Gut Hormones (7-8) Flashcards
What are some features of gut hormones?
→ all peptide hormones
→ many found elsewhere (e.g. brain)
→ act in both paracrine and endocrine fashion
What are some hormones of the upper gut/stomach?
Ghrelin → hunger, growth hormone releasing
Gastrin → acid secretion
What are some hormones of the middle gut/duodenum?
Secretin → pancreatic exocrine secretion
GIP → incretin activity
Motilin → gastrointestinal motility
What is the gross anatomy of the GI tract?
GI = gastrointestinal
→ a long continuous muscular digestive tube
involved in: ingestion, propulsion, mechanical digestion, chemical digestion, absorption, defecation
What are some functional considerations of the GI tract?
→ substances in the GI tract lumen are outside of the body
→ multiple sensors and receptors line the GI tract to monitor contents and respond to conditions
→ controls: intrinsic (local control) and extrinsic (CNS)
What are the four tunics of the GI tract?
Mucosa → epithelium, lamina propria, muscular mucosae
Submucosa → glands, receptors
Muscularis externa → longitudinal muscle, circular muscle
Serosa → epithelium, connective tissue
Does the innermost mucosa differ throughout the GI tract?
The histology/morphology is slightly different throughout
→ oesophagus, stomach, small intestine, large intestine differ - functional diversity
→ same tunics are there
→ e.g. small intestine - more absorpative
Where are the endocrine cells found?
Gastric pits in the stomach lining
→ gastric pits lead to gastric glands
Cells in gastric gland change as you go down
→ mucous cells, parietal cells, chief cells and enteroendocrine cells
What is the function of parietal cells?
Produce HCL
→ maintain acidic environment for proper digestion and nutrient absorption
→ controlled by enteroendocrine cells
→ acidity changes biology of Na H+ pumps
What is the function of chief cells?
Role in secreting enzyme pepsinogen
→ becomes active form pepsin in acidic environment
What is the function of enteroendocrine cells?
Paracrine
Neuronal → afferent vagal, splanchnic and enteric nerves
Endocrine → enters blood
Regulates digestive and metabolic functions, appetite and energy homeostasis
What are 7TM chemosenesors?
G-protein couples receptors found on entero-endocrine cells in the GI tract
→ have 7 transmembrane domains
→ involved in detecting luminal contents - nutrients, metabolites etc
e.g. short chain fatty acids → GPR41
proteolytic products → GPR93
bile acids → GPR131
activation causes release of GI-tract hormones
What are G-cell endocrine cells?
Type of endocrine cell found in stomach responsible for releasing gastrin
Food enters stomach
→ signals in pit to G cell
→ G cells sense increase Ca2+
→ release gastrin
→ gastrin regulates parietal cells
→ release of HCl
regulate gastric acid secretion and maintaining digestive function
How does gastrin work?
Controls acid secretion directly → via CCK receptors on parietal cells
Control acid secretion indirectly → through inducing histamine containing ECL cells
Regulated by pH and somatostatin
Also drives mucosal growth and effects gastric motility
What signals to parietal cells?
Parietal cells have many signals - lots of things controlling them
→ direct from gastrin
→ histamine from ECL
→ neural input
→ feedback via somatostatin from D cells
How is the movement of membrane and vesicles regulated in parietal cells?
Primarily driven by the action of proton pumps and transporters in the cell membrane
Proton pump → H+ out of cytoplasm, K+ into cytoplasm contributing to the acidic environment
Chloride ions → Cl out of cytoplasm into stomach lumen following gradient established by proton pumps
Fusion of vesicles leads to secretion of HCl
Regulated by hormones like gastrin, somatostatin and histamine
What are proton pump inhibitors?
Used for indigestion, peptic uncles and increased acid secretion
e.g. omeprazole
massive industry
How do parietal cells regulate vitamin B12 absorption?
Parietal cells secrete intrinsic factor
→ glycoprotein hormone required for vitamin B12 absorption in the ilium
Loss of parietal cells can lead to pernicious anaemia (changes avg volume of RBC)
How is gastrin synthesised?
Gastrin gene transcribed and translated in G cell nucleus - forms preprogastrin (precursor of gastrin)
Preprogastrin undergoes post-translational modifications as it moves through ER → signal peptide removed forming progastrin
Further processing produces mature gastrin peptides - gastrin34gly, gastrin34, gastrin17
Stored in secretory vesicles in G cells
Metabolised by kidney, intestine and liver
How is somatostatin regulated in the stomach?
Low gastric pH stimulates delta cells (found in antrum where they are open to the lumen) that secrete somatostatin and inhibit gastrin release
Also influenced by
→ mechanical stimulation
→ dietary components of a meal
→ other hormones and neurotransmitters
What are the functions of somatostatin?
In the gut somatostatin has broad inhibitory action
→ reduces gastric acid production
→ reduces pepsinogen secretion (form chief cells)
→ inhibits pancreatic enzyme, fluid and bicarbonate secretion
→ reduces bile flow
→ inhibits gut motility
→ reduces intestinal transport of nutrients and fluid
→ inhibits tissue growth and proliferation
What is Zollinger-Ellison syndrome?
Gastrin secreting tumours in the pancreas/duodenum
→ excessive secretion of gastrin - stimulates stomach acid production
→ results in severe peptic ulcers
How is glucose controlled after a meal?
Stimulation of insulin secretion from pancreatic beta cells
Inhibition of hepatic gluconeogenesis by suppression of glucagon secretion
Delaying delivery of carbohydrates to the small intestine by inhibiting gastric emptying
What is the entero-insular axis?
The communication pathway between the entero-endocrine cells in the GI tract and the pancreas
→ allows for coordinated regulation insulin and glucagon secretion in response to changing nutrient availability
→ 50% of insulin release driven by GI hormones called incretins e.g. GLP-1, GIP
What are incretins?
Hormones produced by the GI tract in response to ingestion of food
→ play a crucial role in regulating glucose metabolism by stimulating insulin
GLP-1 (glucagon like peptide) → stimulates insulin secretion from pancreatic beta cells, inhibits glucagon secretion, delaying gastric emptying
GIP (gastric inhibitory peptide) → stimulates insulin secretion from pancreatic beta cells in response to elevated blood glucose, promotes fat storage in adipose tissue
What is the structure of insulin?
2 chains → A and B, linked with disulphide bonds
Intermediate C-peptide → cleaved to make insulin correctly, clean C peptide can assume insulin made right
What is the incretin effect?
Oral ingestion of nutrients results in a greater stimulation of insulin secretion compared to intravenous - with the same amount of nutrients
→ attributed to the action of incretin hormones like GLP-1 and GIP which stimulate insulin secretion from pancreatic beta cells when glucose levels are high
→ significant role in glucose homeostasis
How are glucagon and GLP-1 made from the same pro hormone?
Glucagon and GLP-1 are made from the same gene and pre protein but have opposite actions
→ tissue specific processing of glucagon pro hormone allows for this
alpha cells → glucagon, pancreas
→ released from pancreas, binds G protein-coupled receptors in skeletal muscle and liver, exerting its glucoregulatory effect
L cells → GLP-1, small intestine
→ stimulates insulin secretion and augments the insulin-releasing effects of glucose on the pancreatic beta cells
What are the outputs of GLP-1?
Pancreas → stimulates insulin secretion (tropic)
→ promotes beta-cell mass increase (trophic - driving mitosis)
→ inhibits alpha-cell glucagon secretion
Nervous system → slows down gastric motility/stomach emptying
How does the glucagon gene undergo tissue specific processing?
Preproglucagon undergoes tissue specific processing depending on where its expressed, due to different prohormone convertases present, for example;
Pancreatic alpha cells → preproglucagon mRNA is processed into proglucagon which is cleaved by Psck2 to produce glucagon
Intestinal L cells → preproglucagon processed into different peptides, Psck1/3 cleaved proglucagon into smaller peptides including GLP-1, GLP-2
Overall ensures the actions of glucagon and its derivatives are tailored to the specific metabolic needs of the different tissues
What is the role of DPP-4 enzyme?
Incretin degrader → particularly inactivates GLP-1 and GIP, rapidly cleaves aa on their N-terminus
→ reducing their ability to induce insulin secretion
Potential therapeutic target with DPP-4 inhibitors → inhibit DPP-4 to promotes incretin effect in diabetes
What are the actions of GLP-2?
Secreted by gut endocrine L cells
→ promotes intestinal growth
→ mucus proliferation
→ maintaining integrity of the intestinal barrier
→ contributes to intestinal motility
What are the roles of GIP?
GIP (gastric inhibitory peptide) is secreted by enteroendocrine K cells proximal intestine/duodenum
→ stimulates insulin secretion from pancreatic beta cells (incretin hormone)
→ inhibits motility and secretion of H+ stomach secretion
What is the potential therapeutic target for type 2 diabetes involving GIP?
DPP IV resistant stable GIP agonists
→ enzyme resistant analogues (with additional amine group to prolong half life) of GIP possessing enhanced agonist activity
→ increase insulin secretion, beta cell mass and glucose-responsiveness
What is ghrelin?
28aa peptide hormone released by the stomach
→ stimulates hunger
→ binds to neurones in hypothalamus to stimulate feelings of hunger
→ as stomach emptying (fasting) ghrelin levels rise - driving appetite
Also plays a role in regulating growth hormone release from anterior pituitary
What structure of ghrelin determines its interaction with membrane and receptors?
Octanoic acid on Ser3
→ anchors to membrane - how it attaches to receptors
How does ghrelin reach its receptor in the brain?
Not good at crossing the blood brain barrier
→ to moves to brain via vagal nerve
→ ghrelin activates NPY and agouti-related protein-producing neurones in the arcuate nucleus of the hypothalamus - involved in regulation of feeding (balanced by leptin)
How can surgery reduce appetite?
Bariatic surgery like proximal gastric bypass surgery (gastric band) or sleeve gastrectomy can reduce circulating ghrelin
→ leading to a reduction in appetite
What is cholecystokinin?
Peptide hormone produced by )-cells of the small intestine
→ secreted into blood following ingestion of a meal
→ forms of CCK ranging in size from 58 to 8 have similar biological activities
→ all forms produced from a a single gene by post-translational processing of a pre-pro-hormone
What are the effects of cholecystokinin?
CCK binds specific CCK1 receptors
Gallbladder → stimulates gallbladder contraction
Pancreas → pancreatic secretion
Smooth muscle of the stomach → regulates gastric emptying
Peripheral nerves → bowel motility
CCK induces satiety (works against ghrelin)
Inhibits gastric secretion → binding to CCK receptors on somatostatin
→ coordinate ingestion, digestion and absorption of dietary nutrients
What is motilin?
22aa peptide hormone produced by M-cells of the duodenum
→ secretion not induced by eating
→ synchronised with inter digestive migrating motor complex under fasting conditions
What is the effect of motilin?
Binds specific receptors on smooth muscle cells of the oesophagus, stomach and intestines to enhance propulsive activity
→ erythromycin and related antibodies act as non-peptide motlilin agonists
