Abstract

Streptozotocin (STZ) is a pancreatic β cell-specific toxicant that is widely used to generate models of diabetes in rodents as well as in the treatment of tumors derived from pancreatic β cells. DNA alkylation , oxidative stress and mitochondrial toxicity have been recognized as the mechanisms for STZ-induced pancreatic β cell damage. Here, we found that pancreatic β cell-specific deficiency of nuclear factor erythroid-derived factor 2-related factor 1 (NFE2L1), a master regulator of the cellular adaptive response to a variety of stresses, in mice led to a dramatic resistance to STZ-induced hyperglycemia . Indeed, fifteen days subsequent to last dosage of STZ, the pancreatic β cell specific Nfe2l1 knockout [ Nfe2l1 (β)-KO] mice showed reduced hyperglycemia, improved glucose tolerance, higher plasma insulin and more intact islets surrounded by exocrine acini compared to the Nfe2l1 -Flox control mice with the same treatment. Immunohistochemistry staining revealed a greater amount of insulin-positive cells in the pancreas of Nfe2l1 (β)-KO mice than those in Nfe2l1 -Flox mice 15 days after the last STZ injection. In line with this observation, both isolated Nfe2l1 (β)-KO islets and Nfe2l1 -deficient MIN6 ( Nfe2l1 -KD) cells were resistant to STZ-induced toxicity and apoptosis . Furthermore, pretreatment of the MIN6 cells with glycolysis inhibitor 2-Deoxyglucose sensitized Nfe2l1 -KD cells to STZ-induced toxicity. These findings demonstrated that loss of Nfe2l1 attenuates pancreatic β cells damage and dysfunction caused by STZ exposure, partially due to Nfe2l1 deficiency-induced metabolic switch to enhanced glycolysis.