Almost 20% of the chromosomal regions associated with the risk of developing of Type 1 diabetes (T1D) identified to date,have no identified candidate causal gene. Often, this is because the genes in those regions have no known roles in the immune system, reflecting the classical view that T1D is caused by the autoimmune destruction of pancreatic islet β cells.One possibility is that the causal gene(s) in these regions are not acting in the immune system but rather on the target tissue (the βcells)or in both. Our ongoing analyses show that >150 genes in over 60 T1D risk regions are expressed in β cells and that several T1D-candidate variants colocalize to regulatory motifs active specifically in human islets and not in immune cells.One region that may act via βcells, rather than the immune system,to predispose to T1D is the chromosomal region 17q21.31. The same genetic signal in region 17q21.31 is also associated with increased 2-hr glucose levels following an oral glucose tolerance test and, importantly, with increased plasma proinsulin levels, thus strengthening the rationale that the association in this region might act via β cells. To date, this region has been extensively studied for its association with neurodegenerative diseases, where highly disease-penetrant mutations have provided evidence that MAPT, encoding for the microtubule-associated protein Tau, is the causal gene. Classically thought of as a neuronal protein, Tau is also expressed in several peripheral tissues, including pancreatic islet βcells.We are currently investigating the role of Tau in β-cellfunction and survival under diabetes-relevant stresses.Using nPOD samples, we aim to examine the expression and subcellular localization of Tau and its pathological, hyperphosphorylated formin human pancreatic β cells from donors of different ages and diabetes status