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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

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