2036-P: I-BET 762 Inhibits Inflammation-Induced Pancreatic Beta-Cell Apoptosis by Controlling Inflammatory Pathways

Diabetes is one of the most prevalent disease in the United States, affecting 9% of the population, which is expected to increase by 54% by 2030. It occurs due to the body’s inability to make or respond to insulin, leading to hyperglycemia and significant risk of chronic complications. Pre-clinical investigations have reported the beneficial effect of an anti-cancer drug, I-BET (inhibitor of bromodomain and extra-terminal protein) on β-cell function but the underlying mechanisms remain unknown. As apoptosis of β-cells is a characteristic event in both T1D and T2D, we were interested in determining the effect of I-BET762 on inflammation induced β-cell apoptosis. In the present study, we found that I-BET was able to reduce the inflammation induced apoptosis in insulinoma cell line (Ins1); as determined by Annexin V-PI staining using flow cytometry (Figure 1) and cleaved caspase-3 quantitation using western blot. In addition, we also found that I-BET was able to reduce hyperglycemia in vivo in the low dose STZ (streptozotocin) model of T1D. This anti-apoptotic effect of I-BET is mediated via a reduction in the cytokine-induced activation of NF-kB and STAT1 signaling. In conclusion, our results indicate that inhibition of bromodomain proteins could be a therapeutic strategy in all forms of diabetes by protecting β-cells from cytokine-induced apoptosis.