Type 1 diabetes (T1D) results from the autoimmune destruction of pancreatic islets. The primary model of T1D is the non-obese diabetic (NOD) mouse, with immunological defects that parallel human T1D. Here we find a new immune-independent component of diabetes susceptibility in the NOD mouse, revealed through transgene-induced unfolded protein stress. In the baseline state, NOD islets have a qualitatively different transcriptional profile to resistant B10 islets. These differences are propagated through the response to cellular stress, resulting in stressed survival on the B10 background and apoptosis and diabetes on the NOD background. Susceptibility to transgene-induced diabetes is controlled by three dominant loci in NOD mice, the effect of which can be replicated in B10 mice through brief exposure to an elevated fat diet or through increased autoimmune burden. Together, these results demonstrate that NOD diabetes susceptibility is broader than genetic defects in immune tolerance, and includes an islet-intrinsic survival defect.