nPOD. Beta Cell Physiology and Dysfunction

Transcription factor:coregulator interactions are compromised in islet cells under diabetogenic conditions

Beta cell dysfunction occurs in the early stages of type 1 (T1D) and type 2 diabetes (T2D) development. Strategies to improve outcomes for the mounting number of diabetic patients requires understanding the complex programs that coordinate a proper insulin release in response to changing blood glucose levels and how these mechanisms falter in diabetogenic settings. It has been proposed that expression and activity of islet enriched transcription factors (TFs) are altered in beta cells from diabetic individuals. We propose that interactions between TFs and their recruited transcriptional coregulators are negatively impacted during diabetes development and detrimentally alter gene expression programs essential for normal beta cell function. The Spaeth lab and others have demonstrated that Pdx1 interacting coregulators such as the Swi/Snf chromatin remodeling complex and the Nucleosome Remodeling and Deacetylase (NuRD) complex positively contribute to normal beta cell function in vitro and in vivo. Preliminary data suggests that beta cells from animals under high fat diet(which mimic human metabolic syndrome) and non-obese diabetic (T1D animal model)have reduced interactions between Pdx1:coregulators. We will utilize nPOD samples to evaluate if interactions between Pdx1 and these important coregulators are altered in primary human tissue from donors with multiple autoantibodies, overt T1D as well as donors that diagnosed as T2D.

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