Peroxiredoxin 1 in Pancreatic Beta-cells

Medical University Of South Carolina, Charleston SC

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Abstract

Research Project 4 - Abstract Pancreatic -cells are responsible for synthesis and secretion of insulin in response to a glucose challenge. Diabetes mellitus occurs when an individual is unable to produce sufficient insulin to meet the needs of their body, causing chronic hyperglycemia. This can occur either by -cell loss or by -cell dysfunction. The formation of reactive oxygen (ROS), such as hydrogen peroxide, has been implicated in the demise of -cells during diabetes development because of its ability to damage DNA, deplete cellular energy stores, and ultimately lead to cell death. Furthermore, it has been suggested that -cells are vulnerable to this oxidative damage due to reportedly low levels of antioxidants. However, this view is at odds with several fundamental characteristics of -cells. First, ROS are produced by the pathway (mitochondrial oxidative metabolism) responsible for glucose sensing and glucose-stimulated insulin secretion, and their production is directly proportional to the blood glucose concentration. Further, -cells are essential for survival of the organism as the only cell type capable of expressing and secreting insulin. Since they are essential, yet have a limited capacity to replicate, it would be evolutionarily advantageous for -cells to possess mechanisms to protect themselves from ROS. In agreement with this view, our previous studies suggest that -cells maintain a robust antioxidant system relying on peroxiredoxins and thioredoxins. Indeed, acute inhibition or depletion of peroxiredoxin 1 (Prx1), encoded by the gene Prdx1, in insulinoma cells or isolated rodent islets significantly increases their sensitivity to hydrogen peroxide, leading us to our central hypothesis: peroxiredoxin 1 is necessary for pancreatic β-cell survival and function. Here, we propose the following aims: (1) to test the hypothesis that Prx1 is necessary for β-cells to protect themselves against ROS in vivo, and (2) to test the hypothesis that Prx1 is necessary for normal β-cell function. The proposed studies will help us better understand the potential dual role of peroxiredoxin 1 not only in protecting -cells from ROS but also in promoting normal -cell function. It is our hope that the pathways that are illuminated in these studies will provide novel targets for therapeutic intervention designed to preserve functional β-cell mass and attenuate or prevent diabetes development.