title: 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.
abstract: 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.
authors.affiliation: Department of Pharmaceutical Sciences; Eugene Applebaum College of Pharmacy and Health Sciences; Wayne State University; Detroit, MI USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Matti
authors.affiliation: Magee Women's Research Institute; Pittsburgh, PA USA.
authors.forename: Chandrashekara
authors.initials: C
authors.lastname: Kyathanahalli
authors.affiliation: Department of Pharmaceutical Sciences; Eugene Applebaum College of Pharmacy and Health Sciences; Wayne State University; Detroit, MI USA; Beta-Cell Biochemistry Research Laboratory; John D. Dingell VA Medical Center; Detroit, MI USA.
authors.forename: Anjaneyulu
authors.initials: A
authors.lastname: Kowluru
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020868:Gene Silencing; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000201:enzymology*; D008715:Methionine / Q000031:analogs & derivatives / Q000494:pharmacology; D008928:Mitochondria / Q000201:enzymology*; D019255:NADPH Oxidases / Q000378:metabolism; D017368:Protein Prenylation; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction; D013386:Succinates / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; C096856:FTI 277; D007328:Insulin; D017382:Reactive Oxygen Species; D013386:Succinates; D008715:Methionine; D019255:NADPH Oxidases; D019883:Alkyl and Aryl Transferases; C064911:p21(ras) farnesyl-protein transferase; C041105:monomethyl succinate