Presenter: Kristopher Wieland
Authors: Kristopher Wieland, Jacob Herring
Faculty Advisor: Jeffery Tessem
Institution: Brigham Young University
Type 2 diabetes (T2D) is the result of impaired glucose stimulated insulin secretion (GSIS) and reduced insulin sensitivity of target tissues. Beta cell dedifferentiation is linked to beta cell failure in diabetes; however, the exact mechanism of this process is not clearly understood. Nkx6.1 is a vital transcription factor to the beta cell that controls the regulatory pathways of insulin secretion. Decreased Nkx6.1 expression is directly related to impaired GSIS. This study aims to understand the role of glucose induced stress on Nkx6.1 expression and regulation. I have shown Nkx6.1 protein concentrations decrease under glucotoxic conditions. I also established that high glucose conditions increase reactive oxygen species (ROS). Finally, I demonstrated that Nkx6.1 migrates from the nucleus under glucotoxic conditions. I have shown that glucotoxicity mediated ROS accumulation induces Nkx6.1 migration potentially via ubiquitination. The use of the antioxidant, N-acetylcysteine (NAC) results in mitigated ROS production and potential recovery of Nkx6.1 protein and GSIS. By understanding the mechanism by which glucotoxicity controls Nkx6.1 localization and stability, this research will lead to potential interventions to inhibit beta cell dedifferentiation and T2D progression.