Type 2 diabetes is characterized by a relative beta-cell deficit as a result of increased beta-cell apoptosis and islet amyloid derived from the beta-cell peptide islet amyloid polypeptide (IAPP). Human IAPP (h-IAPP) but not mouse IAPP (m-IAPP) induces apoptosis when applied to cells in culture, a property that depends on the propensity of h-IAPP to oligomerize. Since beta-cell mass is regulated, the question arises as to why it is not adaptively increased in response to insulin resistance and hyperglycemia in type 2 diabetes. This adaptation might fail if dividing beta-cells preferentially underwent apoptosis. We tested the hypothesis that beta-cells are preferentially vulnerable to h-IAPP-induced apoptosis. We established a microculture environment to perform time-lapse video microscopy (TLVM) and studied beta-cells (RIN) and HeLa cells undergoing replication or apoptosis. Sequential images (every 10 min for 36 h in RIN or 24 h in HeLa cells) of cells in vivo were analyzed, and each mitotic and apoptotic event was documented. Freshly dissolved h-IAPP caused a dose-dependent increased rate of apoptosis (P < 0.0001) in both cell types. At low and medium levels of toxicity, cells that had previously undergone mitosis were more vulnerable to h-IAPP-induced apoptosis than nondividing cells (P < 0.05). In the first 3 h after mitosis (full cell cycle length 26 +/- 0.6 h), beta-cells were particularly susceptible to h-IAPP-induced apoptosis (P < 0.05). Neither m-IAPP nor mature amyloid aggregates of h-IAPP were cytotoxic (P = 0.49). To corroborate these cell culture studies, we examined sections of human pancreatic tissue (five cases of type 2 diabetes) and human islets incubated for 48 h +/- h-IAPP. Both were stained for apoptosis with the transferase-mediated dUTP nick-end labeling method and analyzed for the presence of paired apoptotic cells anticipated in the event of postmitotic apoptosis. In human pancreatic tissue 26 +/- 5% (single plane of examination) and in human islets incubated with h-IAPP 44 +/- 4% of apoptotic islet cells were paired. In conclusion, replicating beta-cells are preferentially vulnerable to h-IAPP-induced apoptosis in cell culture. Postmitotic apoptosis was also documented in humans with type 2 diabetes and in human islet tissue. We postulate that beta-cell deficiency in type 2 diabetes may result in part from failure to adaptively increase beta-cell mass due to increased vulnerability of replicating beta-cells to undergo apoptosis. If this postulate is correct, then inhibition of apoptosis should allow recovery of beta-cell mass in type 2 diabetes.