Gastrointestinal endocrinology Flashcards
What is the role of the GI tract as an endocrine organ (4)
- GI Tract initially seen as only responsible for digestion and nutrient absorption.
- Produces hormones and regulatory peptides.
- Communicates with the brain, pancreas, liver, and adipose tissue to regulate metabolism and appetite.
- Helps maintain homeostasis.
What are the major mechanisms that regulate and control digestive activities (3)
- Local factors
- Neural control mechanisms
- Hormonal control mechanisms
What are local factors (2)
- the primary stimulus for digestive activities
- changes pH, contents of the lumen wall or presence of chemicals/chemical messengers released by the cells of the mucosa
What is the neural control mechanism (6)
- Movement and secretory functions are controlled by local factors
- Short reflexes are triggered by stretch chemoreceptors.
- The controlling neurons of short reflexes are in the myenteric plexus. Reflexes are called myenteric reflexes
- Long reflexes involve interneurons and motor neurons in the CNS
- Long reflexes provide a higher level of control over digestive and glandular activities, controlling the large-scale peristatic waves that move from one region of the digestive tract to another.
- Long reflexes may involve parasympathetic motor fibres in the glossopharyngeal, vagus or pelvic nerves that synapse in the myenteric plexus.
What are the hormonal control mechanisms (4)
- The GI produces at least 18 hormones that affect almost every aspect of digestive function
- The hormones affecting digestive function are peptides produced by the enteroendocrine cells (endocrine cells in the epithelium of the digestive tract).
- Local factors → secretory cells → buffers, acids, enzymes released
- Local factors → enteroendocrine cells→ Hormones released (via bloodstream) → secretory cells → buffers, acids, enzymes released
What GI hormones does the stomach produce (4)
- Ghrelin
- Gastrin
- Somatostatin (via enterochromaffin-like cells (ECL cells))
- Histamine
What GI hormones does the small intestine (duodenum & jejunum) produce (6)
- CCK (cholecystokinin)
- secretin
- GIP
- motilin
- ghrelin
- Gastrin
What GI hormones does the pancreas produce (4)
- Insulin
- Glucagon
- Pancreatic polypeptide
- Amylin
What GI hormones does the large intestine (colon) produce (4)
- GLP-1
- GLP-2
- Oxyntomodulin
- PYY3-36
What are enterochromaffin-like (ECL) cells
an enteroendocrine cell subtype
What are the functions of CCK (cholecystokinin) (6)
- gall bladder contraction
- gastrointestinal motility
- Pancreatic exocrine secretion: lipases, amylase, and proteases
- Trophic effects on the exocrine pancreas and gallbladder
- Secretion of bicarbonate from the pancreas
- Inhibits gastric emptying
What is the function of secretin (5)
- pancreatic exocrine secretion
- Inhibits gastrin, and growth of stomach mucosa
- Stimulates biliary secretion of bicarbonate and fluid
- Secretion of bicarbonate from the pancreas
- Trophic effect on the exocrine pancreas
What is the function of GIP (7)
- Incretin activity
- Stimulation of insulin secretion
- Induces satiety
- In large doses, decreases gastric acid secretion
- In large doses, decreases the motor activity of the stomach and therefore slows gastric emptying when the upper small intestine is already full of food products.
- Stimulates the activity of lipoprotein lipase in adipocytes
- Protects beta-cells of the pancreas from destruction by apoptosis
What is the function of motilin
Gastrointestinal motility
What are the functions of ghrelin (2)
- hunger
- growth hormone release
What is the function of gastrin
acid secretion
What is the function of insulin and glucagon
glucose homeostasis
What are the functions of pancreatic polypeptides (2)
- Gastric motility
- Satiation (thesatisfied feeling of being full after eating)
What are the functions of amylin (2)
- glucose homeostasis
- gastric motility
What are the functions of GLP-1 (5)
- Incretin activity
- Decreases gastric emptying
- Satiation (thesatisfied feeling of being full after eating)
- Increases sensitivity of pancreatic beta-cells to glucose.
- GLP-1 agonists use for diabetes and weight loss (dulaglutide, exenatide, liraglutide, lixisenatide, semaglutide
What are the functions of GLP-2 (2)
- gastrointestinal growth
- gastrointestinal motility
What are the functions of oxyntomodulin (2)
- satiation (thesatisfied feeling of being full after eating)
- acid secretion
What is the function of PYY3-36
satiation (thesatisfied feeling of being full after eating)
What are enteroendocrine cells (EECs) (2)
- Specialised cells that secrete numerous hormones in the GI tract
- These cells are dispersed along the GI tract and respond to luminal contents like nutrients, pH changes, and mechanical stimuli.
What are the gut-brain axis regulators (7)
- Diet
- Delivery method
- Medication
- Environment
- Social interaction
- Genetics
- Sex differences
What are the causes of lipogenesis and lipolysis (2)
- Lipogenesis - energy intake (carbohydrates, lipids, proteins)
- Lipolysis - energy expenditure (BMR, physical activity, thermogenesis)
What causes GI hormone release (2)
- The release of GI hormones is in response to input from G-protein-coupled receptors that detect changes in luminal contents.
- Some of these receptors only respond to selective luminal substances and subsequently release GI hormones from their respective enteroendocrine cells through unknown mechanisms.
What diverse set of actions in the body do gastrointestinal hormones manage (5)
- Contraction and relaxation of smooth muscle wall and sphincters
- Secretion of enzymes for digestion
- Secretion of fluid and electrolytes
- Trophic (growth) effects on tissues of GI tract
- Regulating secretion of other GI peptides (i.e., somatostatin inhibits secretion of all GI hormones)
What are GI hormones composed of
Gastrointestinal hormones are composed of polypeptides that can divide into two structurally homologous families that include the hormones responsible for a majority of regulation of GI function.
How is the first GI hormone family described (2)
- The first hormone family consists of gastrin and CCK because both hormones share an identical 5 C-terminal amino acid sequence, also known as “pentagastrin.”
- The pentagastrin sequence includes the tetrapeptide that is minimally required for gastrin activity but is only about one-sixth as potent as the entire 17-amino acid gastrin peptide.
How is the structure of gastrin described (4)
- 5 C-terminal amino acid sequence, also known as “pentagastrin.”
- The pentagastrin sequence includes the tetrapeptide that is minimally required for gastrin activity but is only about one-sixth as potent as the entire 17-amino acid gastrin peptide.
- Gastrin also exists in a 34-amino acid form called “big” gastrin which gets secreted during the inter-digestive period. During meal ingestion, the 17-amino acid form of gastrin, also called “little” gastrin, is secreted.
- Although each form of gastrin has its own distinct biosynthetic pathway, the mediation of the action of both gastrin peptides is via binding of cholecystokinin (CCK-2) receptors.
How is the second GI hormone family described (2)
- The second hormone family consists of secretin, glucagon, GLP-1, and GIP.
- In contrast with the gastrin-CCK family, all amino acids in the polypeptide are necessary for biological activity, and these two polypeptides only share 14 common amino acids.
How is the structure of secretin described (2)
- Secretin has 27 amino acids
- structurally similar to glucagon, which has 29 amino acids.
How is the structure of glucagon described (4)
- Glucagon derives from a 180-amino acid precursor peptide called proglucagon
- proglucagon undergoes tissue-specific post-translation processing to produce different peptides in different cell types.
- Proglucagon is cleaved to form glucagon in the pancreas
- in the intestines, proglucagon undergoes processing to produce a 30-amino acid peptide called GLP-1.
How is the structure of GIP described (3)
- GIP is 42 amino acids long
- shares 9 amino acids with secretin
- shares 16 amino acids with glucagon.
What is the role of gastrin and how does it work (4)
- Gastrin controls acid release within the stomach.
- The main site of gastrin production is within G cells (via exocytosis) of the gastric antrum.
- Exocytosis is positively regulated by gastrin-releasing peptide which is expressed within neuronal fibres in the stomach, whilst somatostatin, produced by D cells in response to luminal acid, inhibits gastrin release from G cells
- Following release into the circulation, gastrin acts on enterochromaffin-like (ECL) cells in the gastric corpus/fundus stimulating release of histamine which in turn binds to H2 receptors and stimulates acid secretion by parietal cells.
What is the primary stimulus for gastrin secretion (3)
- The presence of certain foodstuffs
- Especially peptides, certain amino acids and calcium, in the gastric lumen.
- Compounds in coffee, wine and beer are potent stimulants for gastrin secretion.
What inhibits gastrin secretion
when the lumenal pH of the stomach becomes very low less than about 3.
What is the intestinal phase (3)
- Nutrients entering the small intestine stimulate hormones:
- CCK triggers bile secretion to emulsify fats and pancreatic enzymes to digest macronutrients.
- Secretin neutralises stomach acid by stimulating bicarbonate secretion from the pancreas
What is the postprandial phase
Hormones like GLP-1 and PYY help slow gastric emptying and reduce appetite to ensure efficient nutrient absorption.
What are the effects of gastrin on the pancreas, intestine, stomach, liver and gall bladder and other functions (6)
- pancreas - induces secretions
- intestine - facilitates the transport of food, Trophic (growth) effects on the mucosa
- stomach - stimulates HCl acid secretion by parietal cells, Trophic (growth) effects on the mucosa
- liver - aids in bile production
- gall bladder - emptying
- Inhibits the actions of Secretin and GIP
What does the protein in meals do (4)
- Protein in meals stimulates the G-cells to release gastrin into the blood.
- Gastrin stimulates the enterochromaffin-like (ECL) cells to release histamine. The histamine then stimulates acid-producing parietal cells.
- This is the gastrin–ECL axis, the main stimulatory pathway of gastric acid secretion.
- The over-production of acid is prevented by negative feedback inhibition by intragastric acidity as low antral pH inhibits gastrin release via somatostatin from D-cells.
What is involved in postprandial events upon gastric emptying (3)
- Stomach gastric emptying
- Activation of hormones: GLP, CCK, 5-HT
- Feedback control/pancreatic secretion control
How does CCK work (4)
- The other member of the gastrin family, CCK, is a 33-amino acid peptide that includes the pentagastrin sequence and the C-terminal tetrapeptide sequence necessary for minimal gastrin activity;
- This enables CCK to demonstrate activity on gastrin (CCK-2) receptors, although it mediates a very weak stimulation of gastric acid secretion.
- The minimally active fragment for CCK activity is its C-terminal heptapeptide, which acts on CCK-1 receptors to mediate gallbladder contraction.
- Gastrin can also act on the CCK-1 receptor, but each hormone is more potent at its own receptor than those of its homolog.
How do hormones regulate appetite (3)
- The gut communicates with the brain via hormones and the vagus nerve to regulate hunger and satiety:
- Ghrelin (hunger hormone): Levels increase before meals, signaling the brain to initiate food intake.
- PYY and GLP-1: Released after meals, signalling satiety to the hypothalamus.
What does postprandial motilin release depend on (3)
- the nutrient composition of the meal.
- Oral lipid intake markedly stimulates motilin secretion, for up to 60min after consumption.
- Gastric acid and bile are both secreted into theduodenumand are considered the two major physiological regulators formotilin release.
What cells produce gastrin
stomach G cells
What cells produce CCK (Cholecystokinin)
duodenum, jejunum I cells
What cells produce secretin
duodenum S cells
What cells produce motilin
small intestine M cells
What cells produce ghrelin
stomach (fundus)
What cells produce peptide YY (PYY)
ileum, colon L cells
What cells produce Glucagon-like peptide (GLP-1)
ileum, colon L cells
What cells produce somatostatin
stomach, pancreas D cells
What is the clinical relevance of GI hormones for pharmacy (4)
- Pharmacists play a key role in managing disorders related to GI hormones. Some therapeutic approaches include:
- Proton Pump Inhibitors (PPIs): Reduce acid secretion in hypergastrinemia.
- GLP-1 Receptor Agonists: Used in Type 2 diabetes and obesity to enhance insulin secretion and reduce appetite.
- Somatostatin Analogues: Manage hormone-secreting tumors, such as in Zollinger-Ellison syndrome.
What is Zollinger-Ellison Syndrome (3)
Excess gastrin secretion by gastrinomas → hyperacidity → peptic ulcers
What are the symptoms of Zollinger-Ellison Syndrome (3)
- Severe GERD
- abdominal pain
- chronic diarrhoea
What pharmacological management is there for Zollinger-Ellison Syndrome
Proton Pump Inhibitors (PPIs) (e.g., omeprazole, lansoprazole):
What is the mechanism of action for PPIs
Irreversibly inhibit H+/K+-ATPase in parietal cells to reduce acid secretion.
What are the side effects of PPIs (3)
- Headache
- diarrhoea
- risk of long-term hypocalcemia
What is the mechanism of action of somatostatin analogues (2)
- Inhibits gastrin secretion from tumours.
- Used in severe cases or metastatic disease.
What causes type 2 diabetes and GLP-1 dysfunction (4)
Reduced GLP-1 activity → impaired insulin secretion, hyperglycemia.
What pharmacological management is there for type 2 diabetes and GLP-1 dysfunction
GLP-1 Receptor Agonists (e.g., liraglutide, semaglutide):
What is the mechanism of action of GLP-1 Receptor Agonists
Mimic GLP-1 to enhance glucose-dependent insulin secretion
What are the benefits of GLP-1 Receptor Agonists (2)
- Weight loss
- reduced HbA1c
What are the side effects of GLP-1 Receptor Agonists (2)
- Nausea
- risk of pancreatitis
How does systemic gastrin arising from G-cells play a role in carcinogenesis (2)
- Systemic gastrin, arising from G-cell secretion may play a role in carcinogenesis in an endocrine manner (pre-clinical studies),
- or gastrin may be locally produced as a result of constitutive expression and secretion by cancer cells leading to paracrine or autocrine activity.
What causes hypergastrinemia (4)
- Systemic hypergastrinaemia may occur through the administration of proton pump inhibitorsor infection withHelicobacter pylori.
- Hypergastrinaemia resulting fromH. pylori infection is associated with the occurrence of gastricand colorectal adenocarcinoma.
- Administration of proton pump inhibitors has not been clearly linked to adenocarcinoma incidence in patients, in spite of the fact that they accelerate tumour progression in animal models
- This suggests that gastrin can promote adenocarcinoma formation but only in conjunction with other co-factors, such as a mutant cell phenotype or bacterial pathogenicity factors, or through synergising with inflammatory events associated withH. pylori infection.
What disorders Associated with GI Hormones (3)
- Hypergastrinemia: Excess gastrin secretion, often seen in Zollinger-Ellison syndrome, causes increased gastric acid and peptic ulcers.
- Malabsorption Syndromes: Disruption in secretin or CCK secretion can impair digestion.
- Obesity and Diabetes: Dysregulation of hormones like ghrelin, GLP-1, and PYY contributes to abnormal appetite and glucose metabolism.
What do parietal cells do in relation to proton pumps (2)
- The parietal cells contain the H+/K+ATPase or “proton pumps” located in the canaliculus of the parietal cell and are responsible for the transport of acid (H+) into the stomach lumen.
- The main stimulants of acid secretion at the level of parietal cells are histamine, acetylcholine and, to a lesser extent, gastrin.
What are PPIs (5)
- PPIs are a class of medications that selectively and irreversibly inhibit the proton pump that accomplishes the final step in acid secretion.
- PPIs are weak bases and therefore accumulate in the acidic space, the secretory canaliculus, of parietal cells.
- After acid-induced activation PPIs covalently bind to the active proton pump (H+/K+-ATPase); the binding is achieved through the disulphide bond between the activated PPI and cysteines of the pump enzyme.
- This covalent binding enables the prolonged inhibition of acid secretion, even after the drug concentration in the blood has waned.
- The duration of the inhibitory activity is variable and affected by pump turnover and the loss of covalently bound PPIs.
What issues have arisen from long-term PPI use (7)
- While PPIs are effective and have a relatively desirable safety profile there is still uncertainty in regards to the safety of long-term, and often life-long, PPI therapy.
- increasing number of reports about adverse events due to long-term use and the implementation of PPI deprescribing to address these issues.
- PPIs are commonly continued long-term although the most common indications such as GERD and mild esophagitis are recommended for short-term use (e.g., eight weeks) to heal inflammation and resolute symptoms in management guidelines.
- Concerns about the appropriateness of their use and potential adverse effects that might stem from continuous PPI therapy have been growing
- There is also inappropriate prescribing of PPIs and in cross-sectional studies only approximately 30% of people were prescribed PPIs with appropriate indication concordant with guideline recommendations.
- PPIs’ clinical efficacy and that they are generally well tolerated is likely the reason for their overutilisation and inappropriate use but concerns regarding their long-term safety are increasing.
- PPI overuse (e.g., poor indication, excessive dose, excessive duration) contributes to polypharmacy and potential risk of drug interactions and side effects.
Why do we deprescribe PPIs (7)
- The aim of deprescribing PPIs in most cases is to reduce medication burden and potential adverse effects while maintaining quality of life.
- PPI deprescribing algorithms have been proposed and published in UK, Canada and Australia.
- Both recommend deprescribing of PPIs in adults who are symptom free after a minimum of four-week PPI therapy for GERD or upper GI-symptoms.
- However, deprescribing can be difficult, and there is no evidence-based method of stopping or reducing PPIs.
- Various different approaches to deprescribing have been outlined in prior trials and guidelines
- Long-term PPI therapy can be appropriate and where there is a clear indication the benefit outweighs potential risk.
- Patients with Barrett’s oesophagus (BE), severe esophagitis grade C or D, and a history of bleeding GI ulcer or bleeding risk with chronic NSAID use are recommended to continue PPIs or consult a gastroenterologist before discontinuation
What is the relationship between PPIs and the fracture risk (3)
- Some studies have shown an association between PPIs and the risk of fracture — particularly hip fracture — while others have not.
- Calcium is absorbed in the small intestine, not the stomach.
- But low stomach acid levels can have downstream effects, especially in the duodenum, and some research shows that one of them could be reduced absorption of calcium, which could lead to osteoporosis, weaker bones, and, consequently, a greater chance of breaking a bone.
What is the relationship between C. difficile risk and PPIs (3)
- People typically developClostridium difficile infections in the hospital after taking antibiotics that have disrupted the natural bacterial ecology of the large intestine.
- The infections cause diarrhoea but can also become a lot more serious, even life-threatening. Studies have shown a fairly strong statistical correlation between PPI use andC. difficile infection (correlation and not proof of direct cause and effect).
- Some experimental evidence suggests that PPIs may change conditions in the gut to be more favourable toC. difficile bacteria.
