Background Glucose toxicity to pancreatic β-cells is defined as irreversible β-cell damage, including apoptosis, caused by chronic exposure to high glucose levels in type-2 diabetes. Oxidative stress is an important mechanism for glucose toxicity to pancreatic β-cells. Reducing sugars produces reactive oxygen species through autoxidation and protein glycosylation. 2-Deoxy-D-ribose (dRib) is a reducing sugar with high reactivity. Methods We investigated whether cAMP-stimulating agents could protect β-cells from dRibinduced oxidative damage. HIT-T15 cells were cultured with various concentrations of dRib for 24 hours. We measured cell survival, intracellular cAMP and H2O2 levels, and apoptosis. Results dRib decreased cell survival in a dose-and time-dependent manner and markedly increased intracellular H2O2 levels and apoptosis. N-Acetyl-L-cysteine decreased dRib-induced rises in intracellular H2O2 and apoptosis to control levels. Forskolin, IBMX, and dbcAMP markedly elevated intracellular cAMP levels and significantly attenuated dRib-induced cytotoxicity and apoptosis, but had no influence on the dRib-induced rise in intracellular H2O2 levels. Conclusion These results demonstrate that dRib produced oxidative stress and apoptosis in pancreatic β-cells and that elevated intracellular cAMP levels reduced dRib-induced damage, independent of reactive oxygen species metabolism. Our data suggest that cAMP-stimulating agents may be possible candidates as drugs againstβ-cell failure in type-2 diabetes.