Author(s): Aubree Bench
Mentor(s): Jeffery S. Tessem
Institution BYU
As of 2021, an estimated 10.5% of adults globally were living with diabetes, a number that’s projected to rise to 12.2% by 2045. Pathogenesis of both Type 1 (T1D) and Type 2 diabetes (T2D) is marked by progressive loss of functional beta cell mass due to programmed cell death and/or beta cell dedifferentiation in response to cytotoxic conditions. Beta cell loss in T1D is mainly characterized by immune mediated signaling such as release of pro-inflammatory cytokines TNF-a, IL-1b, and IFN-y. T2D, on the other hand, is facilitated by chronic over-exposure to free fatty acids (FFAs) and hyperglycemia, creating a condition referred to as ‘glucolipotoxicity’. In response to either pathogenic condition, beta cells increase expression of the nuclear receptor Nr4a1 as an ‘immediate-early’ stress response. Previous data implicates Nr4a1 as a major moderator of beta cell apoptosis as well as genes key to beta cell identity, making it a promising target in diabetes intervention. Here we present the effect of Nr4a1 overexpression under T1D or T2D cytotoxic conditions in terms of metabolic activity, apoptosis, and retention of key beta cell identity and function markers. By characterizing and targeting beta cell loss and dedifferentiaton mechanisms, novel direction can be obtained to improve quality of life and outcomes for those that suffer from diabetes.