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What we gastroenterologists must
(should) know about pancreatic
physiology
Joachim Mössner
University of
Leipzig
Prague, April 16, 2010
Physiology of Pancreatic Enzyme Secretion
•
•
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Pancreas synthesizes and secretes digestive enzymes
and secretes HCO3
Both are necessary for normal digestion
Pancreas stimulated acutely by feeding:
– Neuronal Mechanisms: Vagus mediates small
cephalic phase
– Importance of vagal afferents
– Vagal-vagal reflexes
– Acinar cells have M1 and M3 receptors
– Some direct innervation of pancreas from gut
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• The pancreas is made up of three functional
components:
• Endocrine – Islets 2%
• Exocrine – Acinar 80% Digestive Enzyme
• Exocrine - Ducts 8% Bicarbonate Rich Fluid
• Innervation
– Vagal: Acetylcholine main transmitter
• Acini
• Ducts
• Islets
– Sympathetic: Norepinephrine main transmitter
• Islets
• Blood Vessels
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Pancreas
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Paracrine stimulation
within the mucosa
Endocrine
stimulation
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Cholecystokinin, CCK
• CCK or CCK-PZ; Greek chole, "bile"; cysto, "sac";
kinin, "move"; move the gallbladdder
• Peptide hormone of the gastrointestinal system &
brain
• Stimulation of digestion of fat & proteins
• CCK, previously called pancreozymin, synthesized
by I-cells in the mucosa of small intestine
• Secreted from the first segment of the small intestine
• Role in inducing drug tolerance to opioids?
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Cholecystokinin, CCK
• Stimulation of release from I-cells by
oligopeptides, certain amino acids
(phenylalanine), fatty acids
• Stimulation of release by releasing peptides
present in pancreatic secretions and duodenal
mucosa (monitor peptide, …)?
• Negative feedback inhibition:
• Destruction of CCK releasing peptides by
trypsin
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Cholecystokinin, CCK
• Inhibition of gastric emptying & gastric
acid secretion
• Stimulation of pancreatic acinar cells to
secrete pancreatic digestive enzymes,
hence the old name pancreozymin
• Stimulation of human acinar cells directly
via CCK-A receptors?
• Stimulation indirectly via CCK-B receptors
of nerves: release of acetylcholine
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Cholecystokinin, CCK
• Enzymes catalyze digestion of fat, protein, &
carbohydrates
• As levels of substances that stimulate release of
CCK drop, concentration of the hormone drops as
well
• Release of CCK inhibited by somatostatin, PYY, …
• CCK causes increased production of hepatic bile
• CCK stimulates contraction of gall bladder &
relaxation of the sphincter of Oddi
• Bile salts form amphipathic micells that emulsify fats
• Triglyceride digestion needs lipase, bile salts,
colipase: 2 fatty acids, 1 monoglyceride
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• Endocrine Mechanisms
• CCK:
• Paracrine stimulation of vagal afferents
• Endocrine effect through blood
• Whether human acinar cells have CCK
receptors is controversial
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• Secretin
– Major stimulant of HCO3 secretion
• Insulin
– Released from islets. Acts on exocrine cells by portal blood
system
• Nutrients
– Supply energy, building blocks and amino acids
– Act as a anabolic signal
• What ends Secretion?
– Exit of food from upper small intestine
– Feedback inhibition by surplus trypsin in intestinal lumen
– Ileal brake
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REGULATION OF PANCREATIC SECRETION
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Stimulus-secretion Coupling of
Pancreatic Enzyme Secretion
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INTRACELLULAR TRANSPORT OF PANCREATIC
SECRETORY PROTEINS
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Secretin
• First hormone identified by William Bayliss &
Ernest Starling in 1902
• Produced in S cells of the duodenum in the
crypts of Lieberkühn
• Secretin encoded by the SCT gene
• Protein with 27 amino acids
• Release by gastric acid entering the duodenum
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Secretin
• Stimulation of watery bicarbonate secretion from,
Brunner glands of the duodenum, pancreatic duct cells
& acinar cells (?)
• Inhibition of gastric acid secretion by inhibition of
gastrin release
• Stimulation of adenylate cyclase activity: cAMP second
messenger
• Control of water homeostasis throughout the body
• Regulation of pH of duodenal contents via control of
gastric acid secretion & buffering with bicarbonate
• Role in osmoregulation in the hypothalamus, pituitary,
& kidneys
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Mechanism of Pancreatic Bicarbonate Secretion
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Regulation of Protein Synthesis in the Pancreas
ACh receptor
Insulin receptor
CCK receptor
PI3-K
Akt/PKB
Phosphatase
eEF2
eEF2
(Active)
(Inactive)
Amino acids
eEF2K
mTOR
Complex 1
Kinase
eIF4E
(off)
p70 s6k
4E-BP1
4E-BP1
S6 Ribosomal protein
eIF4E
m7GTP
40 S
eIF4A
eIF4G
mRNA
AUG
Stop AAAAA
60 S
80 S initiation complex
Concentration of Ions in Pancreatic Juice
as a Function of Flow
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Function of the Exocrine Pancreas
Trypsin(ogen)
Trypsininhibitor
CFTR
Duct Cell
Acinar Cell
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Trypsin
Trypsin
Inhibitor
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Trypsinogen Activation Peptide
N29I
N- *
** *** *
R122H
** *** **** *
-C
TAP
N- Ala-Pro-Phe-Asp-Asp-Asp-Asp-Lys-
A16V
D19A
D22G K23R
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Activation of Pancreatic Proenzymes in the Intestine
involves Enterokinase and activated Trypsin
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Pancreatic Bicarbonate output increases in response
to low Duodenal pH
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Regulation of Growth of the Pancreas
CCK
Amino Acids
Ca2+
mTOR
calcineurin
eIF4E
4E-BP1
mRNA
S6K1
eIF4E
Translational
Control of
Protein Synthesis
MAPKs
?
NFATs
NFATs
Transcriptional
Control of
Gene Expression
Pancreatic Growth
(Mitogenesis & Hypertrophy)
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• Long term effects of hormones and nutrients
– Adaptive Growth as in pregnancy, lactation and high
protein diet
– Regeneration
• Limited after partial resection or fibrosis
• Nearly complete after mild acute pancreatitis
• Newer Material
– Role of Vagal afferents in responding to nutrients and CCK
– Feedback inhibition on CCK release and pancreatic
secretion by active trypsin in lumen
– Mechanism of high HCO3 secretion
– Importance of nutrients particularly amino acids for the
pancreas
– Question of enteral vs parenteral feeding
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Somatostatin
• Somatostatin (growth hormone-inhibiting hormone,
GHIH, somatotropin release-inhibiting factor, SRIF)
• Peptide hormone
– Regulation of the endocrine system
– Affects on neurotransmisson & cell proliferation
– Interaction with G-protein-coupled somatostatin receptors
• Two active forms produced by alternative cleavage
of a single preproprotein: one of 14 amino acids, the
other of 28 amino acids
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Somatostatin:
Stomach
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Somatostatin
• Inhibition of release of numerous secondary hormones
– gastrin, CCK, secretin, motilin, VIP, GIP, enteroglucagon
• Lowers rate of gastric emptying
• Reduces smooth muscle contractions & blood flow
within the intestine
• Suppresses release of pancreatic hormones
• Inhibits insulin release when somatostatin is released
from granules in alpha-1 cells of pancreatic islets of
Langerhans
• Inhibits release of glucagon
• Suppresses exocrine pancreatic secretion
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Pancreatic Polypeptide
• Secreted by PP cells
predominantly in the head of the
pancreas
• 36 amino acids
• Function: selfregulation of
pancreas secretion activities
(endocrine and exocrine)
• Effects on hepatic glycogen levels
& gastrointestinal secretions
• Secretion in humans increased
after a protein meal, fasting,
exercise & acute hypoglycemia,
decreased by somatostatin &
intravenous glucose
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Peptide Tyrosin Tyrosin, PYY
• Released by the ileum
• Inhibition of pancreatic enzyme secretion
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Duodenal Lipase and Steatorrhea
DiMagno et al: N Engl J Med 1973;288:813
100
ll
Fecal fat, %
75
ll
l
50 l
ll
l
25 l
0
l
ll l
ll l
l
0
25
Upper limit of normal
l
l
50
ll l l l l l l l
75
100
125
Lipase output, % normal
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Negative Feedback Inhibition of
Pancreatic Enzyme Secretion
Proteases destroy CCK
releasing peptides
Plasma CCK
Enzyme secretion
Pancreatic duct pressure
Pain
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Palliation of Pain in Chronic Pancreatitis:
Use of Enzymes
• Metaanalysis
• 6 randomized, double blind, placebo
controlled studies
• Statistical analysis demonstrates no
benefit for pancreatic enzymes
Mossner: Surg Clin North Am 1999; 79: 861-72
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Genes and Pancreatitis
• Hereditary chronic pancreatitis
– Mutations: cationic trypsinogen
• Cystic fibrosis
– CFTR-mutations
• Idiopathic chronic pancreatitis
– Mutations of CFTR: special form of cystic fibrosis
– Mutations or trypsin inhibitor SPINK
– Chymotrypsin C mutations
• Tropical pancreatitis
– SPINK-mutations, CTRC-mutations
• Alcohol induced chronic pancreatitis
– Polygenetic disease?
• Role of protective mutations?
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Risk Factor: Chymotrypsin C
• p.R254W & p.K247_R254del overrepresented in
pancreatitis
• 30 / 901 3.3% with idiopathic or hereditary pancreatitis vs
• 21 / 2,804 0.7% controls
• Replication study in alcohol-related diseases:
• 10 / 348 2.9% in chronic pancreatitis vs
• 3 / 432
0.7% in liver disease
• Indian subjects with tropical chronic pancreatitis:
• 10 / 71
14.1% vs
• 1 / 84
1.2% control
•
OR = 13.6; CI = 1.7-109.2; P = 0.0028
– Rosendahl, Witt, …. Mössner, Teich, Sahin-Toth: Nature Genetics 2008;
40: 78-82
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Risk Factor:
Chymotrypsin C
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Summary & Conclusion
• CCK: Stimulator of digestive enzyme secretion
– Directly via CCK-A receptors on acinar cells (?)
– Indirectly via CCK-B receptors: acetylcholine release
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CCK: Stimulator of gallbladder contraction
Secretin: Stimulator of bicarbonate secretion
Activation of trypsinogen by enterokinase
Activation of proenzymes by trypsin
Termination of enzyme secretion:
– Negative feedback (destruction of CCK releasing peptides
by trypsin ?)
– Ileal brake (PYY, somatostatin)
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I would like to thank my
former mentor
John A. Williams, MD, PhD
Professor of Medicine and
Physiology
Ann Arbor, Michigan
for providing me several of
the slides and teaching me
in pancreatic physiology
during my stay in San
Francisco 1983 - 1985
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600 Years University of Leipzig
dies academicus, December 2, 2009
Pancreas Group
Leipzig
Hans Bödeker
Sebastian Gaiser
Albrecht Hoffmeister
Volker Keim
Jonas Rosendahl
Lena Selig
Niels Teich
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