What we gastroenterologists must What we gastroenterologists must (should) (should) know aboutknow about pancreatic pancreatic

physiologyphysiology

What we gastroenterologists must What we gastroenterologists must (should) (should) know aboutknow about pancreatic pancreatic

physiologyphysiology

Joachim Mössner

University of

Leipzig

Prague, April 16, 2010Prague, April 16, 2010

Physiology of Pancreatic Enzyme SecretionPhysiology of Pancreatic Enzyme Secretion

• 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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PancreasPancreas

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Paracrine stimulationwithin the mucosa

Endocrinestimulation

Cholecystokinin, CCKCholecystokinin, 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, CCKCholecystokinin, 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, CCKCholecystokinin, 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, CCKCholecystokinin, 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 SECRETIONREGULATION OF PANCREATIC SECRETION

Stimulus-secretion Coupling ofStimulus-secretion Coupling ofPancreatic Enzyme SecretionPancreatic Enzyme Secretion

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INTRACELLULAR TRANSPORT OF PANCREATIC INTRACELLULAR TRANSPORT OF PANCREATIC SECRETORY PROTEINS SECRETORY PROTEINS

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SecretinSecretin

• 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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SecretinSecretin

• 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 SecretionMechanism of Pancreatic Bicarbonate Secretion

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S6 Ribosomal protein

p70 s6k

Insulin receptor CCK receptor

Akt/PKB

PI3-K

mTORComplex 1

mTORComplex 1

mRNAeIF4E

eIF4Gm7GTP

4E-BP1eIF4E

4E-BP1

eIF4A

eEF2K (off)

eEF2eEF2

(Active) (Inactive)

eEF2eEF2

Phosphatase

Amino acids

ACh receptor

Regulation of Protein Synthesis in the PancreasRegulation of Protein Synthesis in the Pancreas

Kinase

80 S initiation complex

60 S

AUG Stop AAAAA

40 S

Concentration of Ions in Pancreatic JuiceConcentration of Ions in Pancreatic Juiceas a Function of Flowas a Function of Flow

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Function of the Exocrine PancreasFunction of the Exocrine Pancreas

Acinar Cell

Trypsin(ogen)Trypsininhibitor

Duct Cell

CFTR

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Trypsin

TrypsinInhibitor

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Trypsinogen Activation PeptideTrypsinogen Activation Peptide

Ala-Pro-Phe-Asp-Asp-Asp-Asp-Lys-N-

D19A D22G K23RA16V

TAP

N- -C*

R122HN29I

* **** ** *** ****** *

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Activation of Pancreatic Proenzymes in the Intestine Activation of Pancreatic Proenzymes in the Intestine involves Enterokinase and activated Trypsininvolves Enterokinase and activated Trypsin

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Pancreatic Bicarbonate output increases in responsePancreatic Bicarbonate output increases in responseto low Duodenal pHto low Duodenal pH

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eIF4E

S6K1

mRNA4E-BP1

Amino Acids

CCK

Ca2+

NFATs NFATs

TranscriptionalControl of

Gene Expression

TranslationalControl of

Protein Synthesis

?eIF4E

MAPKs

calcineurinmTOR

Pancreatic Growth(Mitogenesis & Hypertrophy)

Regulation of Growth of the PancreasRegulation of Growth of the Pancreas

• 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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SomatostatinSomatostatin

• 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: Somatostatin: StomachStomach

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SomatostatinSomatostatin

• 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 PolypeptidePancreatic 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 Peptide Tyrosin Tyrosin, PYY

• Released by the ileum

• Inhibition of pancreatic enzyme secretion

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Duodenal Lipase and SteatorrheaDuodenal Lipase and Steatorrhea DiMagno et al: N Engl J Med 1973;288:813

lllllllllllllllll

llllllllll

ll

0

25

50

75

100

0 25 50 75 100 125

Fec

al f

at,

%

Lipase output, % normal

Upper limit of normal

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Proteases destroy CCK releasing peptides

Plasma CCK

Enzyme secretion

Pancreatic duct pressure

Pain

Negative Feedback Inhibition ofNegative Feedback Inhibition ofPancreatic Enzyme SecretionPancreatic Enzyme Secretion

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Palliation of Pain in Chronic Pancreatitis:Palliation of Pain in Chronic Pancreatitis:Use of EnzymesUse 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 PancreatitisGenes 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 CRisk 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: Risk Factor: Chymotrypsin CChymotrypsin C

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Summary & ConclusionSummary & Conclusion

• CCK: Stimulator of digestive enzyme secretion– Directly via CCK-A receptors on acinar cells (?)– Indirectly via CCK-B receptors: acetylcholine release

• 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, PhDProfessor of Medicine and

PhysiologyAnn 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 600 Years University of Leipzig dies academicus, December 2, 2009dies academicus, December 2, 2009

Pancreas GroupLeipzig

Hans BödekerSebastian Gaiser

Albrecht HoffmeisterVolker Keim

Jonas RosendahlLena SeligNiels Teich