Effect of Conversion to CTLA4Ig on Tacrolimus-Induced Diabetic Rats.

BACKGROUND: The effect of conversion to cytotoxic T lymphocyte-associated protein 4 immunoglobulin (CTLA4Ig) treatment on tacrolimus (TAC)-induced renal dysfunction is well known, but its effect on TAC-induced diabetes mellitus (DM) is still undetermined. In the present study, we tested the diabetogenicity of CTLA4Ig and evaluated the effect of conversion to CTLA4Ig treatment on TAC-induced diabetic rats.

METHODS: We tested diabetogenicity of CTLA4Ig by escalating doses (0.25, 0.5, 1, 2, and 4 mg/kg weekly) for 4 weeks. In the conversion study, we administered TAC (1.5 mg/kg) for 3 weeks and confirmed TAC-induced DM by intraperitoneal glucose tolerance test. Thereafter, TAC administration was continued, withdrawn, or replaced by CTLA4Ig treatment (1 or 2 mg/kg) for additional 3 weeks. The effect of CTLA4Ig on TAC-induced DM in vivo and in vitro was evaluated by assessing pancreatic islet function, histopathology, oxidative stress, apoptosis, and macrophage infiltration.

RESULTS: Intraperitoneal glucose tolerance test in the CTLA4Ig groups did not differ from the control group. In addition, plasma insulin level, glucose-induced insulin secretion, and islet viability were not different between the CTLA4Ig and control groups. In the conversion study, TAC withdrawal ameliorated pancreatic islet dysfunction compared with the TAC group, and conversion to CTLA4Ig further improved pancreatic islet function compared with the TAC withdrawal group. TAC-induced oxidative stress, apoptotic cell death, and infiltration of macrophages decreased with TAC withdrawal, and CTLA4Ig conversion further reduced those values. In the in vitro study, CTLA4Ig decreased TAC-induced pancreatic islet cell death and reactive oxygen species production.

CONCLUSIONS: CTLA4Ig was not diabetogenic, and conversion to CTLA4Ig reduced TAC-induced pancreatic islet injury.