Cell-permeable pentapeptide V5 inhibits apoptosis and enhances insulin secretion, allowing experimental single-donor islet transplantation in mice.
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.
Rivas-Carrillo
Jorge D
JD
Department of Surgery, Okayama University Graduate School of Medicine and Dentistry, Shikata-cho, Okayama, Japan.
Soto-Gutierrez
Alejandro
A
Navarro-Alvarez
Nalu
N
Noguchi
Hirofumi
H
Okitsu
Teru
T
Chen
Yong
Y
Yuasa
Takeshi
T
Tanaka
Kimiaki
K
Narushima
Michiki
M
Miki
Atsushi
A
Misawa
Haruo
H
Tabata
Yasuhiko
Y
Jun
Hee-Sook
HS
Matsumoto
Shinichi
S
Fox
Ira J
IJ
Tanaka
Noriaki
N
Kobayashi
Naoya
N
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
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