Author(s): Sara Rapp
Mentor(s): Jeffery S. Tessem
Institution BYU
Diabetes affects one in ten people globally, directly accounting for 1.5 million deaths each year. Both type 1 and 2 diabetes (T1D and T2D) are characterized by decreased functional beta-cell mass (defined by the beta-cell proliferation rate, beta-cell survival rate, and insulin secretion rate), resulting in reduced glucose-stimulated insulin secretion (GSIS) and loss of glucose homeostasis. Thus, inducing beta-cell proliferation in patient islets could act as a potential therapeutic route to improve glucose homeostasis. Previous research found that the orphan nuclear receptor Nr4a1 is sufficient to induce beta-cell proliferation and is essential to proper beta-cell function and GSIS, regulating insulin secretion and, therefore, blood glucose levels. Additionally, studies demonstrate Nr4a1 expression is decreased within human and rodent T2D islets, highlighting the relationship between Nr4a1 regulation and diabetes. Studies on tumor suppression have shown that Nr4a1, which is linked to tumor cell proliferation, was inhibited and reduced tumor size via a bis-indole–derived drug: cDIM-pPHOH (CDIM-OH). We hypothesized that beta-cells treated with cDIM-OH would have reduced Nr4a1 expression, proliferation rates, and GSIS. Here, we present the effects of drug-induced Nr4a1 inhibition in the INS-1 beta-cell line, particularly Nr4a1 expression and beta-cell processes controlled by Nr4a1, including proliferation and GSIS. Understanding Nr4a1’s role in beta cell function and diabetes will help elucidate molecular pathways involved in the disease and may lead to advances in future diabetes treatments.