Relationship Between Exocrine and Endocrine Pancreas

Department of Gastroenterology and Metabolism, University of Occupational and Environmental Health, Japan,

School of Medicine

Makoto Otsuki, MD, PhD

• accounts for 1 to 2% of the volume of the pancreas

• about 1 million islets in the pancreas

• the islets contain 4 major types of endocrine cells

• the islet is composed of about 5,000 endocrine cells

accounts for about 85% of the volume of the pancreas

is usually regarded as two separate organ systems.

The Pancreas

The exocrine pancreasThe exocrine pancreas

The endocrine pancreasThe endocrine pancreas

Endocrine and Exocrine PancreasEndocrine and Exocrine Pancreasare closely linked both anatomically and physiologically

Secrete hormones into

the blood streamSecrete digestive enzymes, waterand bicarbonate

into the duodenum

Pancreatic Portal System

(Insulo-Acinar Axis)

The exocrine pancreas receives a large part of its blood flow through the islets and is thereforeexposed to high concentrations of islet hormones

The exocrine pancreas

The endocrine pancreas

Blood Flow

Effect of Hypoinsulinemia on the

Exocrine Pancreas

Effect of Hypoinsulinemia on the

Exocrine Pancreas

1. Reduced serum and fecal pancreatic enzyme levels2. Reduced secretagogue-stimulated secretion3. Reduced enzyme content in the pancreas

1. Reduction of pancreatic size (US and CT images) 2. Changes of pancreatic duct system by ERCP3. Histological changes; acinar atrophy, fibrosis,

fatty degeneration

Diabetes Mellitus Often Associates Exocrine Pancreatic Abnormalities

•Lack of trophic hormone (insulin)•High level of inhibitory hormone (glucagon, somatostatin)•Inadquate perfusion of the exocrine pancreas (atherosclerosis)

Functional Alterations

Morphological Alterations

Size of the Pancreas

•The pancreas is smaller in DM patients than in control subjects. The reduction in size is more pronounced in type 1 DM than in type 2 DM•The body of the pancreas is significantly reduced in all three groups.•Size of the pancreas in patients with type 2 DM who require insulin therapy is nearly the same as that in patients with type 1 DM.

AJR 159:527-531,1992

10 Head Body Tail

18

16

12

14

Control

Type 1 DM

Type 2 DM, Insulin Rx(-)

Type 2 DM, Insulin RX(+)

Thic

knes

s of

the

Pan

crea

s (m

m)

Relationship between FPG and Serum Amylase Activity in Patients with Type 2 DM

Am

ylas

e A

ctiv

ity (S

U/1

00m

l)

160

140

120

100

80

60

400

<120 120-159 160-199 ≥200

180

FPG (mg/100ml)

Pancreatic Exocrine Function in Patients with Type 2 DM -CCK-Secretin Test-

100

50

Max

imum

Bic

arbo

nate

(mE

q/L)

3

2

1

Tota

l Vol

ume

(ml/k

g B

W) 6000

3000

Am

ylas

e O

utpu

t (S

U/k

g B

W)

Control Diabetics Control Diabetics Control Diabetics

n.s. n.s. p<0.02

150

100

50

0

IR-T

ryps

in (n

g/m

l)

FPG (mg/100ml)Control <140 140-179 180-219 220≦

means±SE

Relationship between FPG Concentrations and Serum Immunoreactive Trypsin Levels

P<0.05P<0.05

IR-T

ryps

in (n

g/m

l) 6050403020100

70

HbAlc (%)Control <7.0 7.0-7.9

Relationship between HbA1c and Serum Immunoreactive Trypsin Levels

#

8.0-8.9

# P<0.05 vs control

#

≧9.0

Serum levels of amylase and trypsin were inversely related to fasting plasma glucose concentration.

Decrease in serum trypsin concentration was related to poor glycemic control.

SummaryIn patients with diabetes mellitus, serum levels of pancreatic enzymes and amylase output were low compared with the control subjects.

Relationship Between the Severity of Diabetes Mellitus and Exocrine Pancreatic Dysfunction

Diabetes Res Clin Pract 1 (1): 21-30, 1985

800

400

0

Blo

od G

luco

se (m

g/dl

)

IRI C

onte

nt (μ

g/m

g pr

otei

n)

1.0

0.5

0 Am

ylas

e C

onte

nt (S

U/m

g pr

otei

n)

600

300

00 30 60 120 Control

STZ (mg/Kg BW)30 45 60 Control

STZ (mg/Kg BW)30 45 60

(A) Blood Glucose (B) Insulin Content (C) Amylase Content

30 mg

45 mg

60 mg

Control

Effect of Hyperinsulinemia on

the Exocrine Pancreas

Effect of Hyperinsulinemia on

the Exocrine Pancreas

•Since there are no significant capsule or basementmembrane around theislets, acinar tissue in thepancreas is in close contactwith the islets.

•These characteristics are related to localhigh insulin levels.

•Acinar cells near the islets, peri-islet acini,are larger, contain larger nuclei and nucleoli,and have more abundant zymogen granulesthan other acini.

Islet

There are no reports that revealedincreased functional activity ofthe exocrine pancreas athyperinsulinemic and normoglycemic state.

Effect of Exogenous and Endogenous Insulin on CCK-Induced Exocrine Secretion

Prot

ein

outp

ut (m

g/m

in)

Exogenous Insulin (mU/ml)

CCK1 mU/ml

CCK1 mU/ml

Glucose 2.5 mMGlucose 2.5 mM Glucose 17.5 mMGlucose 17.5 mM

(B) Endogenous Insulin

Saito et al.J Clin Invest 1980;65:777-82.

Low GlucoseLow Glucose High GlucoseHigh Glucose

(A) Exogenous Insulin

Exocrine Pancreatic Function in Patients with

Insulin-Producing Tumors

Bani D, et al. Int J Pancreatol 1989;5:239-248

•Marked and significant decrease in zymogengranule content in acinar cells.

•Slight reduction in the mean cell area.

•Increase in centroacinar/ductular cell area and cell number.

•No significant difference in the zymogen granule content between peri- and tele-insular acini.

Endocrine Pancreatic Function in Rat with Insulin-Producing Tumors

Insulinoma-bearing pancreas

Exocrine Pancreatic Function in Rat with Insulin-Producing Tumors

Dig Dis Sci 29 (5): 443-7, 1984

Insulinoma-bearing pancreasControl pancreas

Insulinoma-bearing pancreas

Effect of Tumor Removal on Endocrine Pancreatic Function in Rat with

Insulin-Producing Tumors

Insulinoma-bearing pancreas

TumorRemoval

Insu

lin (n

g/m

l)

Insulinoma

Effect of Tumor Removal on Endocrine Pancreatic Function in Rat with

Insulin-Producing TumorsIn

sulin

(ng/

ml)

Insulinoma-removed pancreas

Effect of Chronic Pancreatitis on the

Endocrine Pancreas

Effect of Chronic Pancreatitis on the

Endocrine Pancreas

Chronic pancreatitis causes pancreatic fibrosis and sometimes results in

diabetes mellitus.

Pancreatogram and Histology of Chronic Pancreatitis

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（（n=4n=4））CPCP

(n=17)(n=17)

1919±±55

257257±±59*59*

1313±±66 1111±±33

201201±±51*51*161161±±45*45*

Jalleh RP et al. Jalleh RP et al. Br J SurgBr J Surg 78: 123578: 1235--7, 1991.7, 1991.

Three to six recordings were obtained at each site. In chronic pancreatitis the pressure (mean +/- s.e.m.) was substantially elevated in all regions of the pancreas compared with reference subjects

Pancreatic Tissue Pressure in Chronic Pancreatitis

Tissue Pressure (mmHg)

Pressure (mmHg) for 60 minPressure (mmHg) for 60 min

Data are means Data are means ±± SD. * SD. * PP<0.0001 vs control<0.0001 vs control

Effect of Intensity and Duration of Pressure on PSC Proliferation

00 4040 8080 120120

100100

00

Brd

U In

corp

orat

ion

Brd

U In

corp

orat

ion

(% o

f con

trol)

(% o

f con

trol)

**** **

(A) Intensity(A) Intensity

120120140140

60608080

40402020

160160

Time (min) at 80 mmHg pressure Time (min) at 80 mmHg pressure 00 3030 6060 120120

****

**

(B) Duration(B) Duration

100100

00

Brd

U In

corp

orat

ion

Brd

U In

corp

orat

ion

(% o

f con

trol)

(% o

f con

trol) 120120

140140

60608080

40402020

160160

Effect of Pressure on PSC Activation

After the application of pressure at 80 mmHg for 60 min, the level of α-SMA protein was analyzed by Western blot.

Control P (-) P (+)P (+)P (+)12 hours

α-SMA

100

0

α-S

MA

Exp

ress

ion

(% o

f con

trol)

200

300

400

500 PP<0.0001<0.0001

(A) α-SMA Expression ControlControl

Activated PSCActivated PSC

Rel

ativ

e m

RN

A E

xpre

ssio

n R

elat

ive

mR

NA

Exp

ress

ion

of C

olla

gen

Iof

Col

lage

n I

00

22

11

PressurePressure (+)(+)((--))

33

Effect of Pressure on Collagen type I mRNA Expression and Collagen Secretion by PSCs

P<0.05

PressurePressure (+)(+)((--))00

Col

lage

n S

ecre

tion

Col

lage

n S

ecre

tion

(% o

f con

trol)

(% o

f con

trol)

100100120120140140

60608080

40402020

160160

P<0.05

Collagen secretion into culture medium during 48 h of incubation after pressure

After the application of pressure at 80 mmHg for 60 min.

Pressureactivates rat PSCs and stimulates type 1 collagensecretion. Increase of pancreatic tissue pressure further accelerates the development of pancreaticfibrosis via proliferation and activation of PSCs in chronic pancreatitis.

Microcirculation in Alcoholic Chronic Pancreatitis

228±23 286±30 351±46

399±43

103±37(23.6%)

86±28(37.7%)

86±28(30.1%)

99±33(24.8%)

436±34

141±47(40.2%)

(A) Normal Pancreas

(B) Chronic Pancreatitis

Blood flow in chronic pancreatitis is significantly lower than that in the corresponding area of the normal pancreas Pancreas 19:21-25,1999

400

200

00 6

Time (Seconds)

Systolic

Diastolic

Perfu

sion

Uni

t

200

00 6Time (Seconds)

SystolicDiastolic

Perfu

sion

Uni

t

Perfusion Unit

Effect of Hypoxia on PSC ActivationEffect of Hypoxia on PSC Activation--Expression of Expression of αα--SMASMA--

ControlControl

HypoxiaHypoxiaHypoxia

Culture 48hCulture 48hCulture 24hCulture 24h

100

0

200

24 hHypoxiaControl

P<0.05

Effect of Hypoxia (3% OEffect of Hypoxia (3% O22) on PSC ) on PSC Proliferation and ActivationProliferation and Activation

Brd

U In

corp

orat

ion

(% o

f con

trol)

Brd

U In

corp

orat

ion

(% o

f con

trol)

100

200

0 HypoxiaControl24 h

P<0.05(B) (B) αα−−SMASMA ExpressionExpression

α-S

MA

Exp

ress

ion

(% o

f con

trol)(A) BrdU Incorporation(A) BrdU Incorporation

0

2

4

6

8

10 P<0.01

Rel

ativ

e m

RN

A E

xpre

ssio

n R

elat

ive

mR

NA

Exp

ress

ion

of C

olla

gen

Iof

Col

lage

n I

Effect of Hypoxia on Collagen type I mRNA Expression and Collagen Secretion by PSCs

24 hHypoxiaControl

0

5

10

15

20

25

Col

lage

n S

ecre

tion

(mg/

ml) P<0.01

HypoxiaControl24 h

Chronic PancreatitisPancreas CirrhosisPancreas Cirrhosis

Liver Cirrhosis

Chronic Pancreatitis

Progression of Pancreatic Fibrosis

Progression of Pancreatic Fibrosis

Tissue Pressure

HypoxiaHypoxia

Activation of PSCsActivation of PSCs

Micro-circulation

Endocrine Endocrine InsufficiencyInsufficiency

Exocrine Exocrine InsufficiencyInsufficiency

Endocrine Pancreatic Function in Patients with Chronic Pancreatitis

Dig Dis Sci 1992;37: 93-6.

2.4

2.0

1.6

1.2

0.8

0.4

0

C-p

eptid

e (p

mol

/ml)

Control(19)

Normal(6)

Moderately(14)

Severely(10)

：Basal C-peptide：△ C-peptide

#

##

#: P<0.001 vs control

Exocrine Function in CP

Glucagon test

Lipase Output--------SC testΔC Peptide Value--Glucagon test

1.81.6

1.2

0.8

0.4

0

△C-p

eptid

e (p

mol

/ml)

0Lipase (x103 IU/30 min)

0.2

0.6

1.0

1.4

5 10 15 20 25 30 35

r = 0.72 P<0.001

Dig Dis Sci 1992;37: 93-6.

Endocrine Pancreatic Function in Patients with Chronic Pancreatitis

Prevalence of Diabetes Mellitus during an 8-year Follow-up Study

of Patients with Chronic Pancreatitis

Prevalence of Diabetes Mellitus during an 8-year Follow-up Study

of Patients with Chronic Pancreatitis

Prevalence of Diabetes Mellitusin Patients with Chronic Pancreatitis

1994

0 20 40 60 80 100 (%)

DM (+)35.1 %

(n=230）

DM (-)63.7 %

(n=418）

Unknown 1.2 % (n=8）

2002DM (+)50.4 %

(n=331）

DM (-)47.9 %

(n=314）

Unknown 1.7 %

(n=11）

Diabetes Mellitus in Patients withChronic Pancreatitis

2002DM (+)35.1%(n=230)

DM (+)35.1%(n=230)

DM (-)(n=418)

DM (+) 90.0 % (n=207)DM (+) 90.0 % (n=207)

DM (-) 10.0 % (n=23)

DM (+) 28.9 % (n=121)DM (+) 28.9 % (n=121)

DM (-) 68.7 % (n=287)

Unknown 2.4 % (n=10)

DM (+) 37.5 % (n=3)DM (+) 37.5 % (n=3)

DM (-) 50.0 % (n=4)

Unknown 12.5% (n=1)

1994

Chronic Pancreatitis

(n=656)

Unknown(n=8)

Incidence of Diabetes Mellitus in Patients with Newly Diagnosed Chronic Pancreatitis

2002DM (+) 37.0 % (n=10)DM (+) 37.0 % (n=10)

DM (-) 55.6 % (n=15)

Unknown 7.4% (n=2)

1994

Chronic Pancreatitis

(n=77)DM (+) 18.0 % (n=9)DM (+) 18.0 % (n=9)

DM (-) 78.0 % (n=39)

Unknown 4.0 % (n=2)

Surgery (+)35.1%(n=27)

Surgery (+)35.1%(n=27)

Surgery (-)64.9%(n=50)

Newly diagnosed chronic pancreatitis in 1994 without diabetes

In 1994 0％ (77）

In 2002 24.7％ (19)

Incidence of Diabetes Mellitusin Patients with Newly Diagnosed

Chronic Pancreatitis without Diabetes

Surgical Rx 37% (9)Medical Rx 18%(10)

Diabetes mellitus was newly found in 28.9% (121/418) of patients with chronic pancreatitis who were NGT in 1994.

During an 8-year Follow-up Period

Diabetes mellitus was found in 24.7%(19/77) of patients with newly diagnosed chronic pancreatitis who were NGT in 1994.

Diffuse irregular narrowing of the MPD

Unique form of Chronic Pancreatitis characterized by infrequent ainfrequent attacks of abdominal pain,

swelling of theswelling of the papancreatic parenchyma, andanddiffuse irregular narrowingdiffuse irregular narrowing of the main pancreatic duct (MPD).

Autoimmune PancreatitisAutoimmune Pancreatitis

Exocrine Pancreatic Function in AIPExocrine Pancreatic Function in AIPExocrine Pancreatic Function in AIP

Secretin Testwas performed in 10 patients with AIP and was abnormal in all of them.

Secretin TestSecretin Testwas performed in 10 was performed in 10 patients with AIP and was patients with AIP and was abnormal in all of them.abnormal in all of them.PA

BA

Exc

retio

n (％

)PA

BA

Exc

retio

n (

PAB

A E

xcre

tion

( ％％))

0

20

40

60

80

100BT-PABA TestBTBT--PABA TestPABA Test

7070％％

Abnormally low in 81% Abnormally low in 81% patients (29/36) with AIP. patients (29/36) with AIP.

•Pancreatic exocrine function is sometimes impaired.

Diabetes Mellitus in Patients with AIP（Definite AIP 167）

15例

56例6

（n=167）

Diabetes Mellitus66.5 %

Type 1 DM4%

Type 2 DM?53%

Type 2 DM?53%

DM type?9%

DM (-)33.5%

ーOnset of DM in Relation to AIPー

（Definite AIP 93）

31例

1例Before AIP33%

With AIP52%

With AIP52%

After PSL Rx14%

After Px1%

Diabetes Mellitus in Patients with AIP

Although DM appeared after steroid therapy in 14%, DM was diagnosed before or simultaneously with the diagnosis of AIP in 85%. Treatment with steroids improved DM in some patients.

Changes of the CT Images of the Pancreas after Steroid Therapy

Following steroid therapy, the pancreas became small andatrophic suggesting that AIP is a progressive disease andthat AIP is a possible early stage of idiopathic chronic pancreatitis.

Before Rx2 wks after Rx

3 mons after Rx

Effect of Hyperglycemia on the Exocrine PancreasEffect of Hyperglycemia

on the Exocrine Pancreas

Effects of Glucose Loading on Serum Amylase Activity

0 30 60 90 120 0 5 10 20 40 60

200

150

100

50

0

Pla

sma

Glu

cose

(mg/

100m

l)120

110

100

90

Ser

um A

myl

ase

(SU

/100

ml)

(A) Per oral (B) Intravenous

Serum Amylase

Plasma Glucose

Time (min) Tine (min)

Serum Amylase

Plasma Glucose

Relationship Between Plasma Glucose Levels and Serum Pancreatic Amylase Activity

r＝0.458p＜0.05

Pan

crea

tic-ty

pe A

myl

ase

(%)

Plasma Glucose (mg/100ml)50 100 150

75

50

25

y＝116.5−0.56x

00

Effect of High Glucose Concentration on

Pancreatic Stellate Cells

Effect of High Glucose Concentration on

Pancreatic Stellate Cells

Glucose (mM)

Glucose (mM)

Effect of Glucose Concentration onPSC Proliferation and Activation

(B) α-SMA Expression

α-S

MA

Exp

ress

ion

Den

sito

met

er u

nits

(%

of c

ontro

l )

5.6 33.625.2

150

100

50

0

p < 0.0 5p < 0.05

PS

C P

rolif

erat

ion(

OD

)

0.4

0.3

0.2

05.6 33.625.2

(A) PSC Proliferation

0.1

p < 0.05

Effect of Osmolarity on PSC Proliferation and Activation

120

5.6 33.628.05.6

- -

0

80

40

PS

C P

rolif

erat

ion

(% o

f con

trol)

Osmolarity control had no influence on PSC proliferation after 48h incubation.

200

0

α-SMA

100

＊300

400

50.4-

5.6- 50.4

-

α-S

MA

Exp

ress

ion

(% o

f con

trol)

Glucose (mM)Glucose (mM)Mannitol (mM)Mannitol (mM)

Negative control 5.6 mM Glucose

33.6 mM Glucose Osmolarity Control

Immunostaining for α-SMA

0

50

100

150

200

250

300

350

5.6 25.2 33.6

Col

lage

n C

once

ntra

tion

in th

e C

ultu

re M

ediu

m (µ

g/m

l) p < 0.05

Glucose (mM)Glucose (mM)

p < 0.05

Effect of Glucose Concentration on Type I Collagen Production in PSCs

High Glucose Concentrations：1. Stimulate PSC proliferation

2. Activate PSCs

3. Stimulate collagen production in PSCs

Fibrosis and Sclerosis of the Pancreas

Diabetes Mellitus

HypoinsulinemiaHyperglycemia

Endocrine Endocrine InsufficiencyInsufficiency

Progression of Pancreatic Fibrosis

Progression of Pancreatic Fibrosis

Activationof PSCs

Activationof PSCs

Chronic Pancreatitis

Acinar cell growthProtein synthesisAcinar cell growthProtein synthesis

PressureHypoxia

Alcoholic, IdiopathicAlcoholic, Idiopathic

Thank you for your attention

PSC ActivationPSC Activation