期刊
CELL TRANSPLANTATION
卷 21, 期 6, 页码 1269-1283出版社
SAGE PUBLICATIONS INC
DOI: 10.3727/096368911X627408
关键词
Diabetes; Islet transplantation; Exendin-4; Macroencapsulation; Hypoxia-inducible factor-1 alpha (HIF-1 alpha)
资金
- regional agreement on medical training and clinical research (ALF) between Stockholm County Council and Karolinska Institutet [20060710, 20080443]
- Swedish Research Council [52120083389]
- Karolinska Institute
- Foundation for International Surgical Cooperation
- Foundation for Oncological Cooperation
- Barndiabetesfonden
In this study, we evaluated the effects of exendin-4 on free and encapsulated islet grafts in a rodent model. We also investigated the role of a transcription factor, hypoxia-inducible factor-1 (HIF-1), in mediating the beneficial effects of exendin-4. Diabetic athymic mice were transplanted with free rat islets under the kidney capsule or with macroencapsulated rat islets SC with or without exendin-4, islet preculture (exendin-4 0.1 nM for 20 h), and/or recipient treatment (IP 100 ng/day, day 0-7). The mice were followed for 4 weeks and the graft function and beta-cell volume were evaluated. The effects of exendin-4 on islet HIF-1 alpha mRNA and protein expression and on ATP content in a rat insulinoma cell line (INS-1E) were also examined. Preculture with exendin-4 followed by recipient treatment improved the outcome of both free (73% graft function vs. 26% in controls, p = 0.03) and macroencapsulated islet grafts (100% vs. 25% in controls, p = 0.02). In macroencapsulated grafts, the exendin-4-treated group had significantly larger endocrine volume, less graft necrosis, and more blood vessels around the capsule. In rat islets cultured with exendin-4. HIF-1 alpha mRNA and protein expression were significantly enhanced. ATP content was increased in excndin-4-treated INS-1E cells under hypoxic conditions. The improved functional outcome after transplantation of a marginal islet mass with a brief initial treatment with exendin-4 is related to a larger surviving endocrine cell volume. Exendin-4 may improve islet graft resistance to hypoxia during the peritransplant period by increasing the expression of HIF-1 alpha.
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