Improved human pancreatic islet isolation for a prospective cohort study of islet transplantation vs best medical therapy in type 1 diabetes mellitus

Garth L. Warnock, R. Mark Meloche, David Thompson, R. Jean Shapiro, Michelle Fung, Ziliang Ao, Stephen Ho, Zehua He, Long Jun Dai, Linnea Young, Lorraine Blackburn, Sharon Kozak, Peter T.W. Kim, David Al-Adra, James D. Johnson, Yu Huan Theresa Liao, Tom Elliott, C. Bruce Verchere, Susan Orloff, William H. MarksNancy L. Ascher

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64 Scopus citations

Abstract

Hypothesis: A local multiorgan donor pancreas procurement program can provide a source for optimized isolation of purified viable islets for transplantation into patients with type 1 diabetes mellitus receiving best medical therapy. Design: Prospective before-after cohort study. Setting: Tertiary referral center. Patients: Glycemic control was assessed in 10 patients with diabetes-induced renal dysfunction who were enrolled in a best medical therapy program and then crossed over to islet transplantation. Interventions: Thirty human pancreata were retrieved from local multiorgan donors and consecutively processed with intraductal collagenase perfusion, continuous digestion, and density gradient purification (group 1, n=9) or similarly processed but impure tissue fractions cultured in vitro and then repurified to retrieve additional islets (group 2, n=21). Islets were implanted by percutaneous portal embolization, providing more than 10 000 islet equivalents (IE) per kilogram of body weight (infusions from 1-3 donors per patient) under cover of antithymocyte globulin, sirolimus, or mycophenolate mofetil and tacrolimus. Main Outcome Measures: Islet yields, purity, and cell viability (caspase 3, terminal deoxynucleotidyl transferase-mediated biotin-deoxyuridine 5-triphosphate nick-end labeling stain, and insulin secretion in vitro) were compared. In patients, monitored metabolic parameters were C-peptide secretion, insulin requirements, glycemic excursion, and hemoglobin A 1c (HbA 1c). Results: For group 1 vs group 2, no differences were observed in pancreas age (43 vs 44 years), cold storage (5 vs 4 hours), or weight (73 vs 82 g). Group 2 yielded 453 690 IE vs 214 109 IE in group 1 (P=.002). Grafts contained 50% or more endocrine cells in both groups. No difference occurred in cell viability or insulin secretion. Islets from 90% of group 2 pancreata met release criteria for transplantation. C-peptide secretion was detected in all recipients and persisted with a median follow-up to 12 months (range, 6-21 months) after full islet transplantation. Daily insulin dependence was reversed in all patients for at least 3 months. Five patients resumed small insulin doses. Compared with the best care program, all patients had improved metabolic stability. The mean±SE HbA 1c level at entry into the study was 7.8%±0.5%, and this decreased to 6.9%±0.2% after best care (P=.38) and further to 6.2%±0.2% at 6 months after transplantation (P=.002 vs entry; P=.15 vs best care; analysis of variance). Conclusions: Local pancreas donor retrieval with islet isolation and culture conditioning enabled an offer of islets for transplantation for 90% of consecutively processed pancreata. Isolated islets secreted insulin during prolonged follow-up after implantation into patients, yielding metabolic control comparable with that achieved by best medical therapy.

Original languageEnglish (US)
Pages (from-to)735-744
Number of pages10
JournalArchives of Surgery
Volume140
Issue number8
DOIs
StatePublished - Aug 1 2005
Externally publishedYes

ASJC Scopus subject areas

  • Surgery

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    Warnock, G. L., Meloche, R. M., Thompson, D., Shapiro, R. J., Fung, M., Ao, Z., Ho, S., He, Z., Dai, L. J., Young, L., Blackburn, L., Kozak, S., Kim, P. T. W., Al-Adra, D., Johnson, J. D., Liao, Y. H. T., Elliott, T., Verchere, C. B., Orloff, S., ... Ascher, N. L. (2005). Improved human pancreatic islet isolation for a prospective cohort study of islet transplantation vs best medical therapy in type 1 diabetes mellitus. Archives of Surgery, 140(8), 735-744. https://doi.org/10.1001/archsurg.140.8.735