Diabetes mellitus is associated to central nervous system damage, which results in impairment of brain functions and cognitive deficits and decline in memory. However, the mechanisms mediating the actions of glucose on the neurons remained elusive. Single-minded 2 (Sim2), a basic helix-loop-helix (bHLH)-PAS transcriptional repressor, is thought to be involved in some symptoms of Down syndrome. We hypothesized that Sim2 mediated hyperglycaemia-induced neuronal injury and impairment of learning and memory. It was found that expression of Sim2 protein in cortical neurons was increased in streptozotocin-induced diabetes mellitus rat model. Drebrin, down-regulated by Sim2, was subsequently decreased as detected by confocal laser scanning microscopy and Western blot analysis. The expression pattern of Sim2 and Drebrin correspond to 50 mmol/L glucose (hyperglycaemia) was also found in primary cultured neurons. Curcumin, one neuroprotective agent, inhibited hyperglycaemia-induced neurotoxicity. Moreover, curcumin alleviated Sim2 expression, and reversely raised Drebrin expression in neurons treated with hyperglycaemia. Finally, we found that silencing Sim2 expression decreased hyperglycaemia-induced neuronal injury. In conclusion, Sim2 may mediate neurotoxicity during hyperglycaemia and thereby play a critical role in the development of hyperglycaemia-induced cognitive deficits.