Human amylin (10 microM) significantly inhibited RINm5F islet beta-cell proliferation and evoked apoptosis associated with typical degenerative ultrastructural changes and DNA fragmentation, whereas rat amylin did not. Time course analysis showed that human amylin elicited apoptosis in a passage-dependent manner. Expression of the apoptosis-related genes p53, bcl-2 and WAF1/CIP1 was examined using Northern blots. mRNAs corresponding to p53 and to p21WAF/CIP1 were remarkably increased following human amylin treatment, whereas no change in bcl-2 was detected. Our data suggest a role of p53 and p21 in human amylin-induced beta-cell apoptosis. Furthermore, cells with higher proliferative potential (lower passage) were found to be more susceptible to apoptosis and to induction of p53, suggesting that beta-cells with different proliferation rates respond differently to human amylin, and that human amylin may be more toxic to proliferating cells.