Emerging evidence suggests beta cell dysfunction and failure precede autoimmune destruction during the development of type 1 diabetes, but the underlying mechanisms are not known. Defining and targeting the changes leading to impaired beta cell function may lead to clinical improvement and prolonged honeymoon period. We have recently discovered that in type 2 diabetes, beta cells suffer major damage to their DNA, and have partly delineated the pathway leading from high glucose levels to breaks in the DNA (Tornovsky, Cell Metabolism, 2014). While the consequences of DNA breaks in beta cells remain unknown, extensive information about the biology of DNA damage in other fields of biology strongly suggests that this is an important pathogenic process that may contribute to beta cell failure via multiple pathways. In unpublished preliminary experiments that form the basis for this proposal, we found increased DNA breaks in beta cells of human patients shortly after diagnosis of type 1 diabetes. We hypothesize that DNA damage precedes, and may contribute to, the development of autoimmune destruction of beta cells, and are seeking evidence for or against this hypothesis using nPOD material. Consistent with this hypothesis, previous studies have shown that DNA breaks can trigger an immune response, and that defects in the DNA repair machinery may lead to autoinflammatory disease.
We request funds to support experiments that will solidify the observation of DNA damage in beta cells shortly after diagnosis with type 1 diabetes, and will test whether DNA damage occurs in beta cells prior to clinical diagnosis. In addition, we will characterize the beta cells and islets that show DNA damage to understand what may control this phenomenon. To so, we will stain histological material of the pancreas from people at risk for type 1 diabetes (autoantibody positive donors) and shortly after diagnosis with type 1 diabetes (as well as controls) for markers of DNA damage, oxidative stress, replicative stress and immune attack. Together, these may point towards DNA damage as a new potential modulator of the development and progression of type 1 diabetes.