Rotenone protects against β-cell apoptosis and attenuates type 1 diabetes mellitus

Type 1 diabetes mellitus (T1DM) is caused by pancreatic beta-cell dysfunction and apoptosis, with consequent severe insulin deficiency. Thus, beta-cell protection may be a primary target in the treatment of T1DM. Evidence has demonstrated that defective mitochondrial function plays an important role in pancreatic beta-cell dysfunction and apoptosis; however, the fundamental effect of mitochondrial complex I action on beta-cells and T1DM remains unclear. In the current study, the pancreas protective effect of complex I inhibitor rotenone (ROT) and its potential mechanism were assessed in a streptozotocin (STZ)-induced mouse model of T1DM and in cultured mouse pancreatic beta-cell line, Min6. ROT treatment exerted a hypoglycemic effect, restored the insulin level, and decreased inflammation and cell apoptosis in the pancreas. In vitro experiments also showed that ROT decreased STZ- and inflammatory cytokines-induced beta-cell apoptosis. These protective effects were accompanied by attenuation of reactive oxygen species, increased mitochondrial membrane potential, and upregulation of transcriptional coactivator PPAR alpha coactivator 1 alpha (PGC-1 alpha)-controlled mitochondrial biogenesis. These findings suggest that mitochondrial complex I inhibition may represent a promising strategy for beta-cell protection in T1DM.