Secretary Functions- Pancreas Flashcards
Pancreatic secretions: source and destination
The exocrine secretions of the pancreas that drain into the small bowel are derived from two distinct cells, ductal cells and acinar cells
Acinar secretions
are enzyme-rich secretions that provide the enzymes necessary for digestion for carbohydrates, proteins, nucleic acids, and lipids
ductal secretions
are HCO3 rich and neutralize acidic chyme to allow for proper function of pancreatic enzymes
Islets of Langerhans produce…
α (A) cells (20%) - Glucagon
β (B) cells (70%) - Insulin (amylin)
d (D) cells (5%) - Somastotatin
pp cells (5%) - Pancreatic polypeptide
pancreatic innervation (what do para and symp do?)
inhibited by sympathetic; stimulated by parasympathetic NS (Note from lecture: we don’t want insulin in the bloodstream during fight or flight; we need that glucose!)
anatomic aspects of the pancreas
Wirsung’s duct-major duct
Ampulla of Vater = hepatopancreatic ampulla or hepatopancreatic duct
Duct of Santorini-accessory collecting duct
Sphincter of Oddi
groups of acini
lobules
lumen drained by…
ductule–> intralobular ducts–> pancreatic duct
Cells of ductule & centroacinar cells produce
large volume of watery fluid containing Na+ HCO3-
Intercalated ducts-receive
secretions from acini
Intralobular ducts-receive
fluid from intercalated ducts
Pancreatic juice: divided into :
Aqueous bicarbonate component, enzymatic component
Aqueous (NaHCO3 - bicarbonate) component of pancreatic secretions
neutralizes HCl in chyme deactivates pepsin when H+ enters duodenum, S cells secrete Secretin, which acts on pancreatic ductal cells to increase HCO3- production prevents damage to duodenal mucosa buffers pH for maximal enzymatic activity
Enzymatic component of pancreatic juice
approx. 15 enzymes are produced
digests proteins, carbohydrates, lipids and nucleic acids when small peptides, amino acids and fatty acids enter duodenum
CCK is released by I cells, stimulating enzyme secretion
Composition of normal human pancreatic juice
Cations (Na, K, Ca, Mg, pH approx 8.0) Anions (HCO3, Cl-, SO4-2, HPO4-2) Digestive enzymes (95% of protein in juice), other proteins 80% by weight of proteins secreted are proteases 40% of proteases is trypsinogen (inactive precursor of trypsin)
What hormones stimulate protein secretion
ACh, CCK, Secretin, VIP stimulates protein secretion
hormones that stimulate protein secretion all increase
Ca 2+ (2nd messenger)
Activation of protein kinases increases acinar cell secretion
ACh & CCK stimulate
NaCl secretion, through phosphporylation of ion channels
Most powerful stimulas for HCO3- secretion?
secretin, which activates adenylyl cyclase
ACh stimulation of HCO3- secretion
ACh activates Gq, which in turn stimluates PLC to release DAG (which stimulates PKC) and IP3 (which releases Ca2+ from internal stores)
Secretin generates…
electrical gradient that favors NaHCO3 co-transport
Activator and Substrate: Amylase
a: Cl-, S: starch, glycogen
Activator and Substrate: Trypsinogen
activated to Trypsin by Enterokinase (brush border of duodenum) Enterokinase released from brush border membrane by bile salts Active trypsin once formed, acts auto-catalytically (like enterokinase) to activate trypsinogen, etc. Substrate: starch, glycogen
Activator and Substrate: Chymotrypsins
a: trypsin (Endo-peptidase), S: proteins, polypeptides, elastin, other proteins
Activator and Substrate: Proelastase-Elastase
a: trypsin (endo-peptidase), S: proteins, polypeptides
Activator and Substrate: Procarboxypeptidase A (carboxypeptidase A)
a: trypsin (exo-peptidase), S: proteins, polypeptides
Activator and Substrate: Procarboxypeptidase B (Carboxypeptidase B)
a: trypsin (exo-peptidase), S: proteins, polypeptides
Lipase substrate
triglycerides
nonspecific esterase
cholesteryl esters
Activator and Substrate: pro-phospholipase A2- (PLA2)
a: trypsin S: phospholiids
Ribonuclease substrate
RNA
Deoxyribonuclease
DNA
Activator and Substrate: Procolipase (Colipase does NOT activate lipase)
a: trypsin, s: fat droplets
Activator and Substrate: monitor peptide
a: intestinal content, s: feedback- secretion
trypsin inhibitors
protects against trypsin in acinar, ductular cells
glycoproteins
protect against protease-mediated mucosal injury
Which pancreatic enzymes do not have proenzymes?
ribonucleases, amylases, lipase
enzyme inhibitors
Pancreas also produces enzyme inhibitors to inactivate trace amounts of active enzyme formed within.
Protection against enzymatic autodigestion
packaging of many digestive proteins as zymogens–> precursor proteins lack enzymatic activity
selective sorting of secretory proteins and storage in zymogen granules–> restricts the interaction of secretory proteins with other cellular compartments
protease inhibitors in the zymogen granule–> block the action of prematurely activated enzymes
condensation of secretory proteins at low pH–> limits the activity of active enzymes
nondigestive proteases –> degrade active enzymes.
Bottom line: pancreatic proteolytic enzymes are stored and secreted in an inactive form (also, a trypsin inhibitor is present in acini and duct cells). Enterokinase- located on intestinal mucosal cells.
Activation of pancreatic proteolytic enzymes
Proteolytic enzymes are secreted into duodenum as inactive precursors, which are activated in gut lumen. The process begins in the lumen, the duodenal brush border enzyme, enterokinase cleaves a hexapeptide from trypsinogen, converting it to active enzyme trypsin. Trypsin then catalyzes the formation of more trypsin and activates chymotrypsinogen, pro-carboxypetidases and pro-phospholipases.
Hormonal control of pancreatic exocrine secretion
acid in duodenal lumen –> secretin release from duodenal mucosa (secretin carried by blood)–> + pancreatic duct cells –> secretion of aqueous NaHCO3 solution into duodenal lumen–> neutralizes acid in duodenal lumen
Fat and protein products –> increase CCK release from duodenal mucosa (CCK carried by blood)–> + pancreatic acinar cells–> increased secreation of pancreatic digestive enzymes into duodenal lumen –> digestion of fat and protein products in duodenal lumen
What is the primary stimulant of fluid and electrolyte secretion in the pancreas?
Secretin
What is the primary stimulant of enzyme secretion in the pancreas?
CCK
What is the primary factor in regulation of amount of fluid and HCO3- secretion by the pancreas?
Amount of acid entering the duodenum
What determines the amount of enzyme secretion by the pancreas?
quantity of fat and protein entering the duodenum
4 things that regulate overall pancreatic secretion
ACH, CCK, Secretin, vagovagal reflexes
Intestinal stimuli promote most secretions, but stimuli during cephalc and gastric phases also promote secretion.
ACh stimulates
acinar secretion and potentiates the Action of CCK by vagovagal reflexes
why is it important to neutralize the acid in the duodenum?
stop duodenal ulcers
pancreatic lipase is inactivated at low pH– need to digest the fat
others?
What receptors do acinar cells of the pancreas have? What about ductal cells?
Acinar cells: CCK (CCK-A) and Ach (M)
Ductal cells: CCK, ACh, secretin
What potentiate the effects of secretin?
CCK and ACh
What’s the most important stimulant for enzyme secretion during the intestinal phase?
CCK
What cells are stimulated to secrete CCK, and what stimulates them?
I cells
stimulated by the presence of amino acids, small peptides an fatty acids in the duodenum
Role of CCK in pancreatic exocrine secretion
CCK- potent stimulus of acinar secretion acts on CCK-B receptors via stimulation of vagal afferents
duodenum vago-vagal refelxes stimulate cholinergic (ACh) and noncholinergic (GRP, VIP) NTs HCO3-
secretion from ductular cells potentiates secretin effect of HCO3- secretion
CCK effects on digestive system outside of pancreas
CCK has multiple effects in duodenal cluster
- coordinates GI activity (secretion) to food
- contracts gall bladder
- relaxes the sphincter of Oddi
- slows gastric motility
- retards gastric emptying
CCK released in response to…
CCK-RP is released in response to fatty acids, aromatic amino acids, etc. into duodenum
large quantities of proteins in duodenum, CCK are released by CCK-PR and MP
What controls release of CCK?
monitor peptide (MP) and CCK-RP controls release of CCK
CCK effects
Bottom Line: increases enzymatic secretion from pancreas
More detail:
ØCCK- potent stimulus of acinar secretion
Ø acts on CCK-B receptors
Ø via stimulation of vagal afferents duodenum
Ø vago-vagal refelxes stimulate cholinergic
(ACh) and noncholinergic (GRP, VIP) NTs
Ø HCO3- secretion from ductular cells
Ø potentiates secretin effect of HCO3- secretion
ØCCK has multiple effects in duodenal cluster
Ø coordinates GI activity (secretion) to food
Ø contracts gall bladder
Ø relaxes the sphincter of Oddi
Ø slows gastric motility
Ø retards gastric emptying
What happens to CCK when little or no protein in diet?
trypsin degrades the peptides (CCK-RP/MP) and terminates the release of CCK
When too much protein in the diet…
both protein and peptides (CCK-RP/MP) compete for trypsin and other proteolytic enzymes and both are are degraded slowly
Monitor peptide
There’s a red box around it, so it must be important.
Role of secretin in pancreatic exocrine release
²Secretin released from S cells in duodenal mucosa, stimulates pancreatic ductular cells when acidic chyme enters duodenum to neutralize H+
²pancreatic secretions volume increases from low volume protein rich fluid to high absolute volume
²as the secretory rate rises, the pH and bicarbonate concentration also rises
concentrations of Cl- and HCO3- are inversely related to those of Na+ and
H+ in stomach
Achlorhydric
= (unable to secrete gastric acid)
secondary to disease
- on drugs, proton pump inhibitors, bicarbonate
fail to release secretin even in presence of a
fatty meal
pancreatic secretions falling below 10%–>
signs of malabsorption and indigestion
Factors causing secretin release
- S cells in duodenal mucosa acts as pH meters
- S cells secretes secretin when pH falls due
to entry of acidic chyme
•Secretin binds to receptors on
- pancreatic ductular cells
- epithelial cells lining bile ducts
- duodenum
- Cells stimulate to secrete HCO3-in duodenum
- Increase in pH will inhibit secretin release
Fatty acid meals evoke secretin release
Secretin release is sensitive to pH
Stages of pancreatic secretion
Cephalic phase: secretions from acinar cells
& Gastric phase secretions are low in volume, high conc of digestive enzymes
cholinergic vagal input during cephalic phase
vago-vagal reflexes by gastric distention during gastric phase
Intestinal phases: secretions from ductular cells and acinar cells
secretions high volume with decreased conc of proteins
secretin stimulates basolateral duct epithelial cells
CCK, ACh, GRP stimulates acinar cells
Stimulants and regulatory pathways of the stages of pancreatic secretion
Cephalic: Sight, smell, Vagal pathways
Taste, Mastication
Gastric: Distention, Vagal-cholinergic
Gastrin?
Intestinal: Amino acids, Cholecystokinin
Fatty acids Secretin
H+ Enteropancreatic reflexes
most common causes of pancreatitis
alcohol abuse and gallstones
cystic fibrosis and the pancreas
genetic disease, disorder of pancreatic secretion that results from a defect in Cl- channel that is caused by a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. This results in a thick secretions into the pancreatic duct that may obstruct the duct and cause pancreatic insufficiency
steatorrhea
feces may float, have an oily appearance, and be particularly foul-smelling. These patients are often treated with supplementary pancreatic enzymes. fat in the stool-early sign of pancreatic dysfunction 60% fat and 30-40% proteins and carbohydrates not absorbed reduced pancreatic enzyme (lipase) and bicarbonate secretion low pH inactivates lipase
pancreatitis (acute and chronic)
retention of secretion in pancreas leads to autodigestion of pacreatic tissue obstructive (gallstone occluding pancreatic duct, or a malignancy)-acute hereditary-expression of a mutated trypsin molecule that is resistant by trypsin inhibitors. Trypsin digests pancreatic tissue-chronic inflammation of the pancreatic tissue (alcohol abuse)-chronic
drugs and toxins causing pancreas pathophysiology
Immunosuppresants, anticonvulsants, thiazides
autoimmune diseases causing pancreas pathophysiology
celiac disease, IgG4,
genetic abnormalities causing pancreas pathophysiology
weak SPINK1, CFTR, CTRC genes and insult by alcohol, gallstones, etc may precipitate pancreatitis – both acute and chronic
cystic fibrosis and pancreas pathophysiology
autosomal recessive genetic mutation in the CFTR Cl channel Primarily affects caucasians Lack chloride transporter at apical membrane Leads to decreased water, HCO3, & Cl excretion, with concentration of protein in acinar ducts and blockage…. gland autodigestion/destruction Progressive pulmonary and pancreatic insufficiency - chronic
Kwashiorkor
–> reduction in pancreatic secretion except amylase
diabetes and the pancreas
Reduced pancreatic enzyme secretion in the absence of pancreatic disease
