Protective mechanisms in pancreatic Beta-cells

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Project Summary/Abstract Pancreatic -cells are responsible for synthesis and secretion of insulin in response to a glucose challenge. They are essential for survival of the organism as the only cell type capable of expressing and secreting insulin. Since they are essential, yet they have a limited capacity to replicate, it would be evolutionarily advantageous for -cells to possess mechanisms to protect themselves from a variety of cellular stresses. The formation of reactive oxygen and nitrogen species (ROS and RNS), such as hydrogen peroxide and nitric oxide, have been implicated in the demise of -cells during diabetes development. Indeed, nitric oxide, produced in -cells in response to proinflammatory cytokines (IL-1β and IFN-γ), inhibits mitochondrial oxidative phosphorylation and insulin secretion, hydrogen peroxide causes oxidation of proteins, lipids, and DNA, and both cause DNA damage that can lead to cell death if the damage is not repaired. Furthermore, it has been suggested that -cells are vulnerable to damage due to reportedly low levels of antioxidants; however, this view is at odds with several fundamental characteristics of -cells. ROS are produced by the pathway responsible for glucose sensing and glucose-stimulated insulin secretion (mitochondrial oxidative metabolism), and their production is directly proportional to the blood glucose concentration. Additionally, this pathway is sensitive to inhibition by nitric oxide. Our central hypothesis is that, because they are essential for organism survival, β-cells are evolutionarily programmed to be protected from damage, and our long-term goal is to identify the mechanisms by which this protection occurs. There are two aims: (1) to test the hypothesis that the thioredoxin/peroxiredoxin antioxidant system promotes β-cell survival and function, and (2) to test the hypothesis that IL-1 signaling promotes protective responses in islet endocrine cells. Using biochemical, molecular, immunological, genetic, and omics approaches, these studies will initiate investigations into the mechanisms by which pancreatic β-cells protect themselves against oxidant, free radical, and environmental challenges. Proposed experiments will begin during the K99 phase, with expertise and technical assistance provided by the mentor and advisory team at MCW, and will be completed upon transition to the independent R00 phase. We believe that the pathways of protection that are identified in these studies will provide novel targets for therapeutic intervention designed to preserve functional β-cell mass and attenuate or prevent diabetes development.