separation of vesicles from RSC
17
Q
How are glucagon and GLP-1 produced?
A
- Pre-pro-hormone contains glucagon and GLP-1 - Pre-pro-hormone is cleaved in the ER to form pro-glucagon - Tissue-specific expression of convertase enzymes responsible for this processing determines whether proglucagon converts to glucagon or GLP-1 - In alpha cells of pancreas, Psck2 convertase enzyme is dominant and pushes processing to glucagon - In brain and intestines, Psck1/3 convertase enzymes are dominant and pushes processing to GLP-1
18
Q
How do glucagon and GLP-1 differ?
A
- Both regulate glucose homeostasis but through different mechanisms - Glucagon is released from pancreatic alpha cells, binds to GPCR on muscle/liver - GLP-1 is released from L-cells in intestine, stimulates insulin secretion from pancreatic beta cells
19
Q
What are some of the additional effects of GLP-1?
A
- Prevents apoptosis within beta cells - Beneficial effects on lungs and kidneys and cardiovascular system
20
Q
What is DPP-4 and what does it do?
A
Enzyme that degrades GLP-1
21
Q
How can the beneficial effects of GLP-1 be promoted?
A
- Can inhibit DPP-4 to prevent GLP-1 degradation - DPP-4 inhibitors = gliptins, exanatide etc
22
Q
Where is GLP-2 produced and what are its functions?
A
- GLP-2 = produced from L cells - Has an effect on insulin secretion - Trophic role = regeneration of mucosal epithelium within GI tract
23
Q
What is GIP? Where is it produced and what does it do?
A
- GIP = gastric inhibitory peptide - It is an incretin so is important in stimulating insulin secretion - Secreted from K-cells in the proximal intestine/duodenum - Inhibits motility and H+ secretion in stomach
24
Q
What effect does DPP-4 have on GIP?
A
- GIP gets converted from agonist to antagonist by DPP-4 - Forms truncated form of GIP that can still bind to its receptor but cannot stimulate/activate it and cause downstream signalling
25
Why might we modify GIP?
- Aim = to prolong GIP half-life (make it more stable) or inhibit GIP breakdown
26
How can GIP be modified?
- Can modify the structure of GIP to make it make stable - E.g can amidate the C terminal end - Makes GIP more stable/longer half-life
27
What are the benefits of using synthetic GIP?
Can make synthetic GIP analogues that act as super agonists --> really good at binding the receptors and promote the effects of GIP
28
How did we use mice to look at the involvement of GIP in obesity?
- If you feed wild-type mouse with high fat diet, mouse gets fat - White areas = visceral fat - If you take mutant mouse with mutation in GIP receptor (no longer recognises GIP) and feed this mouse with a high fat diet, they don't get fat anymore - Idea that maybe we can develop GIP antagonists as an anti-obesity treatment as lack of/block of GIP receptors seems to prevent obesity
29
What is Grehlin? What is it produced by?
- 28AA peptide from the stomach - Also secreted from a group of neurones called the arcuate nucleus in the hypothalamus - Called the 'feed me' hormone - It is orexigenic (stimulates hunger/food intake) - Counter-part of leptin
30
When is Grehlin released and what effect does this have?
- As stomach shrinks, Grehlin = released and travels by blood or vagus nerve to neurones in hypothalamus - Binds to receptor on Mp1 neurones and activates the neurone response - Stimulates appetite and increased food intake
31
How is the structure of Grehlin different to other peptide hormones?
- Modification of peptide --> octanoic acid on Ser3 - Determines its interactions with cell membranes and its receptor
32
When are Grehlin levels high?
Levels in circulation increase during fasting
33
When are Grehlin levels low?
Grehlin levels are low after eating and in people with obesity
34
What are the functions of Grehlin?
- Stimulates GH secretion - Increases food intake - Produces weight gain - Stimulates gastric contraction - Enhances stomach emptying
35
What are the main sources of Grehlin?
- Gastric fundus - Intestine - Pancreas (ε-cells) - Hypothalamus and pituitary - Kidney - Placenta
36
In which cells is Grehlin produced in humans?
P/D1 cells
37
In which cells is Grehlin produced in rats?
X/A cells
38
What are the 2 conformations of Grehlin-producing cells and where are they found?
- Open type on lumen - Closed type --> proximity to capillary network
39
How is Grehlin able to reach its target in the brain even though it can't cross the blood brain barrier (BBB)? How was this studied?
- Grehlin has major target in the brain but can't cross the BBB - Not sure how it gets to these neural targets - One idea = released from gut, enters vagus nerve and somehow travels up to the brain - Ligature: - If you ligate the vagal nerve in mouse, you will affect food intake and feeding behaviour - Not sure if it's because you are ligaturing the vagal nerve or preventing Grehlin from travelling up the vagal nerve
40
What effect does Grehlin have in the brain? How is this balanced?
- Grehlin from the stomach acts on the vagus nerve - Grehlin activates neurons in arcuate nucleus of hypothalamus - Regulates feeding - This effect is balanced by leptin
41
What effect does bariatric surgery have on Grehlin?
- Reduction in stomach size - Decrease in availability of Grehlin for release and in circulating Grehlin --> reduction of appetite
42
What effect does bariatric surgery have on GLP-1?
Increased GLP-1 --> increase insulin secretion, but faster delivery of nutrients to ileum
43
What is cholecystokinin (CCK)? What is it secreted by?
- Peptide hormone produced by I-cells in the small intestine - Secreted post-prandially - Several forms of CCK ranging in size from CCK-8 to CCK-58 - All produced from a single gene by post-translational processing of a pre-pro-hormone - All have similar biological activities
44
What does CCK bind to?
Binds to CCK-1 receptor on tissues in GI tract
45
What are the tissue-specific effects of CCK?
- Gallbladder --> stimulates contraction - Pancreas --> stimulates pancreatic secretion - Stomach smooth muscle --> regulates gastric emptying - Peripheral nerves --> regulates bowel motility - D-cells in stomach --> inhibits gastric acid secretion
46
What do the effects of Grehlin coordinate?
Coordinate ingestion, digestion and absorption of dietary nutrients
47
What are some of the major stimulators of CCK (and Grehlin) release?
- Ingested fat - Ingested protein
48
What is motilin? What is it secreted by and when?
- 22AA peptide hormone - Secreted from the M-cells of the duodenum - Secretion is NOT induced by eating - Synchronised with interdigestive migrating motor complex (MMC) under fasting conditions
49
Where does motilin bind and what are its effects?
- Motilin binds to specific receptors on smooth muscle cells of the oesophagus, stomach, intestines (small and large) - Enhances GI propulsion
50
What condition is motilin involved in?
IBS
51
What is secretin? Where is it secreted from and when?
- Peptide hormone
- Secreted by S-cells of the duodenum
- Secreted in response to low pH in duodenum to promote bicarbonate secretion by pancreas to neutralise acidic chyme
52
How does secretin function in a feedback loop?
- Secretin release is stimulated by gastric acid in the duodenum
- Stimulates bicarbonate secretion from pancreas to neutralise the acid
- Also inhibits acid secretion from the stomach (negative feedback loop)
53
What is somatostatin? Where is it secreted from?
- Peptide hormone secreted by D-cells in the GI tract, pancreas, and hypothalamus
- Inhibits secretion of other hormones like insulin, glucagon, and gastrin
54
What is the function of somatostatin in the GI tract?
Inhibits gastric acid secretion, slows gastric emptying, and reduces motility in the GI tract
55
What are the effects of somatostatin on pancreatic hormones?
- Inhibits insulin and glucagon secretion from the pancreas
56
What is the role of pancreatic polypeptide (PP)?
Secreted by F-cells in the pancreas, regulates appetite and digestion
57
Where is pancreatic polypeptide (PP) secreted from?
From the F-cells of the pancreas
