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β-Cell Preservation and Regeneration
After Islet Transplantation
Jyuhn-Huarng Juang, MD
Division of Endocrinology and Metabolism,
Department of Internal Medicine,
Chang Gung University and Memorial Hospital,
TAIWAN
Nature History of Type 1 Diabetes
N Engl J Med 1986; 314:1360-1368
Human Islet
Transplantation
Year rate patient no.
1893-1998 8% 493 (total)
1990-1999 11% 237 (type 1)
Human Islet Transplantation
Insulin independence: at 1 year
Year rate patient no.
1893-1998 8% 493 (total)
1990-1999 11% 237 (type 1)
1992-1998 25% (SIK) Giessen
27% (IAK)
Human Islet Transplantation
Insulin independence: at 1 year
Year rate patient no.
1893-1998 8% 493 (total)
1990-1999 11% 237 (type 1)
1992-1998 25% (SIK) Giessen
27% (IAK)
1999-2000 100% (ITA) 7 (Edmonton)
2002 85% (ITA) 33 (Edmonton)
Human Islet Transplantation
Insulin independence: at 1 year
Year rate patient no.
1893-1998 8% 493 (total)
1990-1999 11% 237 (type 1)
1992-1998 25% (SIK)
27% (IAK)
1999-2000 100% (ITA) 7 (Edmonton)
2002 85% (ITA) 33 (Edmonton)
2006 44% 36 (9 sites)
Human Islet Transplantation
Insulin independence: at 1 year
Edmonton Protocol
(Shapiro AMJ et al. N Engl J Med 2000;343:230-8)
• High quality of human islets
• Glucocorticoid-free
immunosuppressive regimen
• Repeat transplants
Human Islet TransplantationInsulin Independence and Graft Function (Edmonton)
Graft β-Cell
Preservation and Regeneration
• Prevent rejection and autoimmune destruction
• Enhance islet engraftment
• Promote beta-cell regeneration
Prevention of Rejection and
Autoimmune Destruction
• Immunosuppression
• Immunomodulation
• Immunoisolation
• Tolerance induction
Approaches to Prevent Rejection
and Autoimmune Destruction
Rejection
MicrocapsuleHsu BRS et al.
Transplant Proc 1996
Cell Transplant 1999
CTLA4 Ig
Lu WT et al.
Transplant Proc 2001
Autoimmune
DCR3 TgSung HH et al.
J Exp Med 2004
FasL/HO-1 TgJuang JH et al.
Transplant Proc 2011
Immunoisolation
Microparticle
Generator
Hsu BRS et al., J Formos Med Assoc 93:240-5, 1994.
Glucose Insulin
Immunoglobulin
Islet
Alginate-Poly-L-Lysine-Alginate
(APA) Microcapsule
APA Microencapsuled Rat Islets
IsletIL-1β
IL-1ra
X
Hsu BRS et al.,
Transplant Proc
28:1961-3, 1996.
15-DSG
X
Hsu BRS et al.,
Cell Transplant
8:307-15, 1999.
Macrophagefibrosis
Overexpression of DCR3
Protected NOD from Insulitis
Sung H-H, Juang J-H et al. J Exp Med 2004;199:1143-1151
DCR3 Transgenic Islets
Prevented Autoimmune DestructionDCR3 Transgenic
Islet Transplantation in NOD Mice
NOD Mice (12 wks)
DCR3 Transgenic NOD Mice
Graft β-Cell
Preservation and Regeneration
• Prevent rejection and autoimmune destruction
• Enhance islet engraftment
• Promote beta-cell regeneration
Problems Related to
Islet Engraftment
• Hyperglycemia
• Hypoperfusion
• Hypoxia
• Ischemia/Reperfusion
• Nonspecific inflammatory response
InsulinJuang JH et al.
Transplant Proc
1998
Approaches to Enhance
the Islet Engraftment
Islet Growth and Function
Additional
IsletsJuang JH et al.
Diabetes 1994
Outcome of Islet Transplantation
DSGJuang JH et al.
Transplant Proc
2002
NDGAHsu BRS et al.
Cell Transplant
2001
RosiglitazoneHsu BRS et al.
Transplant Proc
2005
Transplant Proc
Fu SH et al.
COPP
2004
PentoxiphyllineJuang JH et al.
Transplant Proc
2000
HBOJuang JH et al.
Cell Transplant
2002
Beneficial Influence of Additional Islets
on Syngeneic Mouse Islet Transplantation
100
125
150
175
200
225
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14
Days after Nephrectomy or Graft Removal
Sham operation (n=5)
Graft Removal (n=16)
Nephrectomy (n=6)
100
200
300
400
500
Blood Glucose (mg/dl)
0 1 2 3 4 5 6 7 8 9 1011121314
Days after Transplantation
Tx with 200X2 islets (n=53)
Tx with 200 islets (n=22)
*
*
*
*P<0.001 vs. data at day 0
*
* *
*
***
* p < 0.05, ** p < 0.01 vs. data at day 0
*
**
***
***
* * *
Juang JH et al., Diabetes 1994;43:1334-9
Beta-Cell Mass and Insulin Content of the Graft
Juang JH et al., Diabetes 1994;43:1334-9
*
*
**
0
0.1
0.2
0.3
0.4
0.5
Beta-Cell Mass (mg)
200 Islets 0 14Days after Graft Removal
or Sham Operation
Sham Operation
Graft Removal
0
1
2
3
4
5
6
7
8
9
Insulin Content (µg)
200 Islets 0 14Days after Graft Removal
or Sham Operation
* P<0.01 vs. 200 islets and day 14
** P<0.05 vs. day 14
Replication Rate of Islet Grafts
Juang JH et al., Diabetes 1994;43:1334-9
*
0.0
0.2
0.4
0.6
0.8
1.0
1.2
1.4Replication Rate (%/4h)
0 3 5 14
Days after One Graft Removal or Sham Removal
Sham Removal
Graft Removal * p < 0.02 vs. other groups in graft removal,
and p < 0.04 vs. day 3 in sham operation
Effect of Insulin Treatment onSyngeneic Mouse Islet Transplantation
0
100
200
300
400
500
Blood Glucose (mg/dl)
0 7 14 21 28
Days After Transplantation
UT (n=30)NS (n=16)
Ultratard or NS sc qd
* ****
**********
******
*********
***
***
*** ******
* P<0.05, ** P<0.01, *** P<0.001 vs. NS
Juang JH et al., Transplant Proc 1998;30:576-7.
Blood Glucose Changes After Transplantation
0
100
200
300
400
500
Blood Glucose (mg/dl)
0 7 14 21 28
Days After Transplantation
UT-B+A (n=5)UT-A (n=30)
UT-B (n=7)Control (n=16)
*
* * * * * *** *
***
* **
*
* * * ***
*
**
**
**
*
**
**
**
*
** *
*
*
*
* *
* *
* P<0.05 vs. NS
Juang JH et al., Transplant Proc 1998;30:576-7.
Beta-Cell Mass of Mouse Islet Grafts
At 4 Weeks After Transplantation
0
0.1
0.2
0.3
0.4
0.5Beta-Cell Mass (mg)
Control UT-B UT-A UT-B+A
* *
** P<0.05 vs. Control
Juang JH et al., Transplant Proc 1998;30:576-7.
Graft β-Cell
Preservation and Regeneration
• Prevent rejection and autoimmune destruction
• Enhance islet engraftment
• Promote beta-cell regeneration
Regeneration Therapy in Islet Recipients
β-cell Mass
Islet Transplant
Islet Regeneration
Time
Graft Failure
Insulin independence threshold
Pancreatic Targets for Expansion of β-Cell Mass
Annu Rev Med 2006;57:265–81
β-Cell
GLP-1 on β-Cell Mass
Endocrine Reviews 2007;28:187–218
Exenatide in Clinical Islet Transplantation
ISLETS
EXENATIDE1
1Exenatide reduces the number of islet infusions to achieve normoglycemia (Am J Transplant 2008;8:1250-61)
2
2Exenatide rescues islet recipients with allograft dysfunction (Transplantation 2008;86:36–45)
3
3Exenatide improves success rates in recipients with supplemental islet infusions (Transplantation 2008;86:1658–65)
500 Control (n=17)
Exendin-4 (n=16)
0
100
200
300
400
0 5 10 15 20 25 30 35 40
Days After Transplantation
Blood Glucose (mg/dl)
* P<0.05 vs. control
*
**** *
* **
Exendin-4 Improves Outcome of
Syngeneic Mouse Islet Transplantation
Blood Glucose
Juang JH et al., Cell Transplant 17:641-7, 2008
Diabetes (%)
Days After Transplantation
* P=0.012 vs. control
Exendin-4
Control (47.5%)
Diabetes (%)
Control (n=17)
Exendin-4 (n=16)
Juang JH et al., Cell Transplant 17:641-7, 2008
Exendin-4 Expands Mouse Graft β-Cell Mass
Juang JH et al., Cell Transplant 17:641-7, 2008
Exendin-4 Control
100 µm 100 µm
Insulin Staining β-Cell Mass
Mouse Islet Graft at 6 Weeks
Exendin-4 Prevents Mouse Graft β-Cell
Apoptosis and Preserves Graft β-Cell Mass
β-Cell Area Apoptosis
Toyoda K et al. Biochem Biophys Res Commun 367:793-9, 2008
Liraglutide Prevents Mouse Graft β-Cell Apoptosis
But Does Not Promote β-Cell Proliferation
Merani S et al. Endocrinology 149:4322–4328, 2008
Apoptotic β-cells (%)48 hr
BrdU+ β-cells (%)
2 wk
Sitagliptin Prolongs Mouse Islet Graft Survival
Kim S-J et al. Diabetes 57:1331–9, 2008
Islets: infected with rAD-TK to allow [18F]FHBG PET imaging
Effects of Dipeptidyl Peptidase-4 Inhibition
on Syngeneic Mouse Islet Transplantation
Juang JH et al. Diabetes 61 (suppl 1):A409, 2012
Blood Glucose
*
MK-0431 LAF 237
P=0.001
Effects of Dipeptidyl Peptidase-4 Inhibition
on Syngeneic Mouse Islet Transplantation
Juang JH et al. Diabetes 61 (suppl 1):A409, 2012
Body Weight
MK-0431 LAF 237
*P=0.057
Effects of Dipeptidyl Peptidase-4 Inhibition
on Syngeneic Mouse Islet Transplantation
Juang JH et al. Diabetes 61 (suppl 1):A409, 2012
Insulin Content and β-Cell Mass
0
2
4
6
8
10
insulin content (ng) β-cell mass (mg)
Control MK-0431
MK-0431 LAF 237
Islet Transplantation
A Cure for Diabetes
Graft β-Cell
Preservation and Regeneration
CGMH Islet Transplant Team
Grant Support� National Science Council, Taiwan
� Industrial Technology Research Institute, Taiwan
� Chang Gung Memorial Hospital, Taiwan