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Instituto de Bioingeniería/Division of Nutrition (I.M., J.A.R., B.S., E.R.), University Miguel Hernández, San Juan, 03550 Alicante, Spain; Centro Regional de Investigaciones Biomédicas and Departamento de Ciencias Médicas (J.J., S.C., V.C.), Facultad de Medicina, University of Castilla-La Mancha, 02071 Albacete, Spain; and Molecular Nutrition Unit (M.P.), Departments of Nutrition and Biochemistry, University of Montréal and the CR-CHUM, H2L 4M1 Montréal, Québec, Canada
Address all correspondence and requests for reprints to: Dr. Enrique Roche, Instituto de Bioingeniería, Universidad Miguel Hernández, Campus de San Juan, 03550 San Juan, Alicante, Spain. E-mail: eroche{at}umh.es.
The potential toxic effects of high extracellular concentrations of fatty acids were tested in ß(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 ß-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 ß-cell apoptosis. Together the results indicate that elevated concentrations of fatty acids are particularly efficient in accelerating the rate of apoptosis of already stressed ß(INS-1)-cells displaying altered mitochondrial function, and that the mitochondrial arm of the apoptosis process is involved in ß-cell lipotoxicity.
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