Endogenously produced reactive oxygen species reportedly stimulate insulin secretion from islet β-cells. However, the molecular machinery that governs the oxidant-induced insulin secretion has yet to be determined. The present study demonstrates, using rat islet β-cell-derived RINm5F cells, the involvement of the transient receptor potential (TRP) cation channels in the insulin secretion induced by the lipid peroxidation product 4-hydroxy-2-nonenal. Short-term (1 h) exposure of 4-hydroxy-2-nonenal induced a transient increase in intracellular Ca 2 concentration and subsequent insulin secretion in a concentration-dependent manner. The increase in intracellular Ca 2 concentration seemed to be due to an influx through the L-type voltagedependent Ca 2 channel, since it was not observed when extracellular Ca 2 was absent and was inhibited almost completely by diltiazem or nifedipine. Ruthenium red, a non-specific inhibitor of TRP channels, inhibited the Ca 2 influx and insulin secretion evoked by 4-hydroxy-2-nonenal. Among the TRP channels, TRPA1 was found to be predominantly expressed, not only in RINm5F cells, but also rat islets. TRPA1 agonists, allylisothiocyanate and 15-deoxy-Δ 12,14 -prostaglandin J 2 , significantly induced Ca 2 influx, and a specific inhibitor TRPA1, HC-030031, blocked the effects elicited by 4-hydroxy-2-nonenal. These results suggest that 4-hydroxy-2-nonenal induces Ca 2 influx via the activation of TRP channels, including TRPA1, which appears to be coupled with the L-type voltage-dependent Ca 2 channel, and ultimately insulin secretion in RINm5F cells. Key words 4-hydroxy-2-nonenal; transient receptor potential channel; islet; voltage-dependent Ca 2 channelDuring the progression of type 2 diabetes, the deterioration of insulin secretion resulting from pancreatic β-cell dysfunction leads to progressive worsening of hyperglycemia. This glucose toxicity associated with irreversible β-cell dysfunction at least in part involves the oxidative stress caused by such continuous hyperglycemia.1,2) Chronic hyperglycemia induces the production of reactive oxygen species (ROS) in a great many tissues, mainly through the glycation reaction. 3,4) ROS increase in turn leads to an increase in the products of protein and DNA oxidation, as well as lipid peroxidation. 4-Hydoroxy-2-alkenals, particularly the highly cytotoxic aldehyde 4-hydroxy-2-nonenal (4-HNE), are commonly produced by the lipid peroxidation reaction and induce the production of further protein adducts as well as inducing the generation of ROS.5) Diabetic complications have been the focus of attention with regard to ROS-mediated dysfunction, and evidence indicating pancreatic β-cells are a target of oxidative stress has been mounting. For instance, the levels of 8-hydroxy-2′-deoxyguanosine, a marker of DNA oxidation, and 4-HNEmodified proteins have been shown to be increased in the pancreatic β-cells of Goto-Kakizaki rats, 6,7) a model of nonobese Type 2 diabetes, as well as in Type 2 diabetic patients. 8)Consequently, oxidative stress origina...