Alejandro, R

Carroll, PB

Ricordi, C

Starzl, TE

Zeng, Y

Transplantation Proceedings

PubMed

Name not available

Glucose homeostasis is regulated by donor islets in xenografts

CARROLL, P. B

ZENG, Y

ALEJANDRO, R

STARZL, T. E

RICORDI, C

University of Miami: Scholarship@Miami

D-Scholarship@Pitt

\ 1 ; i ! i I-------------D~-Glucose Homeostasis is Regulated by Donor Islets in Xenografts P.B. Carroll, Y. Zeng, R. Alejandro, T.E. Starzl, and C. Ricordi A FEW successful human islet allograft transplants allowing for prolonged insulin independence have demonstrated the feasibility of clinical islet cell transplan-tation in man. l -4 The possibility to alter islet immunoge-nicity may allow for this procedure to be performed without immunosuppression in the future. One major obstacle to applying this technique to many patients would be a lack of donors. Pancreatic islet xenografts have recently been proposed as an alternative to allotransplan-tation in patients with type I diabetes. Trials of islet xenografts (pig to man) have been reported, resulting in an increased interest in this approach.5 In the present study, we have used purified adult human islets to determine whether glucose homeostasis is regulated by xenogeneic donor islets. METHODS Human islets were isolated from cadaveric donor pancreata obtained from multiorgan donors.6•7 The islets were isolated using a modificationS of the automated method previously described.9 Athymic male nude mice (Sprague-Dawley) were made diabetic by a single intravenous injection of streptozocin (165 mglkg) into the tail vein. Diabetes was confirmed if random plasma glucose following the injection was >300 mgldL. Three to 5 days later. if diabetes was verified, each animal (n = II) received an aliquot of approximately 600 (l50-1J.lll) human islet equivalents that were transplanted beneath the left renal capsule. 10 Two weeks follow-ing the transplantation. the animals underwent a standard intra-peritoneal glucose tolerance test (lPGTI).11 Following an over-night fast. the animals were injected with 2 glkg IP of a 2S% dextrose solution. Samples were obtained for analysis of plasma glucose at 0, IS, 30. and 60 minutes following the injection. Non-streptozocin-injected male nude mice (n = 10) from the same litter served as controls for the IPGTT. Statistics are presented as mean :!: SEM and significance of difference was assessed by the Student t test. RESULTS Fasting glucose levels in the nude mice bearing human islet xenografts was 52.4 ± 4.1 compared with 73.6 ± 4.4 mgldL (P < .05). Plasma glucose at every time point was significantly lower than in control nude mice (Fig 1). DISCUSSION There is evidence that pancreatic xenografts regulate glu-cose homeostasis in a recipient in a manner similar to that observed in the donor species. 12 In addition, there is evidence that donor human fetal pancreatic tissue13 regu-lates glucose homeostasis recipient animals. Our data 500 '6 400 ..... CI .§ w rn o o ::J -1 <.? 300 200 100 0 -- CONTROL (N-101 T T 1 --- +HlTx (N-1 l' ~ 0 30 60 TIME (min) 90 120 Fig 1. Results of IPGTI in control nude mice and diabetic nude mice transplanted with human islets (HITx). All glucose values In the transplanted mice were significantly different than control animals (P < .05). confirm these findings with adult human islet grafts and suggest that the islet xenografts regulate the glucose levels to the donor levels and not to normal recipient levels. The source of xenogeneic islets for use in clinical trials should therefore be carefully selected based upon the donor species glucose tolerance and expected glycemic excur-sions desired in the recipient. REFERENCES 1. Scharp DW. Lacy PE, Santiago JV. et a1: Diabetes 39:515, 1990 2. Tzakis A, Ricordi C. Alejandro R. et a1: Lancet 336:402, 1990 3. Warnock GL. Kneteman NM. Ryan E. et a1: Diabetologica 34:55. 1991 4. Altman n. Cugnenc PH. Tessier C, et a1: Honn Metab Res 25(suppl): 136. 1991 S. Groth CG. Anderson A. Korsgren 0, et a1: Transplant Proc 24:677, 1992 From the Departments of Medicine (p.e.c.) and Surgery (Y.z.. R.A .• T.E.S .• C.R.), University of Pittsburgh Medical Center, Pitts-burgh, Pennsytvania, Supported In pan by grants from the Juvenile Diabetes Foun-dation #1911421, Clinical Research Unit #5M01RROOO56. the Veterans Administration, and Project Grant DK 29961 from the National Institutes of Health. Bethesda. Maryland. Address reprint requests to Dr Carroll, Transplant Division. 3601 Fifth Avenue. Pittsburgh. PA 15213. ~ 1992 by Appleton & Lange 0041-1345192/$3.001+0 2980 Transplantation Proceedings. Vol 24. No 6 (December), 1992: pp 2980-2981 GLUCOSE HOMEOSTASIS REGULATION 6. Starzl TE. Todo S. Tzakis A. et al: Ann Surg 210:374. 1989 7. Starzl TE. Miller C. Broznick B. et al: Surg Gynecol Obstet 165:343. 1987 8. Ricordi C. Tzakis AG. Carroll PB. et al: Transplantation 53:407. 1992 9. Ricordi C. Lacy PE. Finke EH. et al: Diabetes 37:413. 1988 2981 10. Ricordi C. Kraus C. Lacy PE: Proc Natl Acad Sci USA 84:234. 1988 11. Kaku K. Fiedorek FT. Province M. et al: Diabetes 37:707. 1988 12. Georgiou HM. Mandel TE: Transplant Proc 19:2922.1987 13. Tuch BE. Monk. RS: Transplantation 51:1156. 1991 

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Glucose homeostasis is regulated by donor islets in xenografts

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