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

Abstract

Recent investigations suggest that cytotoxic cytokines such as tumor necrosis factor (TNF)α and interleukin (IL)-1β or free radicals play an essential role in destruction of pancreatic β cells in Type 1 diabetes and that, therefore, anti-oxidant or anti-TNFα and IL-1β therapy could prevent the development of Type I diabetes. Troglitazone belongs to a novel class of antidiabetic agent possessing the ability to enhance insulin action provably through activating PPAR γ and to scavenge free radicals. In the present study, we examined whether troglitazone can prevent the development of Type 1 diabetes in multiple, low-dose streptozotocin (MLDSTZ)-injected mice, hi addition, effects of troglitazone on cytokine-induced pancreatic β 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 was administered as a 0.2% food admixture (240 mg/kg/day) for 4 weeks from the start of or immediately after STZ injection. MLDSTZ injection elevated plasma 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 TNFα production from intraperitoneal exudate cells. TNFα (10 pg ml ) and IL-1β (1 pg ml ) addition to hamster insulinoma cell line HIT-T15 for 7 days in vitro decreased insulin secretion and cell viability. Simultaneous troglitazone addition (0.03 ~ 3 μM) significantly improved cytokine-induced decrease in insulin secretion and in cell viability. These findings suggest that troglitazone prevents the development of Type 1 diabetes in the MLDSTZ model by suppressing insulitis associated with decreasing TNFa production from intraperitoneal exudate cells and the subsequent TNFα and IL-1β-induced β cell damage.