title: Mitochondrial dysfunction is involved in apoptosis induced by serum withdrawal and fatty acids in the beta-cell line INS-1.
abstract: The potential toxic effects of high extracellular concentrations of fatty acids were tested in beta(INS-1)-cells cultured in the absence of serum, a condition known to alter cell survival in various systems. This may in part mimic the situation in type 1 or 2 diabetes where beta-cells are already insulted by various stressful conditions, such as cytokines and oxidative stress. Serum removal caused, over a 36-h period, oxidative stress and an early impairment of mitochondrial function, as revealed by increased superoxide production and markedly reduced mitochondrial membrane potential, but a lack of cytochrome c and apoptosis-inducing factor release in the cytosol. The fatty acids palmitate and oleate considerably accelerated the apoptosis process in serum-starved cells, as revealed by fluorescence-activated cell sorting analysis, morphological changes, chromatin condensation, DNA laddering, poly(ADP-ribose) polymerase cleavage, cytochrome c and apoptosis-inducing factor release, and increased levels of Bax and cytosolic caspase-2. The fatty acids also increased nitric oxide production, apparently independently of inducible nitric oxide synthase induction. Under the same experimental conditions, elevated glucose alone had only a marginal effect on beta-cell apoptosis. Together the results indicate that elevated concentrations of fatty acids are particularly efficient in accelerating the rate of apoptosis of already stressed beta(INS-1)-cells displaying altered mitochondrial function, and that the mitochondrial arm of the apoptosis process is involved in beta-cell lipotoxicity.
authors.affiliation: Instituto de Bioingeniería/Division of Nutrition, University Miguel Hernández, San Juan, 03550 Alicante, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: Maestre
authors.forename: Joaquín
authors.initials: J
authors.lastname: Jordán
authors.forename: Soledad
authors.initials: S
authors.lastname: Calvo
authors.forename: Juan Antonio
authors.initials: JA
authors.lastname: Reig
authors.forename: Valentín
authors.initials: V
authors.lastname: Ceña
authors.forename: Bernat
authors.initials: B
authors.lastname: Soria
authors.forename: Marc
authors.initials: M
authors.lastname: Prentki
authors.forename: Enrique
authors.initials: E
authors.lastname: Roche
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D051033:Apoptosis Inducing Factor; D001769:Blood; D053143:Caspase 2; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival; D002843:Chromatin / Q000648:ultrastructure; D016895:Culture Media, Serum-Free; D003574:Cytochrome c Group / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D053938:DNA Fragmentation; D005227:Fatty Acids / Q000494:pharmacology*; D005420:Flavoproteins / Q000378:metabolism; D005434:Flow Cytometry; D005947:Glucose / Q000494:pharmacology; D007515:Islets of Langerhans / Q000187:drug effects / Q000648:ultrastructure*; D008564:Membrane Potentials; D008565:Membrane Proteins / Q000378:metabolism; D008928:Mitochondria / Q000502:physiology* / Q000648:ultrastructure; D009569:Nitric Oxide / Q000378:metabolism; D019301:Oleic Acid / Q000494:pharmacology; D018384:Oxidative Stress; D019308:Palmitic Acid / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2; D013481:Superoxides / Q000378:metabolism; D051028:bcl-2-Associated X Protein
chemical_list: D051033:Apoptosis Inducing Factor; D002843:Chromatin; D016895:Culture Media, Serum-Free; D003574:Cytochrome c Group; D005227:Fatty Acids; D005420:Flavoproteins; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D013481:Superoxides; D019301:Oleic Acid; D019308:Palmitic Acid; D009569:Nitric Oxide; D053143:Caspase 2; D020169:Caspases; D005947:Glucose