Troglitazone can prevent development of type 1 diabetes induced by multiple low-dose streptozotocin in mice

Recent investigations suggest that cytotoxic cytokines such as tumor necros is factor (TNF)alpha and interleukin (IL)-1 beta or free radicals play an e ssential role in destruction of pancreatic beta cells in Type 1 diabetes an d that, therefore, anti-oxidant or anti-TNF alpha and IL-1 beta therapy cou ld prevent the development of Type I diabetes. Troglitazone belongs to a no vel class of antidiabetic agent possessing the ability to enhance insulin a ction provably through activating PPAR gamma and to scavenge free radicals. In the present study, we examined whether troglitazone can prevent the dev elopment of Type 1 diabetes in multiple, low-dose streptozotocin (MLDSTZ)in jected mice. In addition, effects of troglitazone on cytokine-induced pancr eatic beta cell damage were examined in vitro. Type 1 diabetes was induced by MLDSTZ injection to DBA/2 mice (40 mg/kg/day for 5 days). Troglitazone w as administered as a 0.2% food admixture (240 mg/kg/day) for 4 weeks from t he start of or immediately after STZ injection. MLDSTZ injection elevated p lasma glucose to 615 +/- 8 mg/dl 4 weeks after final STZ injection and was accompanied by infiltration of leukocytes to pancreatic islets (insulitis). Troglitazone treatment with MLDSTZ injection prevented hyperglycemia (230 +/- 30 mg/dl) and, suppressed insulitis and TNF alpha production from intra peritoneal exudate cells. TNF alpha (10 pg/ml) and IL-1 beta (1 pg/ml) addi tion to hamster insulinoma cell line HIT-T15 for 7 days in vitro decreased insulin secretion and cell viability. Simultaneous troglitazone addition (0 .03 similar to 3 mu M) significantly improved cytokine-induced decrease in insulin secretion and in cell viability. These findings suggest that trogli tazone prevents the development of Type 1 diabetes in the MLDSTZ model by s uppressing insulitis associated with decreasing TNF alpha production from i ntraperitoneal exudate cells and the subsequent TNF alpha and IL-1 beta-ind uced beta cell damage.