-
Function of pancreas
- exocrine: 90%. enzymes and neutralization. 1.5L/d
- endocrine: 10%.
-
Structure/function of exocrine pancreas
- acinar cells -> synthesizing and secreting digestive enzymes, low volume
- centroacinar cells -> add volume, similar to plasma
- duct cells -> large volume of alkaline juice; HCO3-; neutralize gastric content to pH 7; discourage ulcers
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Unlike saliva, the secretion of pancreas is regulated by
- both neurocrine and endocrine, which allows it to regulate under a wider range of
- conditions.
- In pancreas, receptors are species specific, and mostly G-protein coupled.
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The pH sensing mechanism is located within ______ that are stimulated to releases _____ when the luminal pH drops below ___.
- the S-cells of the intestine
- secretin
- 4.5
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Structural Compartmentalization of pancreas
- - resembles salivon
- - secretes aqueous and organic component
-
acinar cells
- – secrete organic component
- - contains digestive enzymes - amylase, protease, lipase
- - low volume fluid - similar to plasma
-
duct cells
- – secrete high volume aqueous alkaline juice
- - neutralizes gastric juice
- - provides optimal pH
- - discourages ulcers
-
Endocrine hormones regulate pancreas
- "full status"
- CCK (cholecystokinin)
- secretin
-
CCK
- released from
- releasing signals
- receptor
- second messengers
- - intestinal I-cells
- - nutrients - fatty acids and amino acids
- - CCK-A (CCK-1) receptor; highly specific for CCK; low affinity to gastrin
- - IP3 and Ca2+
-
Secretin
- released by
- releasing signals
- second messenger
- S-cells of upper small intestine
- gastric acid in duodenum
- cAMP
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Neural Regulation of pancreas
- ACh: most important; M3; IP3/Ca
- VIP: less important postganglionic peptide
- GRP: less important postganglionic peptide
- sympathetic: celiac and superior mesenteric plexus; indirectly inhibit secretion via reducing blood flow, not receptors.
-
Direct Regulation of Enzymatic Component (historical textbook; rodent model):
agonist binds directly to basolateral receptor on acinar or duct cells
-
Direct Regulation of Enzymatic Component (historical textbook; rodent model):
Acinar cells
- 1) CCK (endo)
- - CCK-A (CCK-1) receptor
- - IP3/Ca2+
- 2) Gastrin (endo)
- - competes with CCK; lower affinity (50%)
- 3) ACh (neural)
- - M3
- - IP3/Ca2+
- - additive to CCK
- - inhibited by vagotomy and atropine
Enzymes
-
Direct Regulation of Enzymatic Component (historical textbook; rodent model):
Duct cells
- Secretin (endo; key mediator)
- - cAMP
- - potentiates CCK and ACh
Alkaline juice
-
Indirect Regulation of Acinar Cell in Humans – new model
- - low expression of acinar CCK-1 receptors and very low affinity
- - CCK still important but indirect
- - neural CCK-1 receptors -> vago-vagal pathway (intestine -> brain -> vagus) ->ACh -> pancreas -> M3 receptor
- - high M3 density
- - most potent enzyme releaser
-
Enzymatic Component
- Enzyme secretion initiated on _______
- ___ determines type of enzymes synthesized
- Control of action:
- food intake; no secretion when sleeping or fasting; protective
- Diet
- active at duodenal pH
-
__ Enzyme Families (over __ enzymes):
- 5
- 20
- 1) Pancreatic Amylases
- 2) Pancreatic Proteases - largest family
- 3) Pancreatic Lipases
- 4) Ribonucleases – degrade nucleic acids
- 5) Pancreatic associated protein - bacteriostatic; increase when damaged
-
1) Pancreatic Amylases
- substrate
- vs. salivary amylase
- releasing signal
2) Pancreatic Proteases
- substrate
- release as ____
- representative:
3) Pancreatic Lipases
- synthesized and secreted ______
- substrate
- – starches
- - 94% identical
- - high carbohydrate diet increases gene expression for amylases
- - released in active form
- – proteins
- - inactive zymogens
- - trypsin
- -- most aggressive enzyme
- -- trypsiogen - major proenzyme; only activated in duodenum
- -- inhibitor in acinar cells prevents premature activation and autodigestion
-
Aqueous Component
rate of synthesis and secretion
- - 1.5L/d isotonic
- - low during fasting or interdigestive states
- - stomach empties (acid) into duodenum, increase 5-20 fold
- - highest rate of synthesis and secretion of any organ
-
Finger print of pancreatic juice
-
The Aqueous Component
- Resting State
- volume ____
- [Na+] ____
- [K+] ____
- [HCO3-] ________
- [Cl-] _________
- relationship among major ions concentration
- pH _____
- osmolarity
- low
- similar to plasma - all rates
- similar to plasma - all rates
- higher than plasma and increases with rate
- lower than plasma and decreases with rate
- [Na+] >[Cl-]>[HCO3-]>[K+]
- slightly alkaline and increases with
- secretory rate
- isotonic at all rates
-
The Aqueous Component
- Simulated State
- volume ____
- [Na+] ____
- [K+] ____
- [HCO3-] ________
- [Cl-] _________
- relationship among major ions concentration
- pH _____
- osmolarity
- high
- similar to plasma
- similar to plasma
- much higher than plasma
- much lower than plasma
- [Na+] > [HCO3-] >> [Cl-] > [K+]
- alkaline (8.1)
- isotonic
- food->duodenum->S cells->secretin->ductal cells
-
HCO3 secretion
- Basolateral absorption sources:
- Apical secretion into duct lumen:
- 1) enters from blood as CO2 -> carbonic anhydrase
- 2) absorption from blood - cotransport with Na+ (NBC-1; 2HCO3:1Na; in response to the alkaline tide)
- - against electrochemical gradient
- - Cl/HCO3 exchanger (key)
- - several other apical chan
- -- CFTR: primary; only in duct cells
-
HCO3 secretion - H+
- 1) Na/H exchanger (NHE-1)
- 2) H-ATPase- some species- neutralizes alkaline tide; acid tide; neutralized by HCO3
-
Cl- secretion
- primary driving force for ______
- basolateral membrane: ______
- apical membrane key: _______
-- resting state - ______
-- stimulated state
--- pathway: ______
volume
Na/K/2Cl – absorption
- Cystic Fibrosis Transmembrane Regulator (CFTR)
- channels closed
- secretin -> basolateral receptor -> cAMP -> PKA -> chan phosphorylated and open
-
How does Cl- secretion helps increasing the lumenal volume?
- - anion increases negativity of duct lumen
- - paracellular Na+ transport
- - water follows via paracellular and transcellular (aquaporins)
-
Disorders of Pancreatic Secretion - Cystic Fibrosis – may develop before birth
- Cause:
- only becomes significant when <10% is normal
- - mutation of gene that encodes for CFTR
- - defective CFTR degraded by endoplasmic reticulum
- - reduces number of channels
-
Symptoms of Cystic Fibrosis:
1) secretion
2) function
- - thickened pancreatic, respiratory, GI secretions
- - mucous obstructed ducts
- - cells and glands destroyed
- - low levels digestive enzymes secreted
- - malnutrition
- - reduced driving force in acinar cells
- - steatorrhea - inactivated lipases; fat in stool; early sign of pancreatic deficiency
- can test CCK and secretin for examining pancreatic functions
-
Treatment for CF
- - oral enzymes
- - ingest medium chain fatty acids
-
Animal models for CF
- rat: unsatisfactory
- piglet: same symptom as human
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