One of the pathways involved in the pathogenesis of diabetic complications is the formation of excessive levels of advanced glycation end (AGE) products. N?-carboxymethyllysine (CML) is one of the best-characterized AGEs. Because little is known about the effects of AGEs on pancreatic beta cells, we investigated the effect of CML on human pancreatic cells and determined the activity and gene expression of glutathione system components. CML at a concentration of 0.5 mM induced cell death in human pancreatic beta cells, which was accompanied by increased intracellular oxidative stress. No changes in the gene expression of the receptor for AGEs (RAGE) were found, although an increase in the level of a target cytokine of RAGE after CML exposure was observed. Additionally we found that CML lowered the levels of GSH and affected the activity and expression of other components of the glutathione system. These changes indicate that the cells are even more vulnerable for oxidative stress after exposure to CML. Since beta cells are low in antioxidant enzymes and repair for oxidized DNA, CML, but most likely also other AGEs, accelerates beta cell dysfunction and increases beta cell death during chronic hyperglycemia.