Author(s): Brigham Blackwell
Mentor(s): Jeffery S. Tessem
Institution BYU
Effects of cytosporone B on β-Cell proliferation and insulin secretion Brigham E. Blackwell, Jeffery S. Tessem There are an estimated 537 million people worldwide who suffer from either type 1 diabetes (T1D) or type 2 diabetes (T2D). This number is expected to increase by over 200 million in the next 20 years, signaling the need for more effective therapeutics to help treat these millions of individuals. While the factors that contribute to the development of both T1D and T2D are greatly varied, both conditions result in a loss of functional β-cell mass, leading to impaired blood glucose homeostasis. Nr4a1, an orphaned member of the nuclear hormone receptor family found in β-cells, regulates glucose-stimulated insulin secretion (GSIS) and promotes β-cell proliferation, both of which are essential for the regulation of glucose homeostasis. Recent studies have shown that cytosporone B (Csn-B), an octaketide isolated from the endophytic fungus Dothiorella sp. HTF3, is a naturally occurring agonist for Nr4a1. Acting as said agonist, Csn-B has demonstrated strong binding affinity that upregulates Nr4a1 transactivational activity. Given Csn-B’s role as an agonist of Nr4a1, we hypothesized that Csn-B will be sufficient to induce beta cell proliferation and insulin secretion, resulting in more viable pancreatic β-cells able to regulate blood glucose levels. Here we demonstrate the effect of Csn-B on β-cell Nr4a1 expression, Nr4a1 target gene expression, and β-cell proliferation and insulin secretion. These findings further our knowledge of molecular pathways that can enhance functional beta cell mass as potential therapeutics to treat type 1 and type 2 diabetes.