Oxidative stress occurs when increased production of cellular oxidants (e.g. Reactive Oxygen Species, or ROS) is not compensated for by an increase in cellular antioxidants/antioxidant enzymes. A considerable body of evidence supports the conclusion that oxidative stress is a common feature of type 1 diabetes (T1D), and that the process of autophagy plays a key role in mitigation of ROS to reduce oxidative stress and promote -cell survival. Indeed, we recently found that coupling of autophagy to the antioxidant response could reduce-cell ROS, and protect against oxidative damage and apoptosis in an STZ model of diabetes in mice. Autophagy has long been known to play a critical role in -cell homeostasis and survival in the context of type 2 diabetes, however much less is known about the role that autophagy plays in the pathogenesis of type 1 diabetes, particularly in humans. Therefore, in this project we propose to analyze autophagy in islets from cadaveric donors with type 1 diabetes. Number, spatial organization of autophagosomes and lysosomes, and colocalization of these vesicles will be quantified. Further, since a specialized form of autophagy known as crinophagy is important for insulin homeostasis, we will also determine if lysosome changes are associated with the changes in proinsulin that have been recently reported in islets from type 1 diabetic individuals.
