Exendin-4 increases the expression of hypoxia-inducible factor-1α in rat islets and preserves the endocrine cell volume of both free and macroencapsulated islet grafts.

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 ß-cell volume were evaluated. The effects of exendin-4 on islet HIF-1α 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-1α mRNA and protein expression were significantly enhanced. ATP content was increased in exendin-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-1α.

Preimplantation of an immunoprotective device can lower the curative dose of islets to that of free islet transplantation: studies in a rodent model.

Islet graft survival inside macroencapsulation devices is suboptimal. We hypothesized that induction of neovascularization by preimplantation of devices would improve the physiological conditions, thereby lowering the number of islets required for cure. Several rat islets were transplanted to TheraCyte immunoprotective devices implanted subcutaneously in diabetic athymic mice. Cure rates in the groups with preimplanted devices were significantly better than in those with freshly implanted devices (375 islets: 8/8 vs. 1/6, P=0.003; 125 islets: 6/6 vs. 0/7, P=0.001). Morphometric evaluations of the 125 islet groups showed higher fractional and absolute volumes of endocrine tissue in the group with preimplanted devices (P<0.001 and P=0.035, respectively). In the following dose titration study, using preimplanted devices, as low as 50 islets cured diabetic mice (100% cure, n=6). We conclude that preimplantation significantly lowers the curative dose of macroencapsulated islets to levels resembling those of free islets transplanted under the renal capsule.

Macroencapsulation protects against sensitization after allogeneic islet transplantation in rats.

BACKGROUND: The aim of this study was to evaluate the risks of sensitization by islet grafts encapsulated in a bilaminar immunoprotective membrane. METHODS: We studied five groups of Lewis rats: one control group (no islets), two groups that received free islets (200 or 1000 s.c.), and two groups that received encapsulated ones (200 or 1000 s.c.) from Dark Agouti (DA) rats. Four weeks later, abdominal heterotopic DA-heart transplantation was performed on the same recipients. The time-to-heart graft rejection was assessed by the cessation of heart contractions. Rejection was confirmed by histological examinations. Antidonor antibodies were determined by fluorescence activated cell sorter (FACS) analysis. RESULTS: The control animals had a mean heart graft survival of 6.4 days. The free islet groups had significantly shorter heart graft survivals-i.e., 4.8 days (200 islets) and 1.0 day (1000 islets) (P < 0.001)-while those of the encapsulated islet groups were about the same as that of the control group-i.e., 6.4 days (200 islets) and 6.0 days (1000 islets). In the free islet groups, anti-DA antibodies developed in 7/10 (200 islets) and 8/8 (1000 islets) animals after the islet transplantation. In the encapsulated groups, 1/10 (200 islets) and 3/8 (1000 islets) animals developed anti-DA antibodies after these transplantations. All animals had anti-DA antibodies at the time of heart graft rejection. On histological examination all grafts showed various features of rejection. CONCLUSIONS: The bilaminar membrane protects against sensitization and prevents accelerated rejection of a subsequent vascularized graft, at least during the first month after the islet transplantation.