The long-term metabolic and functional effects of a dietary deprivation of long-chain polyunsaturated omega3 fatty acids were recently investigated in second-generation omega3-depleted rats. This study represents the first attempt to explore the direct, but not immediate, effects of omega3 fatty acids on insulin-producing cells. For this purpose, BRIN-BD11 cells were cultured for 24 h in the absence or presence of both C20:5omega3 and C22:6omega3 (50 microM each) and, thereafter, examined for their phospholipid and triglyceride fatty acid pattern, and their metabolic, ionic, and secretory responses to D: -glucose and/or non-nutrient insulinotropic agents. The prior culture in the presence of the two omega3 fatty acids provoked an enrichment of cell lipids in such omega3 fatty acids, changes in the phospholipid fatty acid pattern of long-chain polyunsaturated omega6 fatty acids as well as saturated and monodesaturated fatty acids, and cell steatosis. It minimized the relative increase in D: -[5-(3)H]glucose utilization and D: -[U-(14)C]glucose oxidation otherwise resulting from an increase in the concentration of the hexose from 1.1 to 11.1 mM. It also minimized the changes in (86)Rb(+) net uptake otherwise provoked by rises in D: -glucose concentration and decreased the absolute values for insulin output. It is concluded that the major changes in metabolic, cationic, and secretory behavior of the omega3-enriched BRIN-BD11 cells are paradoxically similar to those encountered in pancreatic islets from omega3-depleted rats and, in both cases, possibly attributable to a phenomenon of lipotoxicity.