To study the contribution of beta-cell vulnerability to susceptibility to diabetes, we studied beta-cell vulnerability to a single high dose of streptozotocin (STZ) in an animal model of type 2 diabetes, the NSY mouse, a sister strain of the STZ-sensitive NOD mouse, in comparison with the STZ-resistant C3H mouse. NSY mice were found to be extremely sensitive to STZ. Introgression of a single Chr 11, where STZ-sensitivity was mapped in the NOD mouse, from NSY mice converted STZ-resistant C3H mice to STZ-sensitive. Two nucleotide substitutions were identified in the nucleoredoxin gene, a positional and functional candidate gene for STZ-induced diabetes on Chr 11. These data, together with the co-localization of type 1 (Idd4) and type 2 (Nidd1n) susceptibility genes on Chr 11, suggest that the intrinsic vulnerability of pancreatic beta cells is determined by a gene or genes on Chr 11, which may also contribute to susceptibility to spontaneous diabetes.