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 microM 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 microM 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.

Propionate inhibits glucose-induced insulin secretion in isolated rat pancreatic islets.

Dietary fibers, probably by generating short chain fatty acids (SCFA) through enterobacterial fermentation, have a beneficial effect on the control of glycemia in patients with peripheral insulin resistance. We studied the effect of propionate on glucose-induced insulin secretion in isolated rat pancreatic islets. Evidence is presented that propionate, one of the major SCFA produced in the gut, inhibits insulin secretion induced by high glucose concentrations (11.1 and 16.7 mM) in incubated and perfused pancreatic islets. This short chain fatty acid reduces [U-(14)C]-glucose decarboxylation and raises the conversion of glucose to lactate. Propionate causes a significant decrease of both [1-(14)C]- (84%) and [2-(14)C]-pyruvate (49%) decarboxylation. These findings indicate pyruvate dehydrogenase as the major site for the propionate effect. These observations led us to postulate that the reduction in glucose oxidation and the consequent decrease in the ATP/ADP ratio may be the major mechanism for the lower insulin secretion to glucose stimulus induced by propionate.