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Cell-permeable Pentapeptide V5 Inhibits Apoptosis and Enhances Insulin Secretion, Allowing Experimental Single-donor Islet Transplantation In Mice

¹Department of Surgery, Okayama University Graduate School of Medicine and Dentistry, 2-5-1 Shikata-cho, Okayama 700-8558, Japan
²Department of Advanced Medicine in Biotechnology and Robotics, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan
³Department of Transplant Surgery, Kyoto University Hospital, 54 Seigoin-Kawaracho, Sakyoku, Kyoto 606-8507, Japan
⁴Department Department of Orthopaedic Surgery, Okayama University Graduate School of Medicine and Dentistry, 2-5-1 Shikata-cho, Okayama 700-8558, Japan
⁵Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan
⁶Rosalind Franklin Comprehensive Diabetes Center, Chicago Medical School, North Chicago, IL 60064 U.S.A
⁷Department of Biochemistry, Chosun University School of Medicine, 375 Seosuk-Dong, Gwangju 501-759, Korea
⁸Second Department of Surgery, Fujita Health University, Toyoake, Aichi 470-11, Japan
⁹Department of Surgery, University of Nebraska Medical Center, Omaha, NE 68198-3285, USA

Correspondence: immortal{at}md.okayama-u.ac.jp

OBJECTIVE: Treatment of diabetic patients by pancreatic islet transplantation often requires the use of islets from 2 to 4 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 up-regulated expression of anti-apoptotic proteins Bcl-2 and XIAP by more than 3- and 11-fold, and down-regulated expression of apoptosis-inducing proteins Bax, Bad, and NFkß-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 4-fold. Following transplantation in streptozotocin-induced diabetic mice, 150 V5-treated islet equivalents (IEQ) functioned as well as 450 control un-treated IEQ 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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