The high rate of protein synthesis in β-cells renders them susceptible to endoplasmic reticulum (ER) stress, a condition that can be aggravated by additional imbalances in ER homeostasis and could potentially contribute to the pathogenesis of type 1 and type 2 diabetes. Islet-specific glucose6-phosphatase catalytic subunit-related protein (IGRP) is an ER-resident protein that is specifically expressed in pancreatic β-cells and is a major target of diabetogenic CD8+ T cell responses in non-obese diabetic (NOD) mice. We produced transgenic mice expressing human IGRP (hIGRP) under the control of rat insulin promoter (RIP) to study epitopes in hIGRP capable of driving diabetogenic human leukocyte antigen (HLA)-restricted CD8+ T cell responses in hIGRP/HLA transgenic NOD mice. Surprisingly, we found that 3 out of 14 lines expressing RIP-hIGRP in a non-T1Dprone genetic background developed a form of early-onset diabetes that was dissociated from autoimmune inflammation of pancreatic islets. We show that diabetes in these 3 lines resulted from increased rates of β-cell death because of ER stress. We hypothesize that IGRP compounds the viability of β-cells undergoing ER stress by generating unfolded proteins in the ER lumen, and that IGRP’s location in the ER accounts, in part, for its exquisite immunogenicity in T1D-prone genetic backgrounds.