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Pravastatin Prevents Primary Nonfunction of Canine Islet Autografts 1
Pravastatin Prevents Primary Nonfunction of Canine Islet Autografts S. Arita, T. Nagai, M. Ochiai, Y. Sakamoto, C.V. Smith, L. Shevlin, and Y. Mullen
N
ONSPECIFIC inflammation is a major cause of primary islet nonfunction. We have previously shown in mice that pravastatin, an HMG-CoA reductase inhibitor, prevents early islet loss by reducing nonspecific inflammation at the graft site.1 In this study, the effect of pravastatin was assessed in a canine model by autotransplanting a marginal number of islets in order to determine whether it is also effective in a large animal species.
plantation. In contrast, four of the five dogs treated with pravastatin maintained normoglycemia (,150 mg/dL) until the end of the observation period of 8 weeks. The percentage of diabetes reversal was significantly higher in pravastatin-treated dogs (80%; 4/5) than in control dogs (0%; 0/4) (P , .05). Pravastatin-treated dogs also showed significantly higher IVGTT-K values (0.94 6 0.28%/min) than control dogs (0.13 6 0.04%/min, P , .01). We have concluded that pravastatin treatment protects islet grafts.
METHODS Following total pancreatectomy, canine islets were digested by our two-step digestion procedure and purified by Euro-Ficoll gradient centrifugation with a COBE2991 cell processor. The fresh islets were then transplanted back into the liver of the same dog through the portal vein. Prior to the study, varying numbers of islets, ranging from 3000 to 10,000 islet equivalents (IEQ)/kg, were transplanted, and 4000 IEQ/kg was determined to be the minimal effective dose. Starting 2 days before transplantation, 20 mg/kg/d of pravastatin was administered for 16 days to dogs that received a marginal number of islets (3000 IEQ/kg). To monitor the diabetic state, fasting blood glucose levels were measured three times each week, and an intravenous glucose tolerance test (IVGTT) was performed 4 weeks after transplantation.
RESULTS AND CONCLUSION
All four dogs without pravastatin treatment developed hyperglycemia (.250 mg/dL) within 2 weeks after trans-
© 1998 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010 Transplantation Proceedings, 30, 411 (1998)
REFERENCES 1. Arita S, Saul J, Joh S, et al: Transplant Proc 28:924, 1996
From the Human Islet Program, Department of Surgery, UCLA and VAMC/WLA, Los Angeles, California. Supported by a grant from the Nora Eccles Treadwell Foundation. Address reprint requests to Dr Y Mullen, Human Islet Program, Department of Surgery, VAMC/WLA, Bldg 304, E1-206, 11301 Wilshire Blvd, Los Angeles, CA 90073.
0041-1345/98/$19.00 PII S0041-1345(97)01331-6 411
N
ONSPECIFIC inflammation is a major cause of primary islet nonfunction. We have previously shown in mice that pravastatin, an HMG-CoA reductase inhibitor, prevents early islet loss by reducing nonspecific inflammation at the graft site.1 In this study, the effect of pravastatin was assessed in a canine model by autotransplanting a marginal number of islets in order to determine whether it is also effective in a large animal species.
plantation. In contrast, four of the five dogs treated with pravastatin maintained normoglycemia (,150 mg/dL) until the end of the observation period of 8 weeks. The percentage of diabetes reversal was significantly higher in pravastatin-treated dogs (80%; 4/5) than in control dogs (0%; 0/4) (P , .05). Pravastatin-treated dogs also showed significantly higher IVGTT-K values (0.94 6 0.28%/min) than control dogs (0.13 6 0.04%/min, P , .01). We have concluded that pravastatin treatment protects islet grafts.
METHODS Following total pancreatectomy, canine islets were digested by our two-step digestion procedure and purified by Euro-Ficoll gradient centrifugation with a COBE2991 cell processor. The fresh islets were then transplanted back into the liver of the same dog through the portal vein. Prior to the study, varying numbers of islets, ranging from 3000 to 10,000 islet equivalents (IEQ)/kg, were transplanted, and 4000 IEQ/kg was determined to be the minimal effective dose. Starting 2 days before transplantation, 20 mg/kg/d of pravastatin was administered for 16 days to dogs that received a marginal number of islets (3000 IEQ/kg). To monitor the diabetic state, fasting blood glucose levels were measured three times each week, and an intravenous glucose tolerance test (IVGTT) was performed 4 weeks after transplantation.
RESULTS AND CONCLUSION
All four dogs without pravastatin treatment developed hyperglycemia (.250 mg/dL) within 2 weeks after trans-
© 1998 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010 Transplantation Proceedings, 30, 411 (1998)
REFERENCES 1. Arita S, Saul J, Joh S, et al: Transplant Proc 28:924, 1996
From the Human Islet Program, Department of Surgery, UCLA and VAMC/WLA, Los Angeles, California. Supported by a grant from the Nora Eccles Treadwell Foundation. Address reprint requests to Dr Y Mullen, Human Islet Program, Department of Surgery, VAMC/WLA, Bldg 304, E1-206, 11301 Wilshire Blvd, Los Angeles, CA 90073.
0041-1345/98/$19.00 PII S0041-1345(97)01331-6 411