Enhancing engraftment of islets using perioperative sodium 4-phenylbutyrate

Abstract

Primary nonfunction (PNF) adversely impacts islet transplantation. In addition to determining whether sodium 4-phenylbutyrate (4-SPB), an anti-inflammatory agent, reduces PNF, this study investigates how 4-SPB affects PNF. Streptozotocin-induced diabetic C57BL/6 mice, that received 75 syngeneic islets underneath left subrenal space, were fed twice daily of either 4-SPB at 500 mg/kg body weight or isotonic saline (NaCl) from 2 days before through 7 days after transplantation. The graft was removed at days 3, 10 and 84 following transplantation. At 68 h following transplantation, serum levels of interleukin-1β (IL-1β) were 2.2 ± 0.4 and 0.4 ± 0.2 pmol/L ( n = 6, p < 0.005) for NaCl and 4-SPB groups, respectively. Graft genetic expression of IL-1β was significantly suppressed in 4-SPB group ( p < 0.01). At day 10, the blood glucose levels were 22.7 ± 1.0 and 17.1 ± 1.7 mmol/L ( n = 12, p < 0.05) and graft insulin contents (IC) were 35.0 ± 8.3 and 107.6 ± 29.7 pmol ( n = 12, p < 0.05) for NaCl and 4-SPB groups, respectively. Moreover, the 4-SPB group had a shorter temporary hyperglycemia (15 ± 2, n = 21 vs. 25 ± 2 days, n = 19, p = 0.001) and a higher cumulative cure rate of diabetes ( p < 0.001) than the NaCl group. In-vitro studies indicated that 4-SPB did not impact the islets function. These experimental results demonstrated that perioperative administration of 4-SPB decreased serum level and graft genetic expression of IL-1β and attenuated PNF, which enhanced islet engraftment in a syngeneic transplantation mouse model.