The Pancreas Flashcards
(30 cards)
what is the function of the pancreas?
- Huge reserve capacity resection
- You can remove 95% of the pancreas and it still has enough functionality - Important in the digestion of nutrients, fats, proteins through production of enzymes
- Provides the appropriate environment for enzymatic digestion in the small bowel
- Produces bicarbonate – neutralise acidic chyme coming into the small intestine - Important in regulating the fed and fasted sates (insulin, glucagon)
what is the gross structure of the pancreas?
The Pancreas is divided into lobules - drain into ductular network (intercalated –> intralobular –> interlobular –> main pancreatic duct)
At its terminal point the Main Pancreatic duct joins with the common bile duct to form a swelling in the duodenal wall called the ampulla of Vater.
The muscular wall is thickened, forming the sphincter of Oddi.
Sphincter of Oddi regulates ductal flow into duodenum & prevents reflux
The contents of the main pancreatic duct and common bile duct empty into the into the descending part of the duodenum at the major duodenal papilla.
The major duodenal papilla marks the transition from the foregut to midgut – the point where the celiac trunk stops supply the gut and the superior mesenteric artery takes over.
Blockage of common bile at distal end where it is in close proximity to pancreatic duct can cause pancreatic disease e.g. pancreatitis.
what is the structure of the pancreas exocrine tissue?
Within the lobules of the pancreas reside the functional secretory units of the gland.
Each secretory unit is composed of an acinus and a small intercalated duct (composed of ductal cells)
The acinus represents a cluster of acinar cells that synthesize and secrete digestive enzymes, zymogens (inactive enzymes precursors) into the lumen of the intercalated duct. They also produce an isotonic, plasma-like fluid that accompanies the secretory proteins.
The products of acinar cells flow through various ducts. (intercalated -> intralobular -> interlobular -> main pancreatic duct).
what are the different pancreatic cell types? (4)
Acinar cells – specialised/polarised for production & export of proteins –> lots of: RER, mitochondria, secretory vesicles –> exocytosis at apical pole
Duct cells – form ductal tree
specialised for transport of electrolytes and production of bicarbonate ions to neutralise acidic chyme (contents of stomach coming into small intestine)
Centroacinar cells – very first cells of intercalated duct –> located at junction of pancreatic acinar & duct cells
Goblet cells – produce mucus for:
lubrication
hydration
mechanical protection of surface epithelia
Immunological role → binding of pathogens + interacting with immune-competent cells, preventing pancreatic infections
what happens when an acinar cell is in an unstimulated state?
In an unstimulated state acinar cells secrete low levels of digestive proteins via constitutive secretion pathway
what is stimulation of pancreatic cells mediated by?
Stimulation of these cells is predominately mediated via CCKA receptors & mAChRs located on basolateral cell membrane.
what are the receptors on pancreatic cells activated by?
Ach
Vagal stimulation results in Ach release
NOTE: ACh also stimulates parietal cell acid secretion. So the same acid is being producing the pancreatic acinar cells are being stimulated to produce zymogens (makes sense as making acid to digest food and then make enzymes to digest what you have consumed).
CCk
Come from specialised I cells in the lumen of small intestine.
When I cell comes into contact with fat (in the chyme) in the SI these cells are tiggered to produce CCK
CCK also stimulates gall bladder contraction to pump bile into small intestine (bile emulsifies fats to then allow lipase to do its job)
what pathway does ACh and CCK use to bind to the receptors?
what are the 2 other proteins and what pathway do they follow?
Phospholipase C (PLC/PKC)/Ca2+ signal transduction pathway, leading to increased enzyme (zymogen) secretion from the acinar cells.
You also have VIP & secretin which when bound to VIP and Secretin receptors on an Acinar Cell activate adenylyl cyclase –> production of cAMP –> activation of PKA –> stimulates acinar cells to secrete zymogen as well.
Therefore there are 4 molecules involved in activation.
what is the principle function of pancreatic duct cells?
Principal function: Secrete HCO3- (bicarbonate) rich fluid to alkalinise & hydrate protein-rich primary acinar secretions
This fluid is also important for enzymatic optimal pH, micelle formation & neutralising acidic chyme of stomach in SI.
how does the secretion of HCO3- out of pancreatic duct cells occur?
The secretion of HCO3- out of pancreatic duct cell occurs via Cl– HCO3- exchanger (need both chloride and bicarbonate)
Bicarbonate is produce from reactions of carbonic anhydrase: (see image)
Therefore, every time bicarbonate is produced a proton is also produced.
This proton effluxes via Na+-H+ exchange on basolateral surface of pancreatic duct cells (not into lumen)
So, these pancreatic duct cells efflux bicarbonate into the lumen of the duct which hydrates contents of the duct and neutralises the acidic chyme when it gets into small intestine.
where do the chloride ions involved in Cl– HCO3- exchanger come from?
The chloride ions come from a chloride channel known as CFTR
CFTR is a cAMP activated Cl- channel that is present on the apical membrane of pancreatic duct cells.
Cl- extruded from duct cells by Cystic Fibrosis Transmembrane Regulator (CFTR) into lumen of duct.
Cl- then cycles back into the cell via the Cl– HCO3- exchanger. This process is termed Cl- recycling.
what are the two major triggers for pancreatic duct cells?
Ach are secretin
what does secretin regulate in the pancreatic duct cell?
Secretin is the most powerful stimulus for secretion of HCO3- from pancreatic duct cells.
Secretin comes from S cell (in small intestine).
When S cell comes into contact with acid chyme of stomach it bathes the S cells which causes then to make secretin. (Thus levels increase in fed state)
Activation of the secretin receptor on the duct cell stimulates adenylyl cyclase, which raises [cAMP] and triggers PKA ultimately stimulating the apical CFTR Cl- channel and the basolateral Na/HCO3- cotransporter
Secretin stimulates HCO3- release to neutralise acidic chyme (which was original trigger).
what does ACh regulate in the pancreatic duct cell?
ACh regulates HCO3- secretion by controlling the CFTR channel
Ach binds to muscarinic receptors on the duct cell causes increased [Ca2+]i and activation of Ca2+ -dependent protein kinases (i.e PKC) in pancreatic duct cells.
how is cystic fibrosis caused?
Disease results from mutations to gene for CFTR channel –> channel prematurely degraded –> disrupts apical transport of duct cell –> decreased secretion of HCO3- & water by ducts
Lack of water results in blockage of the ducts by the acinar cells thick secretions because they are not diluted.
This will eventually result in pancreatic tissue destruction (enzymes auto digest the pancreas)
This may result in diabetes (due to destruction of pancreas)
Also, subsequent deficiency of pancreatic enzymes leads to maldigestion of nutrients - i.e. steatorrhoea (excess fat in stool)
what is the composition and function of pancreatic secretion?
Product of acinar, duct and goblet cells result in secretion of a pancreatic juice (Protein-Rich alkaline fluid)
The pancreas exhibits the highest rates of protein synthesis and secretion of any organ in the body.
Producing 1.5l of pancreatic fluid each day containing 5-15g of protein.
The pancreas secretes over 20 proteins, most of which are either inactive zymogens (e.g trypsinogen,chymotrypsinogen, proelastase, procarboxypeptidase A, procarboxypeptidase B ) or active digestive enzymes (e.g Lipase and co-lipase).
what is the rate of pancreatic secretion dependent on?
dependent on whether you are fed of fasted
This process is tightly interlinked with biliary/gastric secretions and intestinal motility.
When you are in the fasted state you do not have Ach mediated stimulation of either acinar cells or duct cells –> low level release of pancreatic enzymes and bicarbonate
In fed state pancreas is stimulated to produce bicarbonate and pancreatic enzymes.
fed/absorptive state – release massively increases 5-20x basal levels
what does the composition of pancreatic fluid alters with?
The composition of pancreatic fluid alters with stimulation
Fasted state – higher chloride ions in the duct as they are not being internalised and relatively low bicarbonate ions.
Fed State: As soon the pancreas is stimulated the amount of bicarbonate in the duct increases and chloride ions become intracellular/
Na+ and Potassium ions remain about the same.
Left: fasted state – trypsin marker of pancreatic secretion. – low level in fasted but as soon as you eat it is higher.
what is Cholecystokinin (CCK) and what is it stimulated by?
how does this change in different states?
CCK is released from duodenal I-cells –> it stimulates pancreatic acinar cells to increase protein secretion.
CCK release increases within minutes of a fatty meal –> likely due to CCKA receptor (direct) or indirectly via paraNS
CCK secretion also stimulated by CCK-releasing factors i.e. LCRF (luminal CCK releasing factor).
These are endogenously produced proteins secreted into gut lumen and which stimulate CCK.
Fasting state: LCRFs degraded by digestive enzymes –> no CCK stimulation
Fed state: digestive enzymes act on chyme & LCRFs stimulate I-cell to release CCK and pancreatic secretion.
name and explain the role of a particular pancreatic secretion inhibitor?
Somatostatin from D-cells in the pancreatic islets of Langerhans inhibit release of secretin (stimulates duct cell) & CCK (which stimulates acinar cell) and insulin & glucagon.
Pancreatic somatostatin is in the form of S-14.
Analogues of somatostatin (i.e. octreotide – longer T1/2) used clinically to inhibit pancreatic secretions (i.e. for pancreatitis)
what is the first phase of secretion?
describe what happens
Cephalic (25% of all pancreatic secretions):
Stimuli: sight, smell, taste of food
Mediated by stimulation of ACh receptors on acinar & (lesser extent) duct cells (no CCK or secretin involvement)
what is the second phase of secretion?
describe what happens
Gastric (10-20%) – secretion elicited by:
Release of gastrin from antral G-cells (stimulated by luminal peptides/AAs) –> signals through CCK receptor (gastrin = weak CCK agonist) –> stimulates pancreatic acinar cells to produce some digestive enzymes.
Stimulating neural pathways: Gastric distension stimulates low level pancreatic secretion via Vagovagal gastropancreatic reflex
what is the third phase of secretion?
what are the 3 mechanisms?
Intestinal (50-80%) – chyme entering proximal SI stimulates pancreatic secretion by three major mechanisms:
Gastric acid stimulates duodenal S-cells to release secretin which stimulates duct cells to secrete HCO3- and fluid
Lipid (monoglycerides/FFA) predominately stimulate duodenal I-cells to release CCK which stimulates acinar cells to release digestive enzymes.
CCK also stimulates Gal bladder contraction.
lipids also activate Vagovagal enteropancreatic reflex that predominantly stimulates acinar cells via M3 receptor.
Patterns of pancreatic enzymatic secretion is going to depend on the relative composition of the chyme (e.g. high carb vs fats)
what are the 4 ways we can prevent Autodigestion?
- Digestive proteins (proteases and lipases) are stored in granules as inactive precursors – if they were to be in an active form they will digest pancreas which results in auto digestion leading to pancreatitis.
Zymogens activated by coming into contact with small intestine brush border enzyme – enterokinase.
This enzyme converts trypsinogen to trypsin (trypsin autocatalytically cleaves more trypsinogen to trypsin) –>what trypsin then activates all other zymogens - Zymogens are packaged into secretory granules. Granule membrane is impermeable to proteins. Thus zymogens & active digestive enzymes are separated from proteins in cytoplasm & other intracellular compartments which could activate them.
- Enzyme inhibitors (i.e. pancreatic trypsin inhibitor SPINK1) co-packaged in granule – ensure enzymes remain inactive
- The condensation of zymogens, low pH, & ionic conditions within secretory granules further limit enzyme activity (back up if they were to become activated)
