Cell-permeable pentapeptide V5 inhibits apoptosis and enhances insulin secretion, allowing experimental single-donor islet transplantation in mice

Jorge D. Rivas-Carrillo, Alejandro Soto-Gutierrez, Nalu Navarro-Alvarez, Hirofumi Noguchi, Teru Okitsu, Yong Chen, Takeshi Yuasa, Kimiaki Tanaka, Michiki Narushima, Atsushi Miki, Haruo Misawa, Yasuhiko Tabata, Hee Sook Jun, Shinichi Matsumoto, Ira J. Fox, Noriaki Tanaka, Naoya Kobayashi

Research output: Contribution to journalArticle

19 Citations (Scopus)

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. 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.

Original languageEnglish (US)
Pages (from-to)1259-1267
Number of pages9
JournalDiabetes
Volume56
Issue number5
DOIs
StatePublished - May 2007
Externally publishedYes

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Val-Pro-Met-Leu-Lys
Islets of Langerhans Transplantation
Tissue Donors
Insulin
Apoptosis
Apoptosis Regulatory Proteins
Graft Survival
Transplantation
X-Linked Inhibitor of Apoptosis Protein
Collagenases
Therapeutics
Streptozocin
Islets of Langerhans
Blood Glucose
Digestion
Research Design
Down-Regulation
Transplants
Glucose

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Rivas-Carrillo, J. D., Soto-Gutierrez, A., Navarro-Alvarez, N., Noguchi, H., Okitsu, T., Chen, Y., ... Kobayashi, N. (2007). Cell-permeable pentapeptide V5 inhibits apoptosis and enhances insulin secretion, allowing experimental single-donor islet transplantation in mice. Diabetes, 56(5), 1259-1267. https://doi.org/10.2337/db06-1679

Cell-permeable pentapeptide V5 inhibits apoptosis and enhances insulin secretion, allowing experimental single-donor islet transplantation in mice. / Rivas-Carrillo, Jorge D.; Soto-Gutierrez, Alejandro; Navarro-Alvarez, Nalu; Noguchi, Hirofumi; Okitsu, Teru; Chen, Yong; Yuasa, Takeshi; Tanaka, Kimiaki; Narushima, Michiki; Miki, Atsushi; Misawa, Haruo; Tabata, Yasuhiko; Jun, Hee Sook; Matsumoto, Shinichi; Fox, Ira J.; Tanaka, Noriaki; Kobayashi, Naoya.

In: Diabetes, Vol. 56, No. 5, 05.2007, p. 1259-1267.

Research output: Contribution to journalArticle

Rivas-Carrillo, JD, Soto-Gutierrez, A, Navarro-Alvarez, N, Noguchi, H, Okitsu, T, Chen, Y, Yuasa, T, Tanaka, K, Narushima, M, Miki, A, Misawa, H, Tabata, Y, Jun, HS, Matsumoto, S, Fox, IJ, Tanaka, N & Kobayashi, N 2007, 'Cell-permeable pentapeptide V5 inhibits apoptosis and enhances insulin secretion, allowing experimental single-donor islet transplantation in mice', Diabetes, vol. 56, no. 5, pp. 1259-1267. https://doi.org/10.2337/db06-1679
Rivas-Carrillo, Jorge D. ; Soto-Gutierrez, Alejandro ; Navarro-Alvarez, Nalu ; Noguchi, Hirofumi ; Okitsu, Teru ; Chen, Yong ; Yuasa, Takeshi ; Tanaka, Kimiaki ; Narushima, Michiki ; Miki, Atsushi ; Misawa, Haruo ; Tabata, Yasuhiko ; Jun, Hee Sook ; Matsumoto, Shinichi ; Fox, Ira J. ; Tanaka, Noriaki ; Kobayashi, Naoya. / Cell-permeable pentapeptide V5 inhibits apoptosis and enhances insulin secretion, allowing experimental single-donor islet transplantation in mice. In: Diabetes. 2007 ; Vol. 56, No. 5. pp. 1259-1267.
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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. 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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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

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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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