Protein farnesylation is requisite for mitochondrial fuel-induced insulin release: further evidence to link reactive oxygen species generation to insulin secretion in pancreatic β-cells

Several lines of recent evidence implicate regulatory roles for Reactive Oxygen Species (ROS) in islet function and Insulin secretion. The phagocyte-like NADPH Oxidase (NOX2) has recently been shown to be one of the sources of ROS in the signaling events leading to glucose stimulated Insulin secretion (GSIS). We recently reported inhibition of glucose- or mitochondrial fuel-induced Nox2-derived ROS by a specific inhibitor of protein farnesyl transferse (FTase; FTI-277), suggesting that activation of FTase might represent one of the upstream signaling events to NOX2 activation. Furthermore, FTase inhibitors (FTI-277 and FTI-2628) have also been shown to attenuate GSIS in INS 832/13 cells and normal rodent islets. Herein, we provide further evidence to suggest that inhibition of FTase either by pharmacological (e.g., FTI-277) or gene silencing (siRNA-FTase) approaches markedly attenuates mitochondrial fuel-stimulated Insulin secretion (MSIS) in INS 832/13 cells. Together, our findings further establish a link between nutrient-induced NOX2 activation, ROS generation and Insulin secretion in the pancreatic β-cell.