Inverse relationship between cytotoxicity of free fatty acids in pancreatic islet cells and cellular triglyceride accumulation

Studies in Zucker diabetic fatty rats have led to the concept that chronica lly elevated free fatty acid (FFA) levels can cause apoptosis of triglyceri de-laden pancreatic beta -cells as a result of the formation of ceramides, which induce nitric oxide (NO)-dependent cell death. This "lipotoxicity" hy pothesis could explain development of type 2 diabetes in obesity. The prese nt study examines whether prolonged exposure to FFA affects survival of iso lated normal rat beta -cells and whether the outcome is related to the occu rrence of triglyceride accumulation. A dose-dependent cytotoxicity was dete cted at 5-100 nmol/l of unbound oleate and palmitate, with necrosis occurri ng within 48 h and an additional apoptosis during the subsequent 6 days of culture. At equimolar concentrations, the cytotoxicity of palmitate was hig her than that of oleate but lower than that of its nonmetabolized analog br omopalmitate. FFA cytotoxicity was not suppressed by etomoxir (an inhibitor of mitochondrial carnitine palmitoyltransferase I) or by antioxidants; it was not associated with inducible NO synthase expression or NO formation. A n inverse correlation was observed between the percentage of dead beta -cel ls on day 8 and their cellular triglyceride content on day 2. For equimolar concentrations of the tested FFA, oleate caused the lowest beta -cell toxi city and the highest cytoplasmic triglyceride accumulation. On the other ha nd, oleate exerted the highest toxicity in islet non-beta -cells, where no FFA-induced triglyceride accumulation was detected. In conditions without t riglyceride accumulation, the lower FFA concentrations caused primarily apo ptosis, both in islet beta -cells and non-beta -cells. It is concluded that FFAs can cause death of normal rat islet cells through an NO-independent m echanism. The ability of normal beta -cells to form and accumulate cytoplas mic triglycerides might serve as a cytoprotective mechanism against FFA-ind uced apoptosis by preventing a cellular rise in toxic free fatty acyl moiet ies. It is conceivable that this potential is lost or insufficient in cells with a prolonged triglyceride accumulation as may occur in vivo.