title: Cell-permeable pentapeptide V5 inhibits apoptosis and enhances insulin secretion, allowing experimental single-donor islet transplantation in mice.
abstract: OBJECTIVE
  Treatment of diabetic patients by pancreatic islet transplantation often requires the use of islets from two to four donors to produce insulin independence in a single recipient. Following isolation and transplantation, islets are susceptible to apoptosis, which limits their function and probably long-term islet graft survival.
  
  
  METHODS
  To address this issue, we examined the effect of the cell-permeable apoptosis inhibitor pentapeptide Val-Pro-Met-Leu-Lys, V5, on pancreatic islets in a mouse model.
  
  
  RESULTS
  V5 treatment upregulated expression of anti-apoptotic proteins Bcl-2 and XIAP (X-linked inhibitor of apoptosis protein) by more than 3- and 11-fold and downregulated expression of apoptosis-inducing proteins Bax, Bad, and nuclear factor-kappaB-p65 by 10, 30, and nearly 50%, respectively. Treatment improved the recovered islet mass following collagenase digestion and isolation by 44% and in vitro glucose-responsive insulin secretion nearly fourfold. Following transplantation in streptozotocin-induced diabetic mice, 150 V5-treated islet equivalents functioned as well as 450 control untreated islet equivalents in normalizing blood glucose.
  
  
  CONCLUSIONS
  These studies indicate that inhibition of apoptosis by V5 significantly improves islet function following isolation and improves islet graft function following transplantation. Use of this reagent in clinical islet transplantation could have a dramatic impact on the number of patients that might benefit from this therapy and could affect long-term graft survival.
authors.affiliation: Department of Surgery, Okayama University Graduate School of Medicine and Dentistry, Shikata-cho, Okayama, Japan.
authors.forename: Jorge D
authors.initials: JD
authors.lastname: Rivas-Carrillo
authors.forename: Alejandro
authors.initials: A
authors.lastname: Soto-Gutierrez
authors.forename: Nalu
authors.initials: N
authors.lastname: Navarro-Alvarez
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Noguchi
authors.forename: Teru
authors.initials: T
authors.lastname: Okitsu
authors.forename: Yong
authors.initials: Y
authors.lastname: Chen
authors.forename: Takeshi
authors.initials: T
authors.lastname: Yuasa
authors.forename: Kimiaki
authors.initials: K
authors.lastname: Tanaka
authors.forename: Michiki
authors.initials: M
authors.lastname: Narushima
authors.forename: Atsushi
authors.initials: A
authors.lastname: Miki
authors.forename: Haruo
authors.initials: H
authors.lastname: Misawa
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Tabata
authors.forename: Hee-Sook
authors.initials: HS
authors.lastname: Jun
authors.forename: Shinichi
authors.initials: S
authors.lastname: Matsumoto
authors.forename: Ira J
authors.initials: IJ
authors.lastname: Fox
authors.forename: Noriaki
authors.initials: N
authors.lastname: Tanaka
authors.forename: Naoya
authors.initials: N
authors.lastname: Kobayashi
mesh_terms: D000818:Animals; D017304:Annexin A5 / Q000235:genetics; D017209:Apoptosis / Q000187:drug effects*; D003922:Diabetes Mellitus, Type 1 / Q000601:surgery; D005260:Female; D005786:Gene Expression Regulation; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000166:cytology / Q000378:metabolism; D016381:Islets of Langerhans Transplantation; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D023421:Models, Animal; D009842:Oligopeptides / Q000138:chemical synthesis / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D014019:Tissue Donors; D014185:Transplantation, Isogeneic; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000235:genetics
chemical_list: D017304:Annexin A5; D007328:Insulin; D009842:Oligopeptides; D019253:Proto-Oncogene Proteins c-bcl-2; C509183:Val-Pro-Met-Leu-Lys; D051636:X-Linked Inhibitor of Apoptosis Protein