relationship between exocrine and endocrine pancreas
TRANSCRIPT
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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
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• 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
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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
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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
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Effect of Hypoinsulinemia on the
Exocrine Pancreas
Effect of Hypoinsulinemia on the
Exocrine Pancreas
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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
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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)
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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)
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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
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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
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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
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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.
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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
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Effect of Hyperinsulinemia on
the Exocrine Pancreas
Effect of Hyperinsulinemia on
the Exocrine Pancreas
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•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
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There are no reports that revealedincreased functional activity ofthe exocrine pancreas athyperinsulinemic and normoglycemic state.
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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
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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.
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Endocrine Pancreatic Function in Rat with Insulin-Producing Tumors
Insulinoma-bearing pancreas
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Exocrine Pancreatic Function in Rat with Insulin-Producing Tumors
Dig Dis Sci 29 (5): 443-7, 1984
Insulinoma-bearing pancreasControl pancreas
Insulinoma-bearing pancreas
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Effect of Tumor Removal on Endocrine Pancreatic Function in Rat with
Insulin-Producing Tumors
Insulinoma-bearing pancreas
TumorRemoval
Insu
lin (n
g/m
l)
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Insulinoma
Effect of Tumor Removal on Endocrine Pancreatic Function in Rat with
Insulin-Producing TumorsIn
sulin
(ng/
ml)
Insulinoma-removed pancreas
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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.
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Pancreatogram and Histology of Chronic Pancreatitis
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HeaHeadd
BodBodyy
TaiTailleferenceeference
((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)
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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
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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
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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.
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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.
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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
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Effect of Hypoxia on PSC ActivationEffect of Hypoxia on PSC Activation--Expression of Expression of αα--SMASMA--
ControlControl
HypoxiaHypoxiaHypoxia
Culture 48hCulture 48hCulture 24hCulture 24h
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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
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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
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Chronic PancreatitisPancreas CirrhosisPancreas Cirrhosis
Liver Cirrhosis
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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
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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
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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
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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
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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)
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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)
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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
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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)
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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.
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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
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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.
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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%
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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.
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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
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Effect of Hyperglycemia on the Exocrine PancreasEffect of Hyperglycemia
on the Exocrine Pancreas
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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
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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
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Effect of High Glucose Concentration on
Pancreatic Stellate Cells
Effect of High Glucose Concentration on
Pancreatic Stellate Cells
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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
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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)
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Negative control 5.6 mM Glucose
33.6 mM Glucose Osmolarity Control
Immunostaining for α-SMA
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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
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High Glucose Concentrations:1. Stimulate PSC proliferation
2. Activate PSCs
3. Stimulate collagen production in PSCs
Fibrosis and Sclerosis of the Pancreas
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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
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Thank you for your attention
PSC ActivationPSC Activation