Physiology of pancreas Flashcards
What are the major secretory products of the acinar and ductal cells?
Acinar: Proenzymes/enzymes
Ductal: Water, electrolytes
What are the major endocrine and neurocrine elements for the acinar (2/4) and ductal cells (1/1) respectively
Acinar: CCK and secretin, Ach, GRP, VIP, Substance P
Ductal: secretin and Ach
What happens to trypsin and CCK output after a meal?
Secretion of trypsin dramatically increases
CCK levels rapidly increase then begin to decline about 30min after meal
Describe the relative enzyme secretion during different phase:
Cephalic: 25% via vagal pathway
Gastric: 10-20% via vagal pathway
Intestinal: 50-80% via vagal, enteropancreatic reflex, CCK and enzyme secretion pathways
What happens to secretin levels after meal?
Increases…. due to CCK, which stimulates pancreas innervation
What is bicarbonate secretion related to?
Duodenal pH
More secreted when pH is low
What is effect of secretin?
Major stimulus for water and bicarbonate from ducts– activates adenylyl cyclase in duct cells, opening CFTR– bicarbonate is then exchanged for luminal chloride
What are some of non-enzymatic acinar cell products?
Bradykinin
Ions
Glycoprotein 2 (GP2)
Pancreatitis associated protein
Describe the process of zymogen activation
Pancreas secretes both zymogens and trypsinogen into duodenum
Duodenal enterocytes contain enterokinase, which cleaves and activates trypsin
Trypsin then cleaves zymogens into active form
Describe relationship between fat excretion and functional lipase– what are implications for other enzymes?
Only observe increased fat excretion once functional lipase is below 10%– essentially once there is significantly reduced pancreas function
This is true for other enzymes as well (think about how many ß cells are left by the time T1DM symptoms are observed)
What is relationship between pancreas and calcium?
Ca is used as 2nd messenger for zymogen secretion
Sustain elevation in Ca levels leads to trypsin activation and can trigger acute pancreatitis
What are mechanisms of intracellular hypercalcemia? (5)
Extracellular hypercalcemia with pancreatic stimulation Acinar cell hyper stimulation Luminal bile salts Alcohol Drugs
What are the mechanisms of acinar cell protection from trypsin activation? (1-5)
Trypsin synthesized in inactive form
Activating enzyme (enterokinase) physically separated from pancreas
Digest enzymes compartmentalized in acinar cells within zymogen granules
Intrahepatocellular [Ca] low, limiting trypsin activation
Acinar cells synthesize PTSI/SPINK1, which inactivate trypsin if in with digestive enzymes
Mechanisms of acinar cell cell protection from trypsin activation: (6-10)
- Trypsin destroyed by chymotrypsin C (CTRC)
- Trypsin activity outside acinar cell leads to protease activated receptor activation, which protects acinar/ductal cells during pancreatitis
- Duct cells secrete bicarb to flush digestive enzymes from pancreatic duct
- High bicarb maintains ductal trypsin in inactive form
- Liver produces 2 inhibitors (a1-antitrypsin and ß2microglobulin)
What are functions of bile? (3)
Excrete polar metabolites of lipid waste
Fat and fat-soluble vitamin absorption
Excrete cholesterol
Where is bile secreted/stored? How is its flow regulated?
Hepatocytes secrete bile into canaliculi
Some bile salts increase canalicular flow; others reduce flow (cholestasis)
How does canaliculus prevent leakage of bile salts and bilirubin into hepatic sinusoids?
Tight junctions on apical membranes prevent back flow
Transporters move bile salts into canaliculi against concentration gradient
What is effect of farnesoid X factor on intracellular bile salts?
FXR senses intracellular bile salt and suppresses bile salt synthesis and increases canalicular secretion
Feedback suppression prevents possibly toxic bile salt level from building in cells
Describe steps of bile salt synthesis (2)
What is the difference between primary and secondary bile salts
Acetate==>cholesterol via HMGCoAreductase
Conversion to bile salts by addition of carboxyl side chains and hydroxyl groups
Primary bile salts are synthesized in liver while secondary bile salts undergo dehydroxylation in colon
Describe important structural element of bile salts
They are amphipathic– hydroxyl/carboxyl groups make one side hydrophilic while other side is hydrophobic
Describe the process of conjugation and its effect
Before bile salts are secreted into bile the carboxyl side chains are conjugated with either taurine or glycine.
This produces stronger acids which ionize in duodenum preventing back diffusion
What is the critical micellar concentration?
Ionized bile salts form micelles (clusters) with hydrophilic portions facing outward above CMC.
What occurs in inner portion of micelle?
How is ability to solubilize cholesterol increased?
Lipids dissolve in the inner portion
The addition of lecithin forms a mixed micelle which is more able to solubilize cholesterol
Describe the enterohepatic circulation of bile salts:
Conjugation/ionization results in limited intestinal absorption– most transport occurs in ileum, where bile salts are returned to liver by portal vein.
Hepatocytes remove bile salts from sinusoids for re-secretion
Describe the process of secondary bile salt formation
10% of bile salt pool pass into colon where bacteria covert bile salts to secondary forms
When would you see increased loss of bile salts?
Ileal disease or resection
What are effects of bacterial overgrowth in small bowel? (2)
Increased pK and protonation leads to bile acid precipitation
Inadequate micelle formation leads to fat and fat-soluble vitamin malabsorption
