Triiodothyronine (T3)-mediated toxicity and induction of apoptosis in insulin-producing INS-1 cells

Thyroid hormones reduce glucose tolerance in humans and animals. This effect is related to a decrease of glucose-induced insulin secretion following a reduction of pancreatic beta cell mass due to beta cell loss. The aim of this study was to analyze in vitro the mechanisms underlying the effects of triiodothyronine (T3) on the cell viability and cell cycle caused by changes of cell death or proliferation rate of insulin-producing INS-1 cells. 72-h Exposure of INS-1 cells to increasing T3 concentrations up to 500 μM resulted in a significant viability reduction. This T3 toxicity was caused by an increased apoptotic cell death rate, which was accompanied by a decreased proliferation rate. Inhibitory effects of T3 on glucose-induced insulin secretion were already seen after 24 h of incubation, indicating that the deleterious effects of T3 were time-dependent, changing from specific cellular dysfunctions to a severe and extended disturbance of the cellular survival program. Only T3 concentrations higher than 250 μM were able to decrease cell viability and proliferation rate, to increase the rate of apoptosis and to reduce glucose-induced insulin secretion. These micromolar T3 concentrations were significantly higher than the concentration range of T3 receptor binding, indicating that other non-receptor-mediated mechanisms beyond the receptor level must be responsible for the observed toxic effects of T3 in vitro.