TY - JOUR
T1 - Cell-permeable pentapeptide V5 inhibits apoptosis and enhances insulin secretion, allowing experimental single-donor islet transplantation in mice
AU - Rivas-Carrillo, Jorge D.
AU - Soto-Gutierrez, Alejandro
AU - Navarro-Alvarez, Nalu
AU - Noguchi, Hirofumi
AU - Okitsu, Teru
AU - Chen, Yong
AU - Yuasa, Takeshi
AU - Tanaka, Kimiaki
AU - Narushima, Michiki
AU - Miki, Atsushi
AU - Misawa, Haruo
AU - Tabata, Yasuhiko
AU - Jun, Hee Sook
AU - Matsumoto, Shinichi
AU - Fox, Ira J.
AU - Tanaka, Noriaki
AU - Kobayashi, Naoya
PY - 2007/5
Y1 - 2007/5
N2 - 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. RESEARCH DESIGN AND 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-κB-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.
AB - 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. RESEARCH DESIGN AND 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-κB-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.
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U2 - 10.2337/db06-1679
DO - 10.2337/db06-1679
M3 - Article
C2 - 17287463
AN - SCOPUS:34248191271
SN - 0012-1797
VL - 56
SP - 1259
EP - 1267
JO - Diabetes
JF - Diabetes
IS - 5
ER -