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
Human Islet Transplantation Insulin independence: at 1 year 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)
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 Transplantation Insulin Independence and Graft Function (Edmonton)
Graftβ-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 Microcapsule Hsu BRS et al. Transplant Proc 1996 Cell Transplant 1999 CTLA4 Ig Lu WT et al. Transplant Proc 2001 FasL/HO-1 Tg Juang JH et al. Transplant Proc 2011 DCR3 Tg Sung HH et al. J Exp Med 2004 Rejection Autoimmune
Immunoisolation Microparticle Generator Alginate-Poly-L-Lysine-Alginate (APA) Microcapsule Immunoglobulin Glucose Islet Insulin Hsu BRS et al., J Formos Med Assoc 93:240-5, 1994.
APA Microencapsuled Rat Islets IL-1ra 15-DSG fibrosis X Macrophage IL-1β X Islet Hsu BRS et al., Cell Transplant 8:307-15, 1999. Hsu BRS et al., Transplant Proc 28:1961-3, 1996.
DCR3 Transgenic Islets Prevented Autoimmune Destruction Overexpression of DCR3 Protected NOD from Insulitis NOD Mice (12 wks) DCR3 Transgenic Islet Transplantation in NOD Mice DCR3 Transgenic NOD Mice Sung H-H, Juang J-H et al. J Exp Med 2004;199:1143-1151
Graftβ-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
Approaches to Enhance the Islet Engraftment Additional Islets Juang JH et al. Insulin Juang JH et al. Transplant Proc HBO Juang JH et al. Cell Transplant Pentoxiphylline Juang JH et al. Transplant Proc NDGA Hsu BRS et al. Cell Transplant DSG Juang JH et al. Transplant Proc Diabetes 1994 1998 2002 2000 2001 2002 COPP Fu SH et al. Transplant Proc 2004 Islet Growth and Function Rosiglitazone Hsu BRS et al. Transplant Proc 2005 Outcome of Islet Transplantation
Beneficial Influence of Additional Islets on Syngeneic Mouse Islet Transplantation Blood Glucose (mg/dl) 500 400 300 200 100 Tx with 200 islets (n=22) Tx with 200X2 islets (n=53) P<0.001 vs. data at day 0 0 1 2 3 4 5 6 7 8 9 1011121314 225 200 175 150 125 100 Graft Removal (n=16) Nephrectomy (n=6) Sham operation (n=5) p < 0.05, p < 0.01 vs. data at day 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Days after Transplantation Days after Nephrectomy or Graft Removal Juang JH et al., Diabetes 1994;43:1334-9
Beta-Cell Mass and Insulin Content of the Graft Graft Removal P<0.01 vs. 200 islets and day 14 0.5 Sham Operation 9 P<0.05 vs. day 14 Beta-Cell Mass (mg) 0.4 0.3 0.2 0.1 0 200 Islets 0 14 Days after Graft Removal or Sham Operation Insulin Content (µg) 8 7 6 5 4 3 2 1 0 200 Islets 0 14 Days after Graft Removal or Sham Operation Juang JH et al., Diabetes 1994;43:1334-9
Replication Rate of Islet Grafts 1.2 1.0 0.8 0.6 0.4 0.2 Replication Rate (%/4h)1.4 Graft Removal Sham Removal p < 0.02 vs. other groups in graft removal, and p < 0.04 vs. day 3 in sham operation 0.0 0 3 5 14 Days after One Graft Removal or Sham Removal Juang JH et al., Diabetes 1994;43:1334-9
Effect of Insulin Treatment on Syngeneic Mouse Islet Transplantation Blood Glucose (mg/dl) 500 400 300 200 100 0 NS (n=16) UT (n=30) P<0.05, P<0.01, P<0.001 vs. NS Ultratard or NS sc qd 0 7 14 21 28 Days After Transplantation Juang JH et al., Transplant Proc 1998;30:576-7.
Blood Glucose Changes After Transplantation 500 Control (n=16) UT-A (n=30) UT-B (n=7) UT-B+A (n=5) Blood Glucose (mg/dl) 400 300 200 100 P<0.05 vs. NS 0 0 7 14 21 28 Days After Transplantation Juang JH et al., Transplant Proc 1998;30:576-7.
Beta-Cell Mass of Mouse Islet Grafts At 4 Weeks After Transplantation 0.5 Beta-Cell Mass (mg) 0.4 0.3 0.2 0.1 P<0.05 vs. Control 0 Control UT-B UT-A UT-B+A Juang JH et al., Transplant Proc 1998;30:576-7.
Graftβ-Cell Preservation and Regeneration Prevent rejection and autoimmune destruction Enhance islet engraftment Promote beta-cell regeneration
Regeneration Therapy in Islet Recipients β-cell Mass Graft Failure Islet Regeneration Insulin independence threshold Islet Transplant Time
Pancreatic Targets for Expansion of β-cell Mass Annu Rev Med 2006;57:265 81
GLP-1 on β-cell Mass β-cell Endocrine Reviews 2007;28:187 218
Exenatide in Clinical Islet Transplantation 1 EXENATIDE 3 2 ISLETS 1 Exenatide reduces the number of islet infusions to achieve normoglycemia (Am J Transplant 2008;8:1250-61) 2 Exenatide rescues islet recipients with allograft dysfunction (Transplantation 2008;86:36 45) 3 Exenatide improves success rates in recipients with supplemental islet infusions (Transplantation 2008;86:1658 65)
Exendin-4 Improves Outcome of Syngeneic Mouse Islet Transplantation Blood Glucose Diabetes (%) Blood Glucose (mg/dl) 500 P<0.05 vs. control Control (n=17) 400 300 200 100 0 Exendin-4 (n=16) 0 5 10 15 20 25 30 35 40 Days After Transplantation Diabetes (%) Days After Transplantation Juang JH et al., Cell Transplant 17:641-7, 2008 P=0.012 vs. control Control (47.5%) Exendin-4
Exendin-4 Expands Mouse Graft β-cell Mass Mouse Islet Graft at 6 Weeks Insulin Staining Exendin-4 Control β-cell Mass 100 µm 100 µm Juang JH et al., Cell Transplant 17:641-7, 2008
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 48 hr Apoptotic β-cells (%) 2 wk BrdU+ β-cells (%) Merani S et al. Endocrinology 149:4322 4328, 2008
Sitagliptin Prolongs Mouse Islet Graft Survival Islets: infected with rad-tk to allow [ 18 F]FHBG PET imaging Kim S-J et al. Diabetes 57:1331 9, 2008
Effects of Dipeptidyl Peptidase-4 Inhibition on Syngeneic Mouse Islet Transplantation Blood Glucose MK-0431 LAF 237 P=0.001 Juang JH et al. Diabetes 61 (suppl 1):A409, 2012
Effects of Dipeptidyl Peptidase-4 Inhibition on Syngeneic Mouse Islet Transplantation Body Weight MK-0431 LAF 237 P=0.057 Juang JH et al. Diabetes 61 (suppl 1):A409, 2012
Effects of Dipeptidyl Peptidase-4 Inhibition on Syngeneic Mouse Islet Transplantation Insulin Content and β-cell Mass MK-0431 LAF 237 Control MK-0431 10 8 6 4 2 0 insulin content (ng) β-cell mass (mg) Juang JH et al. Diabetes 61 (suppl 1):A409, 2012
Islet Transplantation Graft β-cell Preservation and Regeneration A Cure for Diabetes
CGMH Islet Transplant Team Grant Support National Science Council, Taiwan Industrial Technology Research Institute, Taiwan Chang Gung Memorial Hospital, Taiwan