A well–recognized feature of pancreatic ß–cells is their limited expression of endogenous antioxidants. From recent support by nPOD and HIRN/CBDS, my lab made the entirely novel observation, using metabolic labeling in pancreatic slices derived from 5 T1D donors, that disulfide–bond formation (i.e., folding) of newly–synthesized (radiolabeled) proinsulin is dramatically impaired with a surprisingly large fraction of fully–reduced or only partially oxidized proinsulin, which we found to be significantly different (p< 0.0001) in pancreatic tissue from either nondiabetic or single autoantibody–positive individuals (this also differs from what we observed in our studies of a type 2 diabetes model, namely, db/db mice—although we prefer, eventually, to check human T2D). Our findings are completely unexpected, and run contrary to the hypothesis that the ER hyperoxidized in T1D; instead the results suggest a state of reductive ER stress. We are able to phenocopy this (i.e., get the same) result by exposing isolated human islets to low doses of reducing agents that not only prevent efficient proinsulin disulfide bond formation but also activate a stress response known as ER stress/ISR. Initial peer review of our work liked the study but said: “Sample size for T1D donors is inadequate for broad conclusions and the availability of nPOD samples appears uncertain.” We hypothesize that a dys–coordination of “redox metabolism” results in an ER defect in T1D ß–cells (in other inflammation–associated diseases, reductive ER stress has also been described). We seek addition nPOD slices from T1D donors in order to critically test this hypothesis using islets in situ. As a longer–term goal, we seek to remediate the proinsulin oxidation problem with pharmacologic agents that might restore redox balance within the ER. These aims offer a potential paradigm shift in our thinking about insulin secretory deficiency in the ß–cells of individuals suffering from T1D.
