title: Antiaging Glycopeptide Protects Human Islets Against Tacrolimus-Related Injury and Facilitates Engraftment in Mice.
abstract: Clinical islet transplantation has become an established treatment modality for selected patients with type 1 diabetes. However, a large proportion of transplanted islets is lost through multiple factors, including immunosuppressant-related toxicity, often requiring more than one donor to achieve insulin independence. On the basis of the cytoprotective capabilities of antifreeze proteins (AFPs), we hypothesized that supplementation of islets with synthetic AFP analog antiaging glycopeptide (AAGP) would enhance posttransplant engraftment and function and protect against tacrolimus (Tac) toxicity. In vitro and in vivo islet Tac exposure elicited significant but reversible reduction in insulin secretion in both mouse and human islets. Supplementation with AAGP resulted in improvement of islet survival (Tac(+) vs. Tac+AAGP, 31.5% vs. 67.6%, P < 0.01) coupled with better insulin secretion (area under the curve: Tac(+) vs. Tac+AAGP, 7.3 vs. 129.2 mmol/L/60 min, P < 0.001). The addition of AAGP reduced oxidative stress, enhanced insulin exocytosis, improved apoptosis, and improved engraftment in mice by decreasing expression of interleukin (IL)-1β, IL-6, keratinocyte chemokine, and tumor necrosis factor-α. Finally, transplant efficacy was superior in the Tac+AAGP group and was similar to islets not exposed to Tac, despite receiving continuous treatment for a limited time. Thus, supplementation with AAGP during culture improves islet potency and attenuates long-term Tac-induced graft dysfunction.
authors.affiliation: Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada Canadian National Transplant Research Program, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Boris L
authors.initials: BL
authors.lastname: Gala-Lopez
authors.affiliation: Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada Canadian National Transplant Research Program, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Pepper
authors.affiliation: Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Rena L
authors.initials: RL
authors.lastname: Pawlick
authors.affiliation: Clinical Islet Transplant Program, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Doug
authors.initials: D
authors.lastname: O'Gorman
authors.affiliation: Clinical Islet Transplant Program, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Kin
authors.affiliation: Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada Canadian National Transplant Research Program, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Antonio
authors.initials: A
authors.lastname: Bruni
authors.affiliation: Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada Canadian National Transplant Research Program, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Nasser
authors.initials: N
authors.lastname: Abualhassan
authors.affiliation: Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Mariusz
authors.initials: M
authors.lastname: Bral
authors.affiliation: Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada Department of Pharmacology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Austin
authors.initials: A
authors.lastname: Bautista
authors.affiliation: Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada Department of Pharmacology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Jocelyn E
authors.initials: JE
authors.lastname: Manning Fox
authors.affiliation: ProtoKinetix Inc., Vancouver, Vancouver, British Columbia, Canada.
authors.forename: Lachlan G
authors.initials: LG
authors.lastname: Young
authors.affiliation: Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada Department of Pharmacology, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Patrick E
authors.initials: PE
authors.lastname: MacDonald
authors.affiliation: Alberta Diabetes Institute, University of Alberta, Edmonton, Alberta, Canada Canadian National Transplant Research Program, University of Alberta, Edmonton, Alberta, Canada Clinical Islet Transplant Program, University of Alberta, Edmonton, Alberta, Canada amjs@islet.ca.
authors.forename: A M James
authors.initials: AM
authors.lastname: Shapiro
mesh_terms: D000818:Animals; D021301:Antifreeze Proteins / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D005089:Exocytosis; D006085:Graft Survival / Q000187:drug effects; D006801:Humans; D007166:Immunosuppressive Agents / Q000633:toxicity*; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007378:Interleukins / Q000378:metabolism; D007515:Islets of Langerhans / Q000187:drug effects* / Q000293:injuries / Q000502:physiology; D016381:Islets of Langerhans Transplantation / Q000379:methods* / Q000502:physiology; D051379:Mice; D018384:Oxidative Stress / Q000187:drug effects; D020011:Protective Agents / Q000494:pharmacology; D016559:Tacrolimus / Q000633:toxicity*
chemical_list: C000608022:AAGP glycopeptide, 580 Da; D021301:Antifreeze Proteins; D007166:Immunosuppressive Agents; D007328:Insulin; D007378:Interleukins; D020011:Protective Agents; D016559:Tacrolimus