Physiology of pancreas

Question 1

What are the major secretory products of the acinar and ductal cells?

Answer 1

Acinar: Proenzymes/enzymes
Ductal: Water, electrolytes

Question 2

What are the major endocrine and neurocrine elements for the acinar (2/4) and ductal cells (1/1) respectively

Answer 2

Acinar: CCK and secretin, Ach, GRP, VIP, Substance P

Ductal: secretin and Ach

Question 3

What happens to trypsin and CCK output after a meal?

Answer 3

Secretion of trypsin dramatically increases

CCK levels rapidly increase then begin to decline about 30min after meal

Question 4

Describe the relative enzyme secretion during different phase:

Answer 4

Cephalic: 25% via vagal pathway
Gastric: 10-20% via vagal pathway
Intestinal: 50-80% via vagal, enteropancreatic reflex, CCK and enzyme secretion pathways

Question 5

What happens to secretin levels after meal?

Answer 5

Increases…. due to CCK, which stimulates pancreas innervation

Question 6

What is bicarbonate secretion related to?

Answer 6

Duodenal pH

More secreted when pH is low

Question 7

What is effect of secretin?

Answer 7

Major stimulus for water and bicarbonate from ducts– activates adenylyl cyclase in duct cells, opening CFTR– bicarbonate is then exchanged for luminal chloride

Question 8

What are some of non-enzymatic acinar cell products?

Answer 8

Bradykinin
Ions
Glycoprotein 2 (GP2)
Pancreatitis associated protein

Question 9

Describe the process of zymogen activation

Answer 9

Pancreas secretes both zymogens and trypsinogen into duodenum

Duodenal enterocytes contain enterokinase, which cleaves and activates trypsin

Trypsin then cleaves zymogens into active form

Question 10

Describe relationship between fat excretion and functional lipase– what are implications for other enzymes?

Answer 10

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)

Question 11

What is relationship between pancreas and calcium?

Answer 11

Ca is used as 2nd messenger for zymogen secretion

Sustain elevation in Ca levels leads to trypsin activation and can trigger acute pancreatitis

Question 12

What are mechanisms of intracellular hypercalcemia? (5)

Answer 12

Extracellular hypercalcemia with pancreatic stimulation
Acinar cell hyper stimulation
Luminal bile salts
Alcohol 
Drugs

Question 13

What are the mechanisms of acinar cell protection from trypsin activation? (1-5)

Answer 13

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

Question 14

Mechanisms of acinar cell cell protection from trypsin activation: (6-10)

Answer 14

6. Trypsin destroyed by chymotrypsin C (CTRC)
7. Trypsin activity outside acinar cell leads to protease activated receptor activation, which protects acinar/ductal cells during pancreatitis
8. Duct cells secrete bicarb to flush digestive enzymes from pancreatic duct
9. High bicarb maintains ductal trypsin in inactive form
10. Liver produces 2 inhibitors (a1-antitrypsin and ß2microglobulin)

Question 15

What are functions of bile? (3)

Answer 15

Excrete polar metabolites of lipid waste
Fat and fat-soluble vitamin absorption
Excrete cholesterol

Question 16

Where is bile secreted/stored? How is its flow regulated?

Answer 16

Hepatocytes secrete bile into canaliculi

Some bile salts increase canalicular flow; others reduce flow (cholestasis)

Question 17

How does canaliculus prevent leakage of bile salts and bilirubin into hepatic sinusoids?

Answer 17

Tight junctions on apical membranes prevent back flow

Transporters move bile salts into canaliculi against concentration gradient

Question 18

What is effect of farnesoid X factor on intracellular bile salts?

Answer 18

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

Question 19

Describe steps of bile salt synthesis (2)

What is the difference between primary and secondary bile salts

Answer 19

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

Question 20

Describe important structural element of bile salts

Answer 20

They are amphipathic– hydroxyl/carboxyl groups make one side hydrophilic while other side is hydrophobic

Question 21

Describe the process of conjugation and its effect

Answer 21

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

Question 22

What is the critical micellar concentration?

Answer 22

Ionized bile salts form micelles (clusters) with hydrophilic portions facing outward above CMC.

Question 23

What occurs in inner portion of micelle?

How is ability to solubilize cholesterol increased?

Answer 23

Lipids dissolve in the inner portion

The addition of lecithin forms a mixed micelle which is more able to solubilize cholesterol

Question 24

Describe the enterohepatic circulation of bile salts:

Answer 24

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

Question 25

Describe the process of secondary bile salt formation

Answer 25

10% of bile salt pool pass into colon where bacteria covert bile salts to secondary forms

Question 26

When would you see increased loss of bile salts?

Answer 26

Ileal disease or resection

Question 27

What are effects of bacterial overgrowth in small bowel? (2)

Answer 27

Increased pK and protonation leads to bile acid precipitation

Inadequate micelle formation leads to fat and fat-soluble vitamin malabsorption