title: Porcine marginal mass islet autografts resist metabolic failure over time and are enhanced by early treatment with liraglutide.
abstract: Although insulin independence is maintained in most islet recipients at 1 yr after transplant, extended follow-up has revealed that many patients will eventually require insulin therapy. Previous studies have shown that islet autografts are prone to chronic failure in large animals and humans, suggesting that nonimmunological events contribute to islet graft functional decay. Early intervention with therapies that promote graft stability should provide a measurable benefit over time. In this study, the efficacy of the long-acting glucagon-like peptide-1 analog liraglutide was explored in a porcine marginal mass islet autograft transplant model. Incubation with liraglutide enhanced porcine islet survival and function after prolonged culture. Most vehicle-treated (83%) and liraglutide-treated (80%) animals became insulin independent after islet autotransplantation. Although liraglutide therapy did not improve insulin independence rates or blood glucose levels after transplant, a significant increase in insulin secretion and acute-phase insulin response was observed in treated animals. Surprisingly, no evidence for deterioration of graft function was observed in any of the transplanted animals over more than 18 months of follow-up despite significant weight gain; in fact, an enhanced response to glucose developed over time even in control animals. Histological analysis showed that intraportally transplanted islets remained highly insulin positive, retained alpha-cells, and did not form amyloid deposits. This study demonstrates that marginal mass porcine islet autografts have stable long-term function, even in the presence of an increasing metabolic demand. These results are discrepant with previous large animal studies and suggest that porcine islets may be resistant to metabolic failure.
authors.affiliation: Department of Surgery, University of Alberta, Edmonton, Alberta, Canada T6G 2E1. juliete@ualberta.ca
authors.forename: Juliet A
authors.initials: JA
authors.lastname: Emamaullee
authors.forename: Shaheed
authors.initials: S
authors.lastname: Merani
authors.forename: Christian
authors.initials: C
authors.lastname: Toso
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Kin
authors.forename: Faisal
authors.initials: F
authors.lastname: Al-Saif
authors.forename: Wayne
authors.initials: W
authors.lastname: Truong
authors.forename: Rena
authors.initials: R
authors.lastname: Pawlick
authors.forename: Joy
authors.initials: J
authors.lastname: Davis
authors.forename: Ryan
authors.initials: R
authors.lastname: Edgar
authors.forename: Jennifer
authors.initials: J
authors.lastname: Lock
authors.forename: Susan
authors.initials: S
authors.lastname: Bonner-Weir
authors.forename: Lotte B
authors.initials: LB
authors.lastname: Knudsen
authors.forename: A M James
authors.initials: AM
authors.lastname: Shapiro
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005260:Female; D052216:Glucagon-Like Peptide 1 / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D005947:Glucose / Q000378:metabolism; D006085:Graft Survival / Q000187:drug effects* / Q000502:physiology; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism / Q000502:physiology / Q000637:transplantation; D016381:Islets of Langerhans Transplantation / Q000379:methods* / Q000534:rehabilitation / Q000662:veterinary; D000069450:Liraglutide; D008659:Metabolic Diseases / Q000517:prevention & control*; D013552:Swine; D013556:Swine, Miniature; D013997:Time Factors; D014182:Transplantation, Autologous
chemical_list: D000069450:Liraglutide; D052216:Glucagon-Like Peptide 1; D005947:Glucose