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 (T 3 ) 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 T 3 concentrations up to 500 μM resulted in a significant viability reduction. This T 3 toxicity was caused by an increased apoptotic cell death rate, which was accompanied by a decreased proliferation rate. Inhibitory effects of T 3 on glucose-induced insulin secretion were already seen after 24 h of incubation, indicating that the deleterious effects of T 3 were time-dependent, changing from specific cellular dysfunctions to a severe and extended disturbance of the cellular survival program. Only T 3 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 T 3 concentrations were significantly higher than the concentration range of T 3 receptor binding, indicating that other non-receptor-mediated mechanisms beyond the receptor level must be responsible for the observed toxic effects of T 3 in vitro.