Alejandro, R

Bereiter, D

Carroll, P

Fung, JJ

Ricordi, C

Rilo, HLR

Starzl, TE

Tzakis, A

Venkataramanan, R

Zeng, Y

Transplantation Proceedings

English

PubMed

Name not available

Effect of FK 506 on human pancreatic islets following renal subcapsular transplantation in diabetic nude mice

D-Scholarship@Pitt

, I ~ I ! "I , ;: " i,., ! , , j 1 Effect of FK 506 on Human Pancreatic Islets Following Renal Subcapsular Transplantation in Diabetic Nude Mice C. Ricordi, Y. Zeng, R. Alejandro, A. Tzakis, P. Carroll, H.L.R. Rilo, R. Venkataramanan, J.J. Fung, D. Bereiter, and T.E. Starzl POSTIRANSPLANT hyperglycemia is a well-recog-nized side effect of most standard immunosuppres-sive drugs including prednisone I and cyclosporine (CyA),2.-4 which are known to be diabetogenic in humans. Similar effects have been ascribed to FK S06 in both experimental5.6 and clinical studies.7 The aim of this study was to test the in vivo effect of FK S06 on human pancreatic islets. MATERIALS AND METHODS Human islets were preparedK~·9 One week after human islet transplantation the ammals were divided into four groups. In group I (n = 10). the animals receIved one injection of 0.5 mL of cremaphor-ethanol-saline (without FK 506) intrapelitoneaUy HP) daily for I week. In group 2 (n = 5). the animals were treated by daily IP injection of 0.3 mglkg FK 506. while in groups 3 (n = 5) and 4 In = 5) the daily injections were I and 3 mglkg FK 506. respectively. Fifteen days after islet transplantation. the animals underwent IP glucose tolerance test ((PGrn. 10 RESULTS AND DISCUSSION IP administration of FK S06 for I week at a dose of 0.3 mglkgld did not produce any significant alteration of glu-cose disappearance after IP administration of glucose. Higher doses of FK S06 produced a significant delay in plasma glucose disappearance. In groups 3 and 4.2 of \0 animals demonstrated hyperglycemia before IPGTI (fast-ing plasma glucose > 200 mgldU. In these animals. the presence offasting hyperglycemIa despite normal levels of human C-peptide indicated that peripheral insulin resis-tance could be responsible for the hyperglycemic effect of FK 506. Nevertheless, at high dose treatment insulin secretion appears to be impaired as well. Furthermore. 5 of 10 animals remained hyperglycemic 1 hour after IP glucose injection. Human C-peptide levels following IPGTI indi-cated that abnormal glucose disappearance in group 4 was associated with an initial impairment of insulin secretion from the engrafted islets. In fact. 15 minutes after glucose injection a decrease in human C-peptide levels was ob-served in group 4. in contrast to the control groups in which a twofold increase in C-peptide was observed. The difference in C-peptide levels between the two groups was statistically significant only at the 15 minute level (P < .028). Histologic studies on the renal subcapsular islets indi-cated that human islets were present in the renal subcap-1042 sular space of all transplanted animals. Nevertheless. in the two animals (one in group 3 and one in group 4) that were hyperglycemic. the beta cells appeared degranulated. In the remaining animals the human islets appeared well preserved with no significant difference between FK S06-treated and control animals. In group I (control) a nephrec-tomy of the kidneys bearing the grafts produced a rapid return to the diabetic state. indicating that the human islets transplanted were responsible for the maintenance of normoglycemia. This study indicates that FK 506 did not produce signif-icant alteration of glucose homeostasis in animals treated with a dose of 0.3 mglkgld for 7 days. Nevertheless. the effect of the drug on insulin secretion and glucose disap-pearance after IP glucose have been observed at higher dosages. Although these levels are significantly higher than the therapeutic levels in current use in patients, the poten-tial accumulation during chronic treatment with the agent in the pancreas. like CyA. may induce islet secretory defects even at therapeutic levels. REFERENCES I. David OS. Cheigh JS. Braun OW. et al: JAMA 243:532. 1980 2. Boudreaux JP. McHugh L. Canafax OM. et al: Transplan-tation 44:376. 1987 3. Ost L. Tyden T. Fehrman I: Transplantation 46:370. 1988 4, Roth D. Milgrom M. Esquenzal V. et al: Transplantation 47:278. 1989 5. Nalesnik MA. Todo S. Murase N. et al: Transplant Proc 19:79. 1987 6. Collier OS]' Caine R. Thiru S. et al: Transplant Proc 19:3975. 1987 7. Mieles L. Todo S. Fung JJ. et aI: Transplant Proc 22:41. 1990 8. Ricordi C. Lacy PE. Finke EH. et al: Diabetes 37:413. 1988 9. Tzakis A. Ricordi C. Alejandro R. et al: Lancet 336:402. 1990 10. Kaku K. Fiedorek fT. Province M. et al: Diabetes 37:707. 1988 From the Transplant Institute. UniversIty of Pittsburgh. Pitts. burgh, PA; The Diabetes Research Institute. University of Miami. Miami. Florida. Supported in part by Juvenile Diabetes FoundatiOn Research Grant no. 1911421. Address repnnt requests to Dr Camillo Ricordi. University of Pittsburgh, School of Medicine. Department of Surgery, 3601 Fifth Ave. Pittsburgh, PA 15213. ~ 1992 by Appleton & Lange 0041·13451921$3.001+0 TrSMPUmtatJotl Proceedings, Vol 24. No 3 (June), 1992: p 1042 

RICORDI, C

ZENG, Y

ALEJANDRO, R

TZAKIS, A

CARROLL, P

RILO, H. L. R

VENKATARAMANAN, R

FUNG, J. J

BEREITER, D

STARZL, T. E

University of Miami: Scholarship Miami

http://d-scholarship.pitt.edu/4721/1/31735062111285.pdf

Effect of FK 506 on human pancreatic islets following renal subcapsular transplantation in diabetic nude mice

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