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International Journal of Pancreatology

, Volume 24, Issue 3, pp 145–168 | Cite as

Clinical islet cell transplantation

Are we there yet?
  • Lawrence Rosenberg
State-of-the-Art
  • 30 Downloads

Summary

Diabetes mellitus is perhaps the most devastating chronic disease of all time. A brief history of the evolution of treatment modalities is provided, culminating in the rationale for the physiologic replacement of a functioning β-cell mass by transplantation. Vascularized pancreas transplantation is discussed briefly as an introduction to the transplantation of the isolated islet. A detailed review of the current state of human islet transplantation for the cure of diabetes is then described. Finally, areas for future development are highlighted.

Key Words

Diabetes mellitus islet cell transplantation DCCT immunosuppression 

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References

  1. 1.
    Krall LP, Levine Rand Barnett A. Introduction, inJoslin's Diabetes Mellitus, 13th ed. (Kahn RC, Weir GC, eds.), Lea and Eitinger, Philadelphia, 1989; p. 1.Google Scholar
  2. 2.
    Kroleuzki AS, Warram JH. inJoslin's Diabetes Mellitus, 13th ed. (Kahn RC, Weir GC, eds.), Lea and Eitinger, Philadelphia, 1989; p. 605.Google Scholar
  3. 3.
    Harris M, Halden WC, Knowles WC, Bennett PH. Prevalence of diabetes and impaired glucose tolerance and plasma glucose levels in the U.S. population aged 20–74 years.Diabetes 1987; 36: 523–534.PubMedGoogle Scholar
  4. 4.
    Libman I, Songer T, Laporte R. How many people in the U.S. have IDDM?Diabetes Care 1993; 16: 841,842.PubMedGoogle Scholar
  5. 5.
    Eisenbarth GS. Type I diabetes mellitus: a chronic autoimmune disease.N Engl J Med 1986; 314: 1360–1368.PubMedCrossRefGoogle Scholar
  6. 6.
    Atkinson MA, MacLaren NK. The pathogenesis of insulin-dependent diabetes mellitus.N Engl J Med 1994; 331: 1428–1436.PubMedGoogle Scholar
  7. 7.
    Nathan DM. Long-term complications of diabetes mellitus.N Engl J Med 1993; 328: 1676–1684.PubMedGoogle Scholar
  8. 8.
    Clark CM, Lee DA. Prevention and treatment of the complications of diabetes mellitus.N Engl J Med 1995; 332: 1210–1217.PubMedGoogle Scholar
  9. 9.
    Selby JV, Fitzsimmons SC, Newman JM, et al. The natural history and epidemiology of diabetic nephropathy: implications for prevention and control.JAMA 1990; 263: 1954–1960.PubMedGoogle Scholar
  10. 10.
    Pi-Sunyer FX. The mission of the American Diabetes Association.Diabetes Care 1993; 16: 1521–1525.PubMedGoogle Scholar
  11. 11.
    Cohen AJ, McGill PD, Rossetti RG, Guberski DL, Like AA. Glomerulopathy in spontaneously diabetic rat. Impact of glycemic control.Diabetes 1987; 36: 944.PubMedGoogle Scholar
  12. 12.
    Engerman RL, Kern TS. Progression of incipient diabetic retinopathy during good glycemic control.Diabetes 1987; 36: 808–812.PubMedGoogle Scholar
  13. 13.
    Wang PH, Lau J, Chalmers T. Meta-analysis of effects of intensive blood-glucose control on late complications of type 1 diabetes.Lancet 1993; 341: 1306–1309.PubMedGoogle Scholar
  14. 14.
    Chase HP, Jackson WE, Hoops SL, Cockerham RS, Archer PG, O'Brien D. Glucose control and the renal and retinal complications of insulin-dependent diabetes.JAMA 1989; 261: 1155–1160.PubMedGoogle Scholar
  15. 15.
    Brownlee M. Glycosylation and diabetic complications.Diabetes 1994; 43: 836–841.PubMedGoogle Scholar
  16. 16.
    Bucala R, Cerami A, Vlassara H. Advanced glycosylation end products in diabetic complications.Diabetes Rev 1995; 3: 258–268.Google Scholar
  17. 17.
    Strowig SM, Raskin P. Glycemic control and the complications of diabetes.Diabetes Rev 1995; 3: 237–257.Google Scholar
  18. 18.
    The Diabetes Control and Complication Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus.N Engl J Med 1993; 29: 977–986.CrossRefGoogle Scholar
  19. 19.
    Purrello F, Pipeleers D. Transplantation in diabetes: A cell biological problem.J Endocrinol Invest 1995; 18: 311–319.PubMedGoogle Scholar
  20. 20.
    Rosenberg L. Pancreatic and islet transplantation, inSurgery: Scientific Principles and Practice (Greenfield LJ, Mulholland M, Oldham KT, Zelenock GB, Lillemoe KD, eds.), Lippincott, Philadelphia, 1993; p. 615–627.Google Scholar
  21. 21.
    Sollinger HW, Geffner SR. Pancreas transplantation.Surg Clin N Am 1994; 74: 1183–1195.PubMedGoogle Scholar
  22. 22.
    American Diabetes Association. Position statement: pancreas transplant for patients with diabetes mellitus.Diabetes Care 1993; 16(Suppl 2): 49.Google Scholar
  23. 23.
    Robertson RP. Pancreatic and islet transplantation for diabetes: cures or curiosities?N Engl J Med 1992; 327: 861–868.Google Scholar
  24. 24.
    Nakache R, Tyden G, Groth CG. Quality of life in diabetic patients after combined pancreas—kidney or kidney transplantation.Diabetes 1989; 38(Suppl 1): 540–542.Google Scholar
  25. 25.
    Piehlmeier W, Bullinger M, Nusser J, Konig A, Illner WD, Abendroth D, Land W, Landgraf R. Quality of life in diabetic patients prior to or after pancreas transplantation in relation to organ function.Transplant Proc 1992; 24: 871–873.PubMedGoogle Scholar
  26. 26.
    Zehr PS, Milde FK, hart LK, Corry RJ. Life quality of pancreatic transplant recipients: a comparison.Transplant Proc 1992; 24: 850,851.PubMedGoogle Scholar
  27. 27.
    Bohman SO, Tyden G, Wilczek H, Lundgren G, Jaremko G, Gunnarsson R, Ostman J, Groth CG. Prevention of kidney graft diabetic nephropathy by pancreas transplantation in man.Diabetes 1985; 34: 306–308.PubMedGoogle Scholar
  28. 28.
    Bilous RW, Mauer SM, Sutherland DE, Najarian JS, Goetz FC, Steffes MW. The effects of pancreas transplantation on the glomerular structure of renal allografts in patients with insulin-dependent diabetes.N Engl J Med 1989; 321: 80–85.PubMedCrossRefGoogle Scholar
  29. 29.
    El-Gebely S, Hathaway DK, Elmer DS, Gaber LW, Acchiardo S, Gaber AD. An analysis of renal function in pancreas—kidney and diabetic kidney-alone recipients at two years following transplantation.Transplantation 1995; 59: 1410–1415.PubMedGoogle Scholar
  30. 30.
    Solders G, Tyden G, Persson A, Groth CG. Diabetic neuropathy four years after pancreas transplantation.Transplant Proc 1992; 24: 856.PubMedGoogle Scholar
  31. 31.
    Kennedy WR, Navarro X, Goetz FC, Sutherland DE, Najarian JS. Effects of pancreatic transplantation on diabetic neuropathy.N Engl J Med 1990; 322: 1031–1037.PubMedCrossRefGoogle Scholar
  32. 32.
    Secchi A, Martinenghi S, Galardi G, Comi G, Canal N, Pozza G. Effects of pancreatic transplantation on diabetic polyneuropathy.Transplant Proc 1991; 23: 1658,1659.PubMedGoogle Scholar
  33. 33.
    Aridge D, Reese J, Niehoff M, Carney K, Lindsey L, Chun HS, George E, Garvin P. Effect of successful renal and segmental pancreatic transplantation on peripheral and autonomic neuropathy.Transplant Proc 1991; 23: 1670,1671.PubMedGoogle Scholar
  34. 34.
    Comi G, Galardi G, Amadio S, Bianchi E, Secchi A, Martinenghi S, Caldara R, Pozza G, Canal N. Neurophysiological study of the effect of combined kidney and pancreas transplantation on diabetic neuropathy: a 2-year follow-up evaluation.Diabetologia 1991; Suppl 1: S103–107.Google Scholar
  35. 35.
    Hathaway DK, Abell T, Cardoso S, Hartwig MS, el Gebely S, Gaber AO. Improvement in autonomic and gastric function following pancreas—kidney versus kidney-alone transplantation and the correlation with quality of life.Transplantation 1994; 57: 816–822.PubMedGoogle Scholar
  36. 36.
    Gaber AO, El-Gebely S, Sugathan P, Elmer DS, Hathaway DK, McCully RB, Shokouh-Amiri MH, Burlew BS. Early improvement in cardiac function occurs for pancreas—kidney but not diabetic kidney-alone transplant recipients.Transplantation 1995; 59: 1105–1112.PubMedGoogle Scholar
  37. 37.
    Ramsay RC, Goetz FC, Sutherland DE, Mauer SM, Robison LL, Cantrill HL, Knobloch WH, Najarian JS. Progression of diabetic retinopathy after pancreas transplantation for insulin-dependent diabetes mellitus.N Engl J Med 1988; 318: 208–214.PubMedCrossRefGoogle Scholar
  38. 38.
    Wang Q, Klein R, Moss SE, Klein BE, Hoyer C, Burke K, Sollinger HW. The influence of combined kidney—pancreas transplantation on the progression of diabetic retinopathy. A case series.Ophthalmology 1994; 101: 1071–1076.PubMedGoogle Scholar
  39. 39.
    Wright FH, Smith JL, Ames SA, Scanbacher B, Corry RJ. Function of pancreas allografts more than 1 year following transplantation.Arch Surg 1989; 124: 796–799.PubMedGoogle Scholar
  40. 40.
    Landgraft R, Nusser J, Riepl RL, Fiedler F, Illner WD, Abendroth D, Land W. Metabolic and hormonal studies of type 1 (insulin-dependent) diabetic patients after successful pancreas and kidney transplantation.Diabetologia 1991; 34 (Suppl 1):S61.Google Scholar
  41. 41.
    Morel P, Brayman KL, Goetz FC, Kendall DM, Moudry-Munns K, Chau C. Long-term metabolic function of pancreas transplants and influence of rejection episodes.Transplantation 1991; 51: 990–1000.PubMedGoogle Scholar
  42. 42.
    Lacy PE, Kostianovsky M. Method for the isolation of intact islets of Langerhans from the rat pancreas.Diabetes 1967; 16: 35–39.PubMedGoogle Scholar
  43. 43.
    Scharp DW, Lacy PE, Santiago JV, McCullough CS, Weide LG, Falqui L, Marchetti P, Gingerich RL, Jaffe AS, Cryer PE, Anderson CB, Flye MW. Insulin independence after islet transplantation into Type I diabetic patients.Diabetes 1990; 39: 515–518.PubMedGoogle Scholar
  44. 44.
    Warnock GL, Kneteman NM, Ryan EA, Rabinovitch A, Rajotte RV. Long-term follow-up after transplantation of insulin-producing pancreatic islets into patients with Type I (insulin-dependent) diabetes mellitus.Diabetologia 1992; 35: 89–95.PubMedGoogle Scholar
  45. 45.
    Socci C, Falqui L, Davalli AM, Ricordi C, Braghi S, Bertuzzi F, Maffi P, Secchi A, Gavazzi F, Freschi M, Magistretti P, Socci C, Vagnali A, Di Carlo V, Pozza G. Fresh human islet transplantation to replace pancreatic endocrine function in Type 1 diabetic patients: report of six cases.Acta Diabetol. 1991; 28: 151–157.PubMedGoogle Scholar
  46. 46.
    International Islet Transplant Registry Newsletter vol. 6, no. 7, December 1996.Google Scholar
  47. 47.
    Pyzdrowski KL, Kendall DM, Halter JB, Nakhleh RF, Sutherland DER, Robertson RP. Preserved insulin secretion and insulin independence in recipients of islet autografts.N Engl J Med 1992; 327: 220–226.PubMedCrossRefGoogle Scholar
  48. 48.
    Farney AC, Najarian JS, Nakhleh RE, et al. Autotransplantation of dispersed pancreatic islet tissue combined with total or near-total pancreatectomy for treatment of chronic pancreatitis.Surgery 1991; 110: 427–443.PubMedGoogle Scholar
  49. 49.
    Kendall DM, Teuscher AU, Seaquist ER, Robertson RP. Defective glucagon secretion and hepatic glucose production during prolonged hypoglycemia in pancreatic autoislet transplant recipients.Diabetes 1994; 43(Suppl 1): 433.Google Scholar
  50. 50.
    Rosenberg L, Duguid WP, eds.Cellular Interrelationships in the Pancreas—Implications for Islet Transplantation. Landes, Austin, TX, 1996.Google Scholar
  51. 51.
    Gores PF, Sutherland DER. Pancreatic islet transplantation: is purification necessary?Am J Surg 1993; 166: 538.PubMedGoogle Scholar
  52. 52.
    Paraskevas S, Duguid WP, Maysinger D, Feldman L, Agapitos D, Rosenberg L. Apoptosis occurs in freshly isolated human islets under standard culture conditions.Transplant Proc 1997; 29: 750–752.PubMedGoogle Scholar
  53. 53.
    Davalli AM, Scaglia L, Zangen DH, Hollister J, Bonner-Weir S, Weir GC. Vulnerability of islets in the immediate posttransplantation period. Dynamic changes in structure and function.Diabetes 1996; 5: 1161–1167.Google Scholar
  54. 54.
    Orloff M, Macedo A, Greenleaf GE, Girard B. Comparison of the metabolic control of diabetes achieved by whole pancreas transplantation and pancreatic islet transplantation in rats.Transplantation 1988; 45: 307–312.PubMedGoogle Scholar
  55. 55.
    Warnock GL. Strategies for increasing islet cell mass: Lessons from islet transplantation.Can J Diabetes Care 1998; in press.Google Scholar
  56. 56.
    Alejandro R, Cutfield RG, Shienvold FL, Polonsky KS, Noel J, Olson L, Dillberger J, Miller J, Mintz DH. Natural history of intrahepatic canine islet cell allografts.J Clin Invest 1986; 78: 1339–1348.PubMedCrossRefGoogle Scholar
  57. 57.
    Warnock GL, Cattral M, Rajotte RV. Normoglycemia after implantation of purified islet cells in dogs.Can J Surg 1988; 31: 421–426.PubMedGoogle Scholar
  58. 58.
    Sutton R, Gray DW, McShane P, Peters M, Morris PJ. The metabolic efficiency and long-term fate of intraportal islet grafts in the Cynomolgus monkey.Transplant Proc 1987; 19: 3575, 3576.PubMedGoogle Scholar
  59. 59.
    Soon-Shiong P, Feldman E, Nelson R, Komebedde J, Smidsrod D, Skjak-Braek G, Espevik T, Heintz R, Lee M. Successful reversal of spontaneous diabetes in dogs by intraperitoneal microencapsulated islets.Transplantation 1992; 54: 769–774.PubMedGoogle Scholar
  60. 60.
    Lanza RP, Sullivan SJ, Chick WL. Islet transplantation with immunoisolation.Diabetes 1992; 41: 1503–1510.PubMedGoogle Scholar
  61. 61.
    Davalli AM, Ogawa Y, Ricordi C, Scharp DW, Bonner-Weir S, Weir GC. A selective decrease in the beta cell mass of human islets transplanted into diabetic nude mice.Transplantation 1995; 59: 817–820.PubMedGoogle Scholar
  62. 62.
    Orloff M, Macedo C, Macedo A, Greenleaf GE. Comparison of whole pancreas and pancreatic islet transplantation in controlling nephropathy and metabolic disorders.Ann Surg 1987; 206: 324–334.PubMedGoogle Scholar
  63. 63.
    London NJM, Robertson GSM, Chadwick DR, Johnson PRV, James RFL, Bell PRF. Human pancreatic islet isolation and transplantation.Clin Transplant 1994; 8: 421–459.PubMedGoogle Scholar
  64. 64.
    Hellman B. The frequency distribution of the number and volume of the islets of Langerhans in man. 1. Studies on non-diabetic adults.Acta Soc Med Upsalien 1959; 64: 432.Google Scholar
  65. 65.
    Saito K, Iwama N, Takahashi T. Morphometrical analysis on topographical difference in size distribution, number and volume of islets in the human pancreas.Tohoku J Exp Med 1978; 124: 177–186.PubMedCrossRefGoogle Scholar
  66. 66.
    Ricordi C, Gray DW, Hering BJ, Kaufman DB, Warnock GL, Kneteman NM, Lake SP, London NJ, Socci C, Alejandro R. Islet isolation assessment in man and large animals.Acta Diabetol Lat 1990; 27: 185–195.PubMedGoogle Scholar
  67. 67.
    Rastogi GK, Sinha MK, Dash RJ. Insulin and proinsulin content of pancreases from diabetic and non-diabetic subjects.Diabetes 1973; 22: 804–807.PubMedGoogle Scholar
  68. 68.
    Wrenshall GA, Bogoch A, Ritchie RC. Extractable insulin of pancreas.Diabetes 1952; 1: 87.PubMedGoogle Scholar
  69. 69.
    Taska Y, Takei M, Hirata Y. C-peptide, insulin and proinsulin components in diabetic and non-diabetic human pancreas.Endocrinol Japan 1979; 26: 313–318.Google Scholar
  70. 70.
    Stefan Y, Orci L, Malaisse-Lagae F, Perrelet A, Patel Y, Unger R. Quantitation of endocrine cell content in the pancreas of nondiabetic and diabetic humans.Diabetes 1982; 31: 694–700.PubMedGoogle Scholar
  71. 71.
    London NJM, Lake SP, Wilson J, Bassett D, Toomey P, Bell PR, James RFL. A simple method for the controlled collagenase digestion of the human pancreas.Transplantation 1990; 49: 1109–1113.PubMedGoogle Scholar
  72. 72.
    Tzakis AG, Ricordi C, Alejandro R, Zeng Y, Fung JJ, Todo S, Demetris AJ, Mintz DH, Starzl TE. Pancreatic islet transplantation after upper abdominal exenteration and liver replacement.Lancet 1990; 336: 402–405.PubMedGoogle Scholar
  73. 73.
    Federlin K, Bretzel RG, Hering B, Geier C, Schultz AO, Vietke R, Watz B.International Islet Transplant Newsletter 1995; 5: 1–27.Google Scholar
  74. 74.
    Cavanagh TJ, Fetterhoff TJ, Lonergan SC, Dwulet FE, Gill JF, McCarthy RC. Collagenase selcetion, inPancreatic Islet Transplantation, vol. 1 (Lanza RP, Chick WL, eds.), Landes, Austin, TX, 1994; pp. 39–51.Google Scholar
  75. 75.
    Gray DWR, Sutton R, McShane P, Peters M, Morris PJ. Exocrine contamination impairs implantation of pancreatic islets transplanted beneath the kidney capsule.J Surg Res 1988; 45: 432–442.PubMedGoogle Scholar
  76. 76.
    Gotoh M, Maki T, Satomi S, Porter J, Monaco AP. Immunological characteristics of purified pancreatic islet grafts.Transplantation 1986; 42: 387–390.PubMedGoogle Scholar
  77. 77.
    Gray DWR, Warnock GL, Sutton R, Peters M, McShane P, Morris PJ. Successful autotransplantation of isolated islets of Langerhans in the cynomolgus monkey.Br J Surg 1986; 73: 850–853.PubMedGoogle Scholar
  78. 78.
    Wahoff DC, Sutherland DER, Hower CD, Lloveras JJ, Gores PF. Free intraperitoneal islet autografts in pancreatectornized dogs: impact of islet purity and posttransplantation exogenous insulin.Surgery 1994; 116: 742–750.PubMedGoogle Scholar
  79. 79.
    Mirkovitch V, Campiche M. Intrasplenic autotransplantation of canine pancreatic tissues, maintenance of normoglycemia after total pancreatectomy.Eur Surg Res 1977; 9: 173–190.PubMedGoogle Scholar
  80. 80.
    Mieny CJ, Smit JA. Autotransplantation of pancreatic tissue in totally pancreatectomized baboons.S Afr I Surg 1978; 16: 19–21.Google Scholar
  81. 81.
    Gores PF, Mayoral JL, Field MI, Sutherland DER. Comparison of the immunogenicity of purified and unpurified murine islet allografts.Transplantation 1986; 41: 529–531.PubMedGoogle Scholar
  82. 82.
    Smith B, Sarver JG, Fournier RL. A comparison of islet transplantation and subcutaneous insulin injections for the treatment of diabetes mellitus.Comput Biol Med 1991; 21: 417–427.PubMedGoogle Scholar
  83. 83.
    Pegg DE. Viability assays for preserved cells, tissues, and organs.Cryobiology 1989; 26: 212–231.PubMedGoogle Scholar
  84. 84.
    Socci C, Davalli AM, Vignali A, et al. Evidence of in vivo human islet graft function despite a weak response to in vitro perifusion.Transplant Proc 1992; 24: 3056, 3057.PubMedGoogle Scholar
  85. 85.
    Evans MG, Rajotte RV, Warnock GL, Kneteman NM. Viability studies on cryopreserved isolated canine islets of Langerhans.Transplant Proc 1989; 21: 3368–3370.PubMedGoogle Scholar
  86. 86.
    Ricordi C, Scharp DW, Lacy PE. Reversal of diabetes in nude mice after transplantation of fresh and 7-day-cultured (24°C) human pancreatic islets.Transplantation 1988; 45: 994–996.PubMedGoogle Scholar
  87. 88.
    London NJ, Thirdborough SM, Swift SM, Bell PR, James RF. The diabetic “human reconstituted” severe combined immunodeficient (SCID-hu) mouse: a model for isogeneic, allogeneic, and xenogeneic human islet transplantation.Transplant Proc 1991; 23: 749.PubMedGoogle Scholar
  88. 87.
    Lake SP, Chamberlain J, Bassett PD, London NJ, Walczak K, Bell PR, James RF. Successful reversal of diabetes in nude rats by transplantation of isolated adult human islets of Langerhans.Diabetes 1989; 38: 244–248.PubMedGoogle Scholar
  89. 88.
    Paraskevas S, Maysinger D, Lakey JRT, Cavanagh TJ, Wang R, Rosenberg L. Activation of JNK, p38 and erk in cultured human, canine and porcine islets.Acta Diabetol 1997; 34: 128.Google Scholar
  90. 89.
    Warnock GL, Kneteman NM, Rajotte RV. Islet transplantation. Experimental results and evolution of clinical trials, inThe Endocrine Pancreas (Samols E, ed.), Raven, New York, 1991; pp. 487–517.Google Scholar
  91. 90.
    London NJM, James RFL, Bell PRF. Islet purification, inPancreatic Islet Cell Transplantation (Ricordi C, ed.), Landes, Austin, TX, 1992; pp. 113–123.Google Scholar
  92. 91.
    Tai J, Tsang A, Tze WJ. Effects of serum and medium supplements, pH, and temperature on the viability of cultured porcine islets.Transplant Proc 1994; 26: 818, 819.PubMedGoogle Scholar
  93. 92.
    Kyriakis JM, AvruchJ. Sounding the alarm: Protein kinase cascades activated by stress and inflammation.J Biol Chem 1996; 271: 24,313–24,316.Google Scholar
  94. 93.
    Canman CE, Kastan MB. Three paths to stress relief.Nature 1996; 384: 213, 214.PubMedGoogle Scholar
  95. 94.
    Rosette C, Karin M. Ultraviolet light and osmotic stress: Activation of the JNK cascade through multiple growth factor and cytokine receptors.Science 1996; 274: 1194–1197.PubMedGoogle Scholar
  96. 95.
    Xia Z, Dickens M, Raingeaud J, et al. Opposing effects of ERK and JNK-p38 MAP kinases on apoptosis.Science 1995; 270: 1326–1331.PubMedGoogle Scholar
  97. 96.
    Cobb MH, Goldsmith EJ. How MAP kinases are regulated.J Biol Chem 1995; 270: 14,843–14,846.Google Scholar
  98. 97.
    Frodin M, Sekine N, Roche E, et al. Glucose, other secretagogues, and nerve growth factor stimulate mitogenactivated protein kinase in the insulin-secreting β-cell line INS-1.J Biol Chem 1995; 270: 7882–7889.PubMedGoogle Scholar
  99. 98.
    Pombo CM, Bonventre JV, Avruch J, et al. The stress-activated protein kinases are major c-Jun amino-terminal kinases activated by ischemia and reperfusion.J Biol Chem 1994; 269: 26,546–26,551.Google Scholar
  100. 99.
    Ham J, et al. A c-Jun dominant negative mutant protects sympathetic neurons against programmed cell death.Neuron 1995; 14: 927–993.PubMedGoogle Scholar
  101. 100.
    Verheij M, Bose R, Lin XH, et al. Requirement for ceramide-initiated SAPK/JNK signalling in stress-induced apoptosis.Nature 1996; 380: 75–79.PubMedGoogle Scholar
  102. 101.
    Jansson L, Korsgren O, Wahlberg J, Andersson A. Pancreatic islet blood flow after syngeneic pancreaticoduodenal transplantation in rats. Differences between the blood perfusion of the native and the transplanted gland.Transplantation 1992; 53: 517–521.PubMedGoogle Scholar
  103. 102.
    Bonner-Weir S, Orci L. New perspectives on the microvasculature of the islets of Langerhans in the rat.Diabetes 1982; 31: 883–889.PubMedGoogle Scholar
  104. 103.
    Stagner JI, Samols E, Bonner-Weir S. Beta-alpha-delta pancreatic islet cellular perfusion in dogs.Diabetes 1988; 37: 1715–1721.PubMedGoogle Scholar
  105. 104.
    Stagner JL, Samols F. The vascular order of islet cellular perfusion in the human pancreas.Diabetes 1992; 41: 93–97.PubMedGoogle Scholar
  106. 105.
    Menger MD, Vajkoczy P, Beger C, Messmer K. Restitution of intra-islet portal system in pancreatic islet isografts.Transplant Proc 1994; 26: 688.PubMedGoogle Scholar
  107. 106.
    Menger MD, Jaeder S, Walter P, Feifel G, Hammersen F, Messmer K. Angiogenesis and hemodynamics of microvasculature of transplanted islets of Langerhans.Diabetes 1989; 38 (Suppl 1): 199.PubMedGoogle Scholar
  108. 107.
    Andersson A, Korsgren O, Jansson L. Intraportally transplanted pancreatic islets revascularised from hepatic arterial system.Diabetes 1989; 38 (Suppl 1): 192.PubMedGoogle Scholar
  109. 108.
    Griffith RC, Scharp DW, Hartmann BK. A morphological study of intrahepatic portal-vein isografts.Diabetes 1977; 26: 201–214.PubMedGoogle Scholar
  110. 109.
    Menger MD, Wolf B, Hobel R, Schorlemmer HU, Messmer K. Microvascular phenomena during pancreatic islet graft rejection.Langenbecks Arch Chir 1991; 376: 214–221.PubMedGoogle Scholar
  111. 110.
    Rayman G, Williams SA, Spencer PD, Smaje LH, Wise PH, Tooke JE. Impaired microvascular hyperemic responses to minor skin trauma in type 1 diabetes.Br Med J 1986; 292: 1295–1298.Google Scholar
  112. 111.
    Cutherbertson RA, Mandel TE. Chronic diabetes harms islet-cell transplants by inhibiting graft vascularization.Med Hypotheses 1990; 31: 171–175.Google Scholar
  113. 112.
    Jansson L, Sandler S. The blood perfusion of transplanted pancreatic islets—evidence of a maturation of the blood-flow response to D-glucose with time after implantation.Transplantation 1992; 53: 1368, 1369.PubMedGoogle Scholar
  114. 113.
    Downing R, Morrissey S, Kiske D, Scharp DW. Does the purity of intraportal islet isografts affect their endocrine function?J Surg Res 1986; 41: 41–46.PubMedGoogle Scholar
  115. 114.
    Sever CE, Demetrias AJ, Zeng Y, et al. Islet cell allotrans-plantation in diabetic patients. Histologic findings in four-adults simultaneously receiving kidney or liver transplants.Am J Pathol 1992; 140: 1255–1260.PubMedGoogle Scholar
  116. 115.
    Kneteman NM, Warnock GL. Prolonged function of canine pancreatic fragments autotransplanted to the spleen by venous reflux.Transplantation 1990; 49: 679–681.PubMedGoogle Scholar
  117. 116.
    Gores PF, Najarian JS, Stephanian E, Lloveras JJ, Kelly SL, Sutherland DER. Insulin independence in type I diabetes after transplantation of unpurified islets from a single donor with 15-deoxyspergualin.Lancet 1993; 341: 19–21.PubMedGoogle Scholar
  118. 117.
    International Islet Transplant Registry 1994; 4(5): 17.Google Scholar
  119. 118.
    Gores PF, Boudreaux JP, Hesse UJ, Najarian JS, Sutherland DE. Canine islet autografts with and without administration of cyclosporine.Surgery 1987; 101: 557–561.PubMedGoogle Scholar
  120. 119.
    Merrell PC, Mahoney ME, Basadonna G, Cobb LF, Maeda M. Failure of canine islet allografts and auto-grafts with cyclosporine.Surgery 1985; 98: 324–329.PubMedGoogle Scholar
  121. 120.
    Neiderberger J. Cyclosporine A in organs including blood, inCyclosporine (Kahan BD, ed.), Grune & Stratton, New York, 1984; p. 182.Google Scholar
  122. 121.
    Menger MD, Wolf B, Jager S, Walter P, Messmer K. The influence of prednisolone on revascularization of pancreatic islet grafts.Transplant Proc 1990; 22: 2042.PubMedGoogle Scholar
  123. 122.
    Rooth P, Dawidson I, Lafferty K, et al. Prevention of detrimental effect of cyclosporin A on vascular ingrowth of transplanted pancreatic islets with verapamil.Diabetes 1989; 38(Suppl 1): 202.PubMedGoogle Scholar
  124. 123.
    Kawana S, Katori M, Ohta M, Nishiyama S. Microcirculatory changes during skin allograft rejection and prolongation of survival time by antiplatelet agents.Int J Tissue Reac 1986; 8: 119–128.Google Scholar
  125. 124.
    Miller RE. Pancreatic neuroendocrinology: peripheral neural mechanisms in the regulation of the islets of Lang-erhans.Endocr Rev 1981; 2: 471–494.PubMedGoogle Scholar
  126. 125.
    Ahren B, Taborsky GJ, Porte D. Neuropeptidergic versus cholinergic and adrenergic regulation of islet hormone secretion.Diabetologia 1986; 29: 827–836.PubMedGoogle Scholar
  127. 126.
    Noda N, Ina K, Yasunami Y, Ryu S, Ono J, Takaki R. Reinnervation of intraportal islet allografts in rats.Transplantation 1993; 55: 664,665.PubMedGoogle Scholar
  128. 127.
    Madureira ML, Adolfo A, Dias J, Sebe M, Carvalhais HA, Von Hafe P. Reinnervation of the endocrine pancreas after autotransplantation of pancreatic fragments in the spleen of the dog: a morphofunctional study.World J Surg 1985; 9: 335–347.PubMedGoogle Scholar
  129. 128.
    Bissell MJ, Hall HG, Parry G. How does the extracellular matrix direct gene expression?.J Theor Biol 1982; 99: 31–68.PubMedGoogle Scholar
  130. 129.
    Stoker AW, Streuli CH, Martins-Green M, Bissell MJ. Designer microenvironments for the analysis of cell and tissue function.Curr Opin Cell Biol 1990; 2: 864–874.PubMedGoogle Scholar
  131. 130.
    Hay ED. Extracellular matrix alters epithelial differentiation.Curr Opin Cell Biol 1993; 5: 1029–1035.PubMedGoogle Scholar
  132. 131.
    Emerman JT, Pitelka DR. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics.In Vitro 1977; 13: 316–28.PubMedGoogle Scholar
  133. 132.
    Ingber D. Extracellular matrix as a regulator of epithelial polarity, cell growth, and tissue pattern, inThe Pancreas: Biology, Pathobiology and Disease (Go VLW, DiMagno EP, Gardiner JD, Lebenthal E, Reber HA, Scheele GA, eds.), Raven, New York, 1993; pp. 369–380.Google Scholar
  134. 133.
    Goustin AS, Loef EB, Shipley GD, Moses HL. Growth factors and cancer.Cancer Res 1986; 46: 1015–1029.PubMedGoogle Scholar
  135. 134.
    Underwood LE, D'Ercole AJ, Clemmons DR, Van Wyk JJ. Paacrine functions of somatomedins.Clin Endocrinol Metabol 1986; 15: 59–77.Google Scholar
  136. 135.
    Sporn MB, Roberts AB. Peptide growth factors are multifunctional.Nature 1988; 332: 217–219.PubMedGoogle Scholar
  137. 136.
    Collins MKL, Perkins GR, Rodriguez-Tarduchy G, Nieto MA, Lopez-Rivas A. Growth factors as survival factors: Regulation of apoptosis.Bioessays 1994; 16: 133–138.PubMedGoogle Scholar
  138. 137.
    Armato U, Romano F, Andreis PG, Paccagnella L, Marchesini C. Growth stimulation and apoptosis induced in cultures of neonatal rat liver cells by repeated exposures to epidermal growth factor/urogastrone with or without associated pancreatic hormones.Cell Tiss Res 1986; 245: 471–480.Google Scholar
  139. 138.
    Raff MC. Social controls on cell survival and cell death.Nature 1992; 356: 397–400.PubMedGoogle Scholar
  140. 139.
    Creutzfeldt W, Folsch UR, Stockmann F. Clinical implications of islet-acinar interactions.Reg Peptide Lett 1990; 2: 11–15.Google Scholar
  141. 140.
    Bendayan M. Anatomic basis of islet-acinar interaction in the pancreas.Reg Peptide Lett 1990; 2: 1–7.Google Scholar
  142. 141.
    Rosenberg L, Clas D, Duguid WP. Trophic stimulation of the ductular-islet cell axis: A new approach to the treatment of diabetes.Surgery 1990; 108: 191–197.PubMedGoogle Scholar
  143. 142.
    Rafaeloff R, Pittenger GL, Barlow SW, Qin XF, Yan B, Rosenberg L, Duguid WP, Vinik AI. Cloning and sequencing of the pancreatic islet neogenesis associated protein (INGAP) gene and its expression in islet neogenesis in hamsters.J Clin Invest 1997; 99: 2100–2109.PubMedGoogle Scholar
  144. 143.
    Ilieva A, Yuan S, Wang RN, Agapitos D, Hill DJ, Rosenberg L. Pancreatic islet cell survival following islet isolation—the role of cellular interactions in the pancreas.J Endocrinol (submitted).Google Scholar
  145. 144.
    Arany E, Petrik J, Hill DJ. Growth factors and islet development.Endocrinology (in press).Google Scholar
  146. 145.
    Socci C, Falqui L, Davalli AM, et al. Fresh human islets transplantation to replace pancreatic endocrine function in type 1 diabetic patients. Report of six cases.Acta Diabetol 1991; 28: 151–157.PubMedGoogle Scholar
  147. 146.
    Scharp DW, Marchetti P, Swanson C, Newton M, McCullough CS, Olack B. The effect of transplantation site and islet mass on long-term survival and metabolic and hormonal function of canine purified islet autografts.Cell Transplant 1992; 1: 245–254.PubMedGoogle Scholar
  148. 147.
    Warnock GL, Degroot T, Untch D, Ellis DK, Rajotte RV. The natural history of pure canine islet autografts in hepatic or splenic sites.Transplant Proc 1989; 21: 2617.PubMedGoogle Scholar
  149. 148.
    Warnock GL, Cattral MS, Rajotte RV. Normoglycemia after implantation of purified islet cells in dogs.Can J Surg 1988; 31: 421–426.PubMedGoogle Scholar
  150. 149.
    Warnock GL, Dabbs KD, Evans MG, Cattral MS, Kneteman NM, Rajotte RV. Critical mass of islets that function after implantation in a large mammalian.Horm Metab Res 1990; 25(Suppl): 156.Google Scholar
  151. 150.
    Munn SR, Kaufman DB, Meloche RM, Field MJ, Sutherland DE. Weight-corrected islet counts are predictive of outcome in the canine intrahepatic islet autograft model.Diabetes Res 1988; 9: 121–124.PubMedGoogle Scholar
  152. 151.
    Kaufman DB, Morel P, Field MJ, Munn SR, Sutherland DE. Purified canine islet autografts. Functional outcome as influenced by islet number and implantation site.Transplantation 1990; 50: 385–391.PubMedGoogle Scholar
  153. 152.
    White JJ, Dupre J. Regulation of insulin secretion by the intestinal hormone, secretin: studies in man via transumbilical portal vein catheterization.Surgery 1968; 64: 204–213.PubMedGoogle Scholar
  154. 153.
    Radziuk J, McDonald TJ, Rubinstein D, Dupre J. Initial splanchnic extraction of ingested glucose in normal man.Metab Clin Exper 1978; 27: 657–669.Google Scholar
  155. 154.
    Warnock GL, Ao Z, Cattral MS, Dabbs KD, Rajotte RV. Experimental islet transplantation in large animals, inPancreatic Islet Cell Transplantation 1892–1992. One Century of Transplantation for Diabetes (Ricordi C, ed.), Landes, Austin, TX, 1992; p. 261.Google Scholar
  156. 155.
    Alejandro R, Mintz DH. Experimental and clinical methods of islet transplantation, inTransplantation of the Endocrine Pancreas in Diabetes Mellitus (Van Schilegaarde R, Hardy MA, eds.), Elsevier Science, Amsterdam, 1988; p. 217.Google Scholar
  157. 156.
    Clavien P-A, Harvey PRC, Strasberg SM. Preservation and reperfusion injuries in liver allografts.Transplantation 1992; 53: 957,978.PubMedGoogle Scholar
  158. 157.
    Nathan CF. Secretory products of macrophages.J Clin Invest 1987; 79: 319–326.PubMedGoogle Scholar
  159. 158.
    Warnock GL, Kneteman NM, Ryan EA, Rabinovitch A, Rajotte RV. Long-term follow-up after transplantation of insulin-producing pancreatic islets into patients with type 1 (insulin-dependent) diabetes mellitus.Diabetologia 1992; 35: 89–95.PubMedGoogle Scholar
  160. 159.
    Boudreaux JP, McHugh L, Canafax DM, et al. The impact of cyclosporine and combination immunosuppression on the incidence of posttransplant diabetes in renal allograft recipients.Transplantation 1987; 44: 376–381.PubMedGoogle Scholar
  161. 160.
    Alejandro R, Feldman EC, Bloom AD, Kenyon NS. Effects of cyclosporin on insulin and C-peptide secretion in healthy beagles.Diabetes 1989; 38: 698–703.PubMedGoogle Scholar
  162. 161.
    Hahn HJ, Laube F, Lucke S, Kloting I, Kohnert KD, Warzock R. Toxic effects of cyclosporine on the endocrine pancreas of Wistar rats.Transplantation 1986; 41: 44–47.PubMedGoogle Scholar
  163. 162.
    Andersson A, Borg H, Hallberg A, Hellerstrom C, Sandler S, Schnell A. Long-term effects of cyclosporin A on cultured mouse pancreatic islets.Diabetologia 1984; 27 (Suppl): 66.PubMedGoogle Scholar
  164. 163.
    Stockmann F, Fehmann HC, Goke B, Siegel EG, Creuzfeldt W. Impairment of stimulated insulin release from the isolated perfused rat pancreas by cyclosporine pretreatment.Transplantation 1989; 48: 381–385.PubMedGoogle Scholar
  165. 164.
    Metrakos P, Hornby L, Rosenberg L. Cyclosporine and islet mass—implications for islet transplantation.J Surg Res 1993; 54: 375–380.PubMedGoogle Scholar
  166. 165.
    Gunnarsson R, Klintmalm G, Lundgren G, et al. Deterioration in glucose metabolism in pancreatic transplant recipients after conversion from azathioprine to cyclosporine.Transplant Proc 1984; 16: 709.PubMedGoogle Scholar
  167. 166.
    Nielsen JH, Mandrup Poulsen T, Nerup J. Direct effects of cyclosporin A on human pancreatic beta-cells.Diabetes 1986; 35: 1049–1052.PubMedGoogle Scholar
  168. 167.
    Jutte NH, Heyse P, Bruining GJ, Zeilmaker GH, Whimar W. Effect of cyclosprin A on glucose-induced insulin secretion by isolated human islets of Langerhans.Transplant Proc 1987; 19: 4152.PubMedGoogle Scholar
  169. 168.
    Nakai I, Omori Y, Aikawa I, Yasumura T, Suzuki S, Yoshimura N, Arakawa K, Matsui S, Oka T. Effect of cyclosporine on glucose metabolism in kidney transplant recipients.Transplant Proc 1988; 20(Suppl 3): 969–978.PubMedGoogle Scholar
  170. 169.
    Yoshimura N, Nakai I, Ohmori Y, Aikawa I, Fukuda M, Yasumura T, Matsui S, Hamashima T, Oka T. Effect of cyclosporine on the endocrine and exocrine pancreas in kidney transplant recipients.Am J Kidney Dis 1988; 12: 11–17.PubMedGoogle Scholar
  171. 170.
    Roth D, Milgrom M, Esquenazi V, Fuller L, Burke G, Miller J. Posttransplant hyperglycemia. Increased ncidence in cyclosporine-treated renal allograft recipients.Transplantation 1989; 47: 278–281.PubMedGoogle Scholar
  172. 171.
    Robertson RP, Franklin G, Nelson L. Glucose homeostasis and insulin secretion during chronic treatment with cyclosporine in nondiabetic humans.Diabetes 1989 38 (Suppl 1): 99.PubMedGoogle Scholar
  173. 172.
    Kahan BD. Individualization of cyclosporine therapy using pharmacokinetic and pharmacodynamic parameters.Transplantation 1985; 40: 457–476.PubMedGoogle Scholar
  174. 173.
    Reid M, Gibbons S, Kwok D, Van Buren CT, Flechner S, Kahan BD. Cyclosporine levels in human tissues of patients treated for one week to one year.Transplant Proc 1983; 15: 2434.Google Scholar
  175. 174.
    Baumgartner D, Schlumpf R, Largiader F. Cyclosporine A interferes with postoperative blood glucose control after clinical pancreas transplantation.Transplant Proc 1987; 19: 4009.PubMedGoogle Scholar
  176. 175.
    Tze WJ, Tai J, Cheung S. In vitro effects of FK 506 on human and rat islets.Transplantation 1990; 49: 1172–1174.PubMedGoogle Scholar
  177. 176.
    Hirano Y, Fujihira S, Ohara K, Katsuki S, Noguchi H. Morphological and functional changes of islets of Langerhans in FK 506-treated rats.Transplantation 1992; 53: 889–894.PubMedGoogle Scholar
  178. 177.
    Yasunami Y, Ryu S, Kamei T. FK 506 as the sole immunosuppressive agent for prolongation of islet allograft survival in the rat.Transplantation 1990; 49: 682–686.PubMedGoogle Scholar
  179. 178.
    Ricordi C, Zeng YJ, Alejandro R, Tzakis A, Venkataramanan R, Fung J, Bereiter D, Mintz DH, Starzl TE.In vivo effect of FK506 on human pancreatic islets.Transplantation 1991; 52: 519–522.PubMedGoogle Scholar
  180. 179.
    Rilo HL, Zeng Y, Alejandro R, Carroll PB, Bereiter D, Venkataramanan R, Tzakis AG, Starzl TE, Ricordi C. Effect of FK506 on function of human islets of Langerhans.Transplant Proc 1991; 23: 3164,3165.PubMedGoogle Scholar
  181. 180.
    Strasser S, Alejandro R, Shaprio ET, Ricordi C, Todo S, Mintz DH. Effect of FK506 on insulin secretion in normal dogs.Metab Clin Exper 1992; 41: 64–67.Google Scholar
  182. 181.
    Scantlebury V, Shapiro R, Fung J, Tzakis A, McCauley J, Jordan M, Jensen C, Hakala T, Simmons A, Starzl TE. New onset of diabetes in FK506 vs cyclosporine-treated kidney transplant recipients.Transplant Proc 1991; 23: 3169,3170.PubMedGoogle Scholar
  183. 182.
    Carroll PB, Rilo H, Reyes J, Alejandro R, Zeng Y, Ricordi C, Tzakis A, Shapiro R, Starzl TE. FK 506-associated diabetes mellitus in the pediatric transplant population is a rare complication.Transplant Proc 1991; 23: 3171,3172.PubMedGoogle Scholar
  184. 183.
    Mieles L, Todo S, Fung JJ, Furukawa H, Susuki M, Starzl TE. Oral glucose tolerance test in liver recipients treated with FK506.Transplant Proc 1990; 22: 41–43.PubMedGoogle Scholar
  185. 184.
    Mieles L, Gordon RD, Mintz DH, Toussaint RM, Imventarza O, Starzl TE. Glycemia and insulin need following FK 506 rescue therapy in liver recipients.Transplant Proc 1991; 23: 949.PubMedGoogle Scholar
  186. 185.
    Sutherland DER, Gores PF, Hering BJ, Wahoff D, McKeehen DA, Gruessner WG. Islet transplantation: An update.Diabet Metab Rev 1996; 12: 137–150.Google Scholar
  187. 186.
    Ruiz JO, Simmons RL, Callender CO, Kjellstrant CM, Buselmeier TJ, Najarian JS. Steroid diabetes in tenal transplant recipients: pathogenetic factors and prognosis.Surgery 1973; 73: 759–765.PubMedGoogle Scholar
  188. 187.
    Ekstrand AV. Effect of steroid-therapy on insulin sensitivity in insulin-dependent diabetic patients after kidney transplantation.J Diabetic Comps 1991; 5: 244–248.Google Scholar
  189. 188.
    Ekstrand AV, Eriksson JG, Gronhagen-Riska C, Ahonen PJ, Groop LC. Insulin resistance and insulin deficiency in the pathogenesis of posttransplant diabetes in man.Transplantation 1992; 53: 563–569.PubMedGoogle Scholar
  190. 189.
    Bookman JJ, Drachman SR, Schaeser LE, Adlersherg D. Steroid diabetes in man: the development of diabetes during treatment with cortisone and corticotropin.Diabetes 1953; 2: 100.PubMedGoogle Scholar
  191. 190.
    Kaufman DB, Morel P, Condie R, Field MJ, Rooney M, Tzardis P, Stock P, Sutherland DE. Beneficial and detrimental effects of RBC-adsorbed antilymphocyte globulin and prednisone on purified canine islet autograft and allograft function.Transplantation 1991; 51: 37–42.PubMedGoogle Scholar
  192. 191.
    Zeng Y, Ricordi C, Lendoire I, et al. The effect of prednisone on pancreatic islet autografts in dogs.Surgery 1993; 113: 98–102.PubMedGoogle Scholar
  193. 192.
    Merrel RC, Mahoney ME, Basadonna GP, Cobb LF, Maeda M. Failure of canine islet allografts and autografts with cyclosporine.Surgery 1985; 98: 324–329.Google Scholar
  194. 193.
    Martin F, Bedoya FJ. Short-term effects of cyclosporine on secretagogue-induced insulin release by isolated islets.Transplantation 1990; 50: 551–553.PubMedGoogle Scholar
  195. 194.
    Viviani GL, Borgoglio MG, Fontana I. Azathioprine decreases insulin secretion in human islets.Transplant Proc 1989; 21: 2714.PubMedGoogle Scholar
  196. 195.
    Xenos ES, Casanova D, Sutherland DER, Farney AC, Lloveras JJ, Gores PE. Thein vivo andin vitro effect 15-deoxyspergualin on pancreatic islet function.Transplantation 1993; 56: 144–147.PubMedCrossRefGoogle Scholar
  197. 196.
    Platz KP, Sollinger HW, Mullett DA, Eckhoff DE, Eugui EM, Allison AC. RS-6243: A new potent immunosuppressive agent.Transplantation 1991; 51: 27–31.PubMedGoogle Scholar
  198. 197.
    Morris RP. Rapamycins: antifungal, antitumor, antiproliferative and immunosuppressive macrolides.Transplant Rev 1992; 6: 39–87.CrossRefGoogle Scholar
  199. 198.
    Yakimets WJ, Lakey JRT, Yatscoff RW, Katyal D, Ao Z, Finegood DT, Rajotte RV, Kneteman NM. Prolongation of canine pancreatic islet allograft survival with combined rapamycin and cyclosporine therapy at low doses.Transplantation 1993; 56: 1293–1298.PubMedGoogle Scholar
  200. 199.
    Granger DK, Matas AJ, Jenkins MK, Moss AA, Chen SC, Almond PS. Prolonged survival without posttransplantation immunosuppression in a large animal model.Surgery 1994; 116: 419–425.Google Scholar
  201. 200.
    Warnock GL, Tsapogas P, Ryan EA, Lakey JRT, Korbutt G, Kneteman NM, Ao Z, Rabinovitch A, Rajotte RV. Natural history of insulin independence after transplantation of multidonor cryopreserved pancreatic islets in type 1 diabetic humans.Transplant Proc 1995; 27: 3159,3160.PubMedGoogle Scholar
  202. 201.
    Alejandro r, Cutfield RG, Shienvold FL, Polonsky HS, Noel J, Olsoon L, Dillberger J, Miller J, Mintz DH. Natural history of intrahepatic canine islet cell autografts.J Clin Invest 1986; 78: 1339–1348.PubMedGoogle Scholar
  203. 202.
    Moller DE, Flier JS. Insulin resistance—mechanisms, syndromes, and implications.N Engl J Med 1991; 325: 938–948.PubMedCrossRefGoogle Scholar
  204. 203.
    Defronzo RA, Hendler R, Simonson D. Insulin resistance is a prominent feature of insulin-dependent diabetes.Diabetes 1982; 31: 795–801.PubMedGoogle Scholar
  205. 204.
    Scharp DW, Marchetti P, Swanson C, Newton M, McCullough CS, Olack B. The effect of transplantation site and islet mass on long-term survival and metabolic and hormonal function of canine purified islet autografts.Cell Transplant 1992; 1: 245–254.PubMedGoogle Scholar
  206. 205.
    Tobin BW, Lewis JT, Tobin BL, Rajotte RV. Finegood DT. Markedly reduced beta-cell function does not result in insulin resistance in islet autografted dogs.Diabetes 1992; 41: 1172–1181.PubMedGoogle Scholar
  207. 206.
    Sato N, Irie M, Kajinuma H, Suzuki K. Glucagon inhibits insulin activation of glucose transport in rat adipocytes mainly through a postbinding process.Endocrinology 1990; 127: 1072–1077.PubMedGoogle Scholar
  208. 207.
    Garvey WT, Olefsky JM, Matthaei S, Marshall S. Glucose and insulin coregulate the glucose trannsport system in primary cultured adipocytes: a new mechanism of insulin resistance.J Biol Chem 1987; 262: 189–197.PubMedGoogle Scholar
  209. 208.
    Kahn BB, Shulman GI, Defronzo RA, Cushman SW, Rossetti L. Normalization of blood glucose in diabetic rats with phlorizin treatment reverses insulin-resistant glucose transport in adipose cells without restoring glucose transporter gene expression.J Clin Invest 1991; 87: 561–570.PubMedGoogle Scholar
  210. 209.
    Leahy JL, Bonner-Weir S, Weir G. Beta-cell dysfunction induced by chronic hyperglycemia. Current ideas on mechanism of impaired glucose-induced insulin secretion.Diabetes Care 1992; 15: 442–455.PubMedGoogle Scholar
  211. 210.
    Davalli AM, Pontiroli AE, Socci C, Bertuzzi F, Fattor B, Braghi S, Di Carlo V, Pozza G. human islets chronically exposed in vitro to different stimuli become unresponsive to the same stimuli given acutely: evidence supporting specific desensitization rather than beta-cell exhaustion.J Clin Endocrinol Metab 1992; 74: 790–794.PubMedGoogle Scholar
  212. 211.
    Davalli AM, Ricordi C, Socci C, Braghi S, Bertuzzi F, Fattor B, Di Carlo V, Pontiroli AE, Pozza G. Abnormal sensitivity to glucose of human islets cultured in a high glucose medium: partial reversibility after an additional culture in a normal glucose medium.J Clin Endocrinol Metab 1991; 72: 202–208.PubMedGoogle Scholar
  213. 212.
    Warnock CL, Kneteman NM, Rajotte RV. Effect of diabetes on the function of transplanted human islets of Langerhans.Transplant Proc 1990; 22: 804.PubMedGoogle Scholar
  214. 213.
    Weir GC. Non-insulin-dependent diabetes mellitus: interplay between β-cell inadequacy and insulin resistance.Am J Med 1982; 73: 461–464.PubMedGoogle Scholar
  215. 214.
    Smith JL, Hunsicker LG, Yuh WTC, Wright FH, Van Vooris L, Corry RJ. Appearance of type II diabetes mellitus in type I diabetic recipients of pancreas allografts.Transplantation 1989; 47: 304–311.PubMedGoogle Scholar
  216. 215.
    Kaufman DB, Platt J, Rabe FL, Dunn DL, Bach FM, Sutherland DER. Differential roles of Mac-1+cells, and CD4=and CD8+ T lymphocytes in primary nonfunction and classic rejection of islet allografts.J Exp Med 1990; 172: 291–302.PubMedGoogle Scholar
  217. 216.
    Kaufman DB, Field MJ, Gruber SA, Farney AC, Stephanian E, Gores PE, Sutherland DER. Extended functional survival of murine islet allograft with 15-deoxyspergualin.Transplant Proc 1992; 24: 1045–1047.PubMedGoogle Scholar
  218. 217.
    Stevens RB, Ansite JD, Lokeh A. The role of nitric oxide in the pathogenesis of early pancreatic islet dysfunction during rat and human intraportal islet transplantation.Transplant Proc 1994; 26: 690–692.Google Scholar
  219. 218.
    Marklund SL. Regulation by cytokines of extra cellular superoxide dismutase and other superoxide dismutase isoenzymes in fibroblasts.J Biol Chem 1992; 267: 6696–6701.PubMedGoogle Scholar
  220. 219.
    Nathan CF, Tsunawakj S. Secretion of toxic oxygen products by macrophages: regulatory cytokines and their effects on the oxidase.Ciba Found Symp 1986; 118: 211–230.PubMedGoogle Scholar
  221. 220.
    Arai KE, Lee F, Mijajima A, Myatake S, Arai N, Yokota T. Cytokines: coordinators of immune and inflammatory responses.Ann Rev Biochem 1990; 59: 783–786.PubMedGoogle Scholar
  222. 221.
    Bendtzen K, Mandrup-Poulsen T, Nerup J, Nielsen JH, Dinarello CA, Svenson M. Cytotoxicity of human p17 interleukin. 1 for pancreatic islets of Langerhans.Science 1986; 232: 1545–1547.PubMedGoogle Scholar
  223. 222.
    Ling Z, Veld PA, Pipeleers DC. Interaction of interleukin-1 with islet β-cells: distinction between indirect, aspecifcic cytotoxicity and direct, specific functional suppression.Diabetes 1993; 42: 56–65.PubMedGoogle Scholar
  224. 223.
    Campbell IL, Iscaro A, and Harrison LC. IFN-g and tumor necrosis factor-a: cytotoxicity to murine islets of Langerhans.J Immunol 1998; 21: 2325–2329.Google Scholar
  225. 224.
    Mandrup-Poulsen T, Bendtzen K, Dinarello CA, Nerup J. Human tumor necrosis factor potentiates human interleukin 1-mediated rat pancreatic B-cells cytototoxicity.J Immunol 1987; 139: 4077–4082.PubMedGoogle Scholar
  226. 225.
    Scharp DW, Lacy PE, Santiago JV, et al. Results of our first nine intraportal islet allografts in type I insulin-dependent diabetic patients.Transplantation 1991; 51: 76–85.PubMedGoogle Scholar
  227. 226.
    Ricordi C, Tzakis AG, Carroll PB, et al. Human islet isolation and allotransplantation in 22 consecutive cases.Transplantation 1992; 53: 407–414.PubMedGoogle Scholar
  228. 227.
    Marks WH, Borgstrom A, Sollinger H, Marks C. Serum immunoreactive anodal trypsinogen and urinary amylase as biochemical markers for rejection of clinical whole-organ pancreas allografts having exocrine drainage into the urinary bladder.Transplantation 1990; 49: 112–115.PubMedGoogle Scholar
  229. 228.
    Villaneuva-Penacarrillo ML, Delgado E, Garcia-Gaya M, Valverde I. Inhibitory effect of insulin upon C-peptide secretion in isolated human pancreatic islets.Diab Nutr Metab 1993; 6: 9–14.Google Scholar
  230. 229.
    Roland CR, Mangino MJ, Duffy BF, Flye WM. Lymphocyte suppression by Kupffer cells prevents portal venous tolerance induction: A study of macrophage function after intravenous gadolinium.Transplantation 1993; 55: 1151–1158.PubMedGoogle Scholar
  231. 230.
    Unanue ER, Allen PM. The basis for the immuno-regulatory role of macrophages and other accessory cells.Science 1987; 236: 551–557.PubMedGoogle Scholar
  232. 231.
    Kawahara DJ, Kenney JS. Species differences in human and rat islet sensitivity to human cytokines. Monoclonal anti-interleukin-1 (IL-1) influences on direct and indirect IL-1-mediated islet effects.Cytokine 1991; 3: 117–124.PubMedGoogle Scholar
  233. 232.
    Arias J, Vara E, Gomez M, Garcia C, Moreno A, Bali-Brea JL. Effect of cytokines on “de novo” lipid synthesis and hormone secretion by isolated human islets.Transplant Proc 1992; 24: 2909.PubMedGoogle Scholar
  234. 233.
    Soldevila G, Buscema N, Doshi M, James RF, Bottazzo GF, Pujol-Borrell R. Cytotoxic effects of IFN-gamma plus TNF-alpha on human islet cells.J Autoimmun 1991; 4: 291–306.PubMedGoogle Scholar
  235. 234.
    Paraskevas S, Maysinger D, Lakey JRT, Cavanagh TJ, Rosenberg L. Modulation of JNK and p38 MAP kinase activity by insulin in human, porcine and canine islets.Acta Diabet 1997; 34: 133.Google Scholar
  236. 235.
    Langrehr JM, White DA, Hoffman RA, Simmons RL. Macrophages produce nitric oxide at allograft sites.Ann Surg 1993; 218: 159–166.PubMedGoogle Scholar
  237. 236.
    Kroncke KD, Rodriguez ML, Kolb H, Kolb-Bachofen V. Cytotoxicity of activated rat macrophages against syngeneic islet cells is arginine-dependent, correlates with citrulline and nitrite concentrations and is identical to lysis by the nitric oxide donor nitroprusside.Diabetologia 1993; 36: 17–24.PubMedGoogle Scholar
  238. 237.
    Bergmann L, Kroncke KD, Suschek C, Kolb H, Kolb Bachofern V. Cytotoxic action of IL-I beta against pancreatic islets is mediated via nitric oxide formation and is inhibited bv NCG-monomethyl-L-arginine.FEBS Lett 1992; 299: 103–106.PubMedGoogle Scholar
  239. 238.
    Xenos ES, Steven RB, Gores PE, et al. IL-lb-induced inhibition of b-cell function is mediated through nitric oxide.Transplant Proc 1994; 25: 994.Google Scholar
  240. 239.
    Eisenbarth GS. Type I diabetes mellitus: A chronic auto-immune disease.N Engl J Med 1986; 314: 1360–1368.PubMedCrossRefGoogle Scholar
  241. 240.
    Lampeter EF, Homberg M, Quabeck K, et al. Transfer of insulin-dependent diabetes between HLA-identical siblings by bone marrow transplantation.Lancet 1993; 341: 1243, 1244.PubMedGoogle Scholar
  242. 241.
    Sutherland DER, Goetz FC, Sibley RK. Recurrence of disease in pancreas transplants.Diabetes 1989; 38: 85–87.PubMedGoogle Scholar
  243. 242.
    Stratta R. Immunosuppression for pancreas transplantation.Graft 1998; 1: 101–110.Google Scholar
  244. 243.
    Kutteh WH, Rainey WE, Carr BR. Glucocorticoids inhibit lipopolysaccharide-induced production of tumor necrosis factor-alpha by human fetal Kupffer cells.J Clin Endocrinol Metab 1991; 73: 296–301.PubMedGoogle Scholar
  245. 244.
    Walter PK, Dickneite G, Schorlemmer HU, et al. Prolongation of graft survival in allogeneic islet transplantation by 15-deoxyspergualin in the rat.Diabetologia 1987; 30: 38–40.PubMedGoogle Scholar
  246. 245.
    Stephanian E, Lloveras JJ, Sutherland DE, et al. Prolongation of canine islet allograft survival by 15-deoxys-pergualin.J Surg Res 1992; 52: 621–624.PubMedGoogle Scholar
  247. 246.
    Palmer JP, Helqvist S, Spinas GA, Molvig J, Mandrup-Poulsen T, Andersen HU, Nerup J. Interaction of beta-cell activity and IL-I concentration and exposure time in isolated rat islets of Langerhans.Diabetes 1989; 38: 1211–1216.PubMedGoogle Scholar
  248. 247.
    Appel MC, Dotta F, O'Neil J, Eisenbarth GS. β-Cell activity regulates the expression of islet antigenic determinants.Diabetologia 1989; 32: 461A.Google Scholar
  249. 248.
    Alejandro R, Latif Z, Plonsky KS, Shienvold FL, Civantos F, Mintz DH. Natural history of multiple intrahepatic canine islet allografts during and following administration of cyclosporine.Transplantation 1988; 45: 1036–1045.PubMedGoogle Scholar
  250. 249.
    Bretzel RG, Hering BJ, Federlin KF. Islet cell transplantation in diabetes mellitus—from bench to bedside.Exper Clin Endocrinol Diabetes 1995; 103: 143–159.CrossRefGoogle Scholar
  251. 250.
    Ricordi C, Hering BJ, London NJM, Rajotte RV, Gray DWR, Sutherland DER, Socci C, Alejandro R, Carroll PB, Bretzel RG, Scharp DW. Islet isolation and assessment, inPancreatic Islet Transplantation (Ricordi C, ed.), Landes, Austin, TX, 1992; pp. 132–142.Google Scholar
  252. 251.
    Hayek A, Lopez AD, Beattie GM. Angiogenic peptides in pancreatic islet transplantation to diabetic rats.Transplantation 1990; 50: 931–933.PubMedGoogle Scholar
  253. 252.
    Stagner JI, Samols E. Induction of angiogenesis by growth factors: relevance to pancreatic islet transplantation.EXS 1992; 61: 381–385.PubMedGoogle Scholar
  254. 253.
    Rosenberg L, Rafaelof R, Clas D, Kakugawa Y, Pittenger G, Vinik AI, Duguid WP. Induction of islet cell differentiation and new islet formation in the hamster—further support for a ductular origin.Pancreas 1996; 13: 38–46.PubMedGoogle Scholar
  255. 254.
    Rosenberg L, Brown RA, Duguid WP. A new model for the development of duct epithelial hyperplasia and the initiation of nesidioblastosis.J Surg Res 1983; 35: 63–72.PubMedGoogle Scholar
  256. 255.
    Rosenberg L. In vivo cell transformation: Neogenesis of beta cells from pancreatic ductal cells.Cell Transplant 1995; 4: 371–384.PubMedGoogle Scholar
  257. 256.
    Rosenberg L, Vinik AI, Pittenger GL, Rafaeloff R, Duguid WP. Islet cell regeneration in the diabetic hamster pancreas with restoration of normoglycemia can be induced by a local growth factor(s).Diabetologia 1996; 39: 256–262.PubMedGoogle Scholar
  258. 257.
    Rafaeloff R, Pittenger GL, Barlow SW, Qin XF, Yan B, Rosenberg L, Duguid WP, Vinik AI. Cloning and sequencing of the pancreatic islet neogenesis associated protein (INGAP) gene and its expression in islet neogenesis in hamsters.J Clin Invest 1997; 99: 2100–2109.PubMedGoogle Scholar
  259. 258.
    Tchervenivanov N, Metrakos P, Kakugawa Y, Rosenberg L. Submucosal transplantation of pancreatic islets.Transplant Proc 1994; 26: 680,681.PubMedGoogle Scholar

Copyright information

© Humana Press Inc 1998

Authors and Affiliations

  • Lawrence Rosenberg
    • 1
    • 2
  1. 1.Department of Surgery and MedicineMcGill UniversityMontrealCanada
  2. 2.Centre for Pancreatic DiseasesMcGill University Health CentreMontrealCanada

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