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Cell-Permeable Pentapeptide V5 Inhibits Apoptosis and Enhances Insulin Secretion, Allowing Experimental Single-Donor Islet Transplantation in Mice

¹ Department of Surgery, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan
² Department of Advanced Medicine in Biotechnology and Robotics, Nagoya University Graduate School of Medicine, Nagoya, Japan
³ Department of Transplant Surgery, Kyoto University Hospital, Kyoto, Japan
⁴ Department of Orthopaedic Surgery, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan
⁵ Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan
⁶ Rosalind Franklin Comprehensive Diabetes Center, Chicago Medical School, North Chicago, Illinois
⁷ Department of Biochemistry, Chosun University School of Medicine, Gwangju, Korea
⁸ Second Department of Surgery, Fujita Health University, Aichi, Japan
⁹ Department of Surgery, University of Nebraska Medical Center, Omaha, Nebraska

Address correspondence and reprint requests to Naoya Kobayashi, MD, PhD, Department of Surgery, Okayama University Graduate School of Medicine and Dentistry, 2-5-1 Shikata-cho, Okayama, 700-8558, Japan. E-mail: immortal{at}md.okayama-u.ac.jp

Abbreviations: FGF-2, fibroblast growth factor-2; HBSS, Hank's balanced salt solution; IL, interleukin; KRBB, Krebs-Ringer balanced buffer; NF-B, nuclear factor-B; TNF-, tumor necrosis factor-; TUNEL, transferase-mediated dUTP nick-end labeling; XIAP, X-linked inhibitor of apoptosis protein

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-B–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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