Islets are particularly vulnerable in the initial days after transplantation when cell death results in the loss of more than half of the transplanted islet tissue. To determine whether a nonspecific inflammation at the grafted site mediated by the local expression of inflammatory cytokines could play a role on the initial damage to transplanted islets, we studied the expressions of interleukin-1b (IL-1b) and inducible form of nitric oxide synthase (iNOS) after syngeneic islet transplantation. Insulintreated streptozotocin-diabetic Lewis rats were syngeneically transplanted with 500 islets. Grafts were harvested 1, 3, or 7 days after transplantation, and the expressions of IL-1b and iNOS genes were determined by RT-PCR. IL-1b and iNOS mRNAs were detected in islets immediately after isolation, and were upregulated after transplantation. IL-1b mRNA was ninefold increased on day 1, was still sevenfold increased on day 3 after transplantation, and declined towards pretransplantation levels on day 7. iNOS mRNA showed a similar pattern of expression to that of IL-1b: on days 1 and 3 after transplantation it was 14-and 4-fold higher respectively than in freshly isolated islets. In addition, IL-1b and iNOS were identified in islet grafts and found to be produced mainly by CD68-positive macrophages. A low number of IL-1b-and iNOS-positive but CD68-negative cells were also identified suggesting that other cell types, in addition to macrophages, were involved in the expression of IL-1b and NO production in islet grafts. The finding of increased IL-1b and iNOS gene expressions in the initial days after islet transplantation and the presence of IL-b and iNOS proteins in the graft confirmed the presence of an early non-specific inflammatory response after islet transplantation. Overall, the data suggest that IL-1b plays a role in the extensive b-cell death found in the initial days after islet transplantation.

β-Cell mass reduction is a central aspect in the development of type 1 and type 2 diabetes, and substitution or regeneration of the lost β-cells is a potentially curative treatment of diabetes. To study the effects of gastrin on β-cell mass in rats with 95% pancreatectomy (95%-Px), a model of pancreatic regeneration, rats underwent 95% Px or sham Px and were treated with [15 leu] gastrin-17 (Px+G and S+G) or vehicle (Px+V and S+V) for 15 d. In 95% Px rats, gastrin treatment reduced hyperglycemia (280 ± 52 mg vs. 436 ± 51 mg/dl, P < 0.05), and increased β-cell mass (1.15 ± 0.15 mg)) compared with vehicle-treated rats (0.67 ± 0.15 mg, P < 0.05). Gastrin treatment induced β-cell regeneration by enhancing β-cell neogenesis (increased number of extraislet β-cells in Px+G: 0.42 ± 0.05 cells/mm(2) vs. Px+V: 0.27 ± 0.07 cells/mm(2), P < 0.05, and pancreatic and duodenal homeobox 1 expression in ductal cells of Px+G: 1.21 ± 0.38% vs. Px+V: 0.23 ± 0.10%, P < 0.05) and replication (Px+G: 1.65 ± 0.26% vs. S+V: 0.64 ± 0.14%; P < 0.05). In addition, reduced β-cell apoptosis contributed to the increased β-cell mass in gastrin-treated rats (Px+G: 0.07 ± 0.02%, Px+V: 0.23 ± 0.05%; P < 0.05). Gastrin action on β-cell regeneration and survival increased β-cell mass and improved glucose tolerance in 95% Px rats, supporting a potential role of gastrin in the treatment of diabetes.