Background: Glucose prevents the development of alloxan-induced diabetes, but the precise protec- tive mechanism of glucose is not yet clearly known. Methods: The protective mechanism of glucose on alloxan-induced B-cell damage as investigated using a Syrian hamster transformed B-cell line,HIT-T15 cells.Results: Alloxan caused cell death, inhibition of insulin release, elevation of cytosolic free Ca, DNA fragmentation and decrease of cellular NAD+and ATP. However, pretreatment of HIT-T15 ce]ls with glucose significantly blocked DNA fragmentation, depletion of intracellular NAD+,ATP and cell viability induced by alloxan, but did not affect the increase of cytosolic free Ca2+.The result indicate that glucose acts between Ca2+ influx and DNA fragmentation on a chain of reactions in the diabetogenesis of alloxan.Conclusion: These protective effects of glucose on alloxan-induced B-cell damage werepletely abolished by pretreatment with inhibitors of glucose-6-phosphate dehydrogenase, dehydroepian- drosterone (DHEA) and epiandrosterone (EPI), suggesting that a metabolic intermediate, such as NADPH, produced from glucose through pentose phosphate pathway plays an important role in the protection of B-cell damage by alloxan.