Insulinoma-associated protein 2-deficient mice develop severe forms of diabetes induced by multiple low doses of streptozotocin

Insulinoma-associated protein 2 (IA-2) is the major autoantigen that contributes to the pathogenesis of type 1 diabetes (T1D). IA-2-deficient (IA-2 -/- ) mice showed impaired insulin secretion after intraperitoneal injection of glucose as well as elevated glucose level in a glucose tolerance test. Despite the fact that 70% of newly diagnosed T1D patients have an antibody against IA-2, the role of IA-2 in the pathogenesis of T1D is largely unknown. In this study, the sensitivity to diabetes induced by streptozotocin (STZ) of IA-2 -/- mice was compared with that of wild-type (WT) mice. STZ injection to IA-2 -/- mice caused significant elevation of blood glucose and depressed insulin concentration in the pancreas. Furthermore, abnormal ultrastructure in the β cells of the IA-2 -/- mice was revealed by electron microscopy, showing a decreased number of insulin containing vesicles and dilation of the ER-Golgi complex. These results demonstrated that IA-2 -/- mice had higher sensitivity to STZ, suggesting a role of IA-2 not only in the secretion but also in the production of insulin.