Exendin-4 Treatment Expands Graft β-Cell Mass in Diabetic Mice Transplanted with a Marginal Number of Fresh Islets

Abstract

Exendin-4 stimulates insulin secretion, suppresses glucagons secretion, increases β-cell replication and neogenesis, and reduces β-cell apoptosis. However, it has been shown that posttransplant exendin-4 treatment did not improve glucose homeostasis in diabetic mice transplanted with a large number of freshly isolated islets. The aim of this study was to test if exendin-4 is beneficial for hyperglycemic recipients with a marginal number of fresh islets. We transplanted 150 C57BL/6 mouse islets under the kidney capsule of inbred streptozotocin-diabetic mice, and then treated the recipients with and without exendin-4 for 6 weeks. Before and after transplantation, recipients' blood glucose, body weight, and intraperitoneal glucose tolerance test were measured. At 6 weeks, the grafts were removed to determine β-cell mass. Blood glucose levels in both groups decreased progressively after transplantation, and the exendin-4-treated group had had lower blood glucose than controls since day 3. By 6 weeks, euglycemia was achieved more in mice treated with exendin-4 than in controls (100% vs. 62.5%, p = 0.018). The time to obtain normoglycemia was shorter in the exendin-4-treated group than in controls (12± 8 vs. 29 ± 13 days, p < 0.001). Blood glucose at 6 weeks was 123 ± 18 and 170 ± 62 mg/dl in the exendin-4-treated group and controls, respectively (p = 0.008). Additionally, the exendin-4-treated group had better glucose tolerance than controls at 2 and 4 weeks (p < 0.02). However, both groups exhibited increased body weight over time, and weight changes did not significantly differ between the two groups throughout the study period. At 6 weeks after transplantation, grafts in the exendin-4-treated group were more prominent and contained more insulin-stained cells than those of controls. They had 2.3-fold β-cell mass of the graft compared with controls (0.30 ± 0.11 vs. 0.13 ± 0.03 mg, p = 0.012). These results indicate posttransplant exendin-4 treatment in the diabetic recipient with a marginal number of fresh islets expands graft β-cell mass and improves transplantation outcome.