We reported recently that fibrillar human islet amyloid polypeptide (IAPP) is cytotoxic to RIN5mF cells but not to HIT-TIE cells, both being insulin-producing cell lines. In the present study, we explored the basis for this difference by studying oxidative stress responses and low density lipoprotein (LDL) binding and uptake. In RINm5F but not in HIT-TIE cells, plasma membrane NADPH oxidase activity and intracellular lipid peroxidation increased by challenge with LAPP fibrils for 24 h (10 mu M), whereas glutathione peroxidase activity was not changed. Furthermore, although both cell lines express I-125-LDL binding sites, IAPP fibrils increased I-125-LDL binding and uptake only in RINm5F cells and not in HIT-TIE cells. The cytotoxic action of IAPP fibrils in RINm5F cells is therefore paralleled by increased oxidative responses and LDL uptake, suggesting that cytotoxic mechanisms of IAPP fibrils in insulin-producing cells involve changes in pathways of cellular oxidative stress systems and lipid homeostasis.