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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. Pancreas synthesizes and secretes digestive enzymes and secretes HCO3

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What we gastroenterologists must should know about pancreatic physiology

What we gastroenterologists must (should) know aboutpancreatic physiology

Joachim Mössner

University of

Leipzig

Prague, April 16, 2010


Physiology of pancreatic enzyme secretion
Physiology 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

JM 2010


What we gastroenterologists must should know about pancreatic physiology

  • 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

JM 2010


Pancreas
Pancreas

JM 2010





What we gastroenterologists must should know about pancreatic physiology

Paracrine stimulation

within the mucosa

Endocrine

stimulation

JM 2010


Cholecystokinin cck
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?

JM 2010


Cholecystokinin cck1
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

JM 2010


Cholecystokinin cck2
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

JM 2010


Cholecystokinin cck3
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

JM 2010


What we gastroenterologists must should know about pancreatic physiology

  • Endocrine Mechanisms

  • CCK:

  • Paracrine stimulation of vagal afferents

  • Endocrine effect through blood

  • Whether human acinar cells have CCK receptors is controversial

JM 2010


What we gastroenterologists must should know about pancreatic physiology

  • 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

JM 2010



Stimulus secretion coupling of pancreatic enzyme secretion
Stimulus-secretion Coupling ofPancreatic Enzyme Secretion

JM 2010



Secretin
Secretin PROTEINS

  • 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

JM 2010


Secretin1
Secretin PROTEINS

  • 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

JM 2010



What we gastroenterologists must should know about pancreatic physiology

Regulation of Protein Synthesis in the Pancreas PROTEINS

ACh receptor

PI3-K

Insulin receptor

CCK receptor

Phosphatase

Akt/PKB

eEF2

eEF2

(Active)

(Inactive)

Amino acids

eEF2K

(off)

mTOR

Complex 1

Kinase

p70 s6k

eIF4E

eIF4E

4E-BP1

4E-BP1

S6 Ribosomal protein

40 S

eIF4A

Stop

AAAAA

mRNA

AUG

m7GTP

eIF4G

60 S

80 S initiation complex


Concentration of ions in pancreatic juice as a function of flow
Concentration of Ions in Pancreatic Juice PROTEINSas a Function of Flow

JM 2010


What we gastroenterologists must should know about pancreatic physiology

CFTR PROTEINS

Trypsin(ogen)

Trypsininhibitor

Duct Cell

Acinar Cell

Function of the Exocrine Pancreas

JM 2010


What we gastroenterologists must should know about pancreatic physiology

JM 2010 PROTEINS


What we gastroenterologists must should know about pancreatic physiology

Trypsin PROTEINS

Trypsin

Inhibitor

JM 2010


Trypsinogen activation peptide

N- PROTEINS

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

A16V

D19A

D22G

K23R

Trypsinogen Activation Peptide

N29I

R122H

N-

-C

*

*

*

*

*

*

*

*

*

*

*

*

*

*

*

*

*

*

TAP

JM 2010


Activation of pancreatic proenzymes in the intestine involves enterokinase and activated trypsin
Activation of Pancreatic Proenzymes in the Intestine involves Enterokinase and activated Trypsin

JM 2010


Pancreatic bicarbonate output increases in response to low duodenal ph
Pancreatic Bicarbonate output increases in response involves Enterokinase and activated Trypsinto low Duodenal pH

JM 2010


What we gastroenterologists must should know about pancreatic physiology

CCK involves Enterokinase and activated Trypsin

Amino Acids

MAPKs

Ca2+

mTOR

calcineurin

eIF4E

4E-BP1

mRNA

?

S6K1

eIF4E

NFATs

NFATs

Transcriptional

Control of

Gene Expression

Translational

Control of

Protein Synthesis

Pancreatic Growth

(Mitogenesis & Hypertrophy)

Regulation of Growth of the Pancreas

JM 2010


What we gastroenterologists must should know about pancreatic physiology

  • Long term effects of hormones and nutrients involves Enterokinase and activated Trypsin

    • 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

JM 2010


Somatostatin
Somatostatin involves Enterokinase and activated Trypsin

  • 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

JM 2010


Somatostatin stomach
Somatostatin: Stomach involves Enterokinase and activated Trypsin

JM 2010


Somatostatin1
Somatostatin involves Enterokinase and activated Trypsin

  • 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

JM 2010


Pancreatic polypeptide
Pancreatic Polypeptide involves Enterokinase and activated Trypsin

  • 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

JM 2010


Peptide tyrosin tyrosin pyy
Peptide Tyrosin Tyrosin, PYY involves Enterokinase and activated Trypsin

  • Released by the ileum

  • Inhibition of pancreatic enzyme secretion

JM 2010


Duodenal lipase and steatorrhea dimagno et al n engl j med 1973 288 813

100 involves Enterokinase and activated Trypsin

l

l

75

l

l

l

l

50

l

l

Fecal fat, %

l

l

25

l

l

l

Upper limit of normal

l

l

l

l

l

l

l

l

l

l

l

l

l

l

l

l

0

0

25

50

75

100

125

Lipase output, % normal

Duodenal Lipase and SteatorrheaDiMagno et al: N Engl J Med 1973;288:813

JM 2010


Negative feedback inhibition of pancreatic enzyme secretion
Negative Feedback Inhibition of involves Enterokinase and activated TrypsinPancreatic Enzyme Secretion

Proteases destroy CCK releasing peptides

Plasma CCK

Enzyme secretion

Pancreatic duct pressure

Pain

JM 2010


Palliation of pain in chronic pancreatitis use of enzymes
Palliation of Pain in Chronic Pancreatitis: involves Enterokinase and activated TrypsinUse 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

JM 2010


Genes and pancreatitis
Genes and Pancreatitis involves Enterokinase and activated Trypsin

  • 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?

JM 2010


Risk factor chymotrypsin c
Risk Factor: Chymotrypsin C involves Enterokinase and activated Trypsin

  • 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

JM 2010


Risk factor chymotrypsin c1
Risk Factor: Chymotrypsin C involves Enterokinase and activated Trypsin

JM 2010


Summary conclusion
Summary & Conclusion involves Enterokinase and activated Trypsin

  • 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)

JM 2010


What we gastroenterologists must should know about pancreatic physiology

I would like to thank my former mentor involves Enterokinase and activated Trypsin

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

JM 2010


What we gastroenterologists must should know about pancreatic physiology

600 Years University of Leipzig involves Enterokinase and activated Trypsindies academicus, December 2, 2009

Pancreas Group

Leipzig

Hans Bödeker

Sebastian Gaiser

Albrecht Hoffmeister

Volker Keim

Jonas Rosendahl

Lena Selig

Niels Teich

JM 2010