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Insulin resistance as well as pancreatic beta-cell failure can be induced by elevated free fatty acid (FFA) levels. We studied the mechanisms of FFA-induced apoptosis in rat and human beta-cells. Chronic treatment with high physiological levels of saturated fatty acids (palmitate and stearate), but not with monounsaturated (palmitoleate and oleate) or polyunsaturated fatty acids (linoleate), triggers apoptosis in approximately 20% of cultured RIN1046-38 cells. Apoptosis restricted to saturated FFAs was also observed in primary cultured human beta-cells, suggesting that this mechanism is potentially relevant in vivo in humans. To further analyze FFA-induced signaling pathways leading to apoptosis, we used RIN1046-38 cells. Apoptosis was accompanied by a rapid (within 15 min) nuclear translocation of protein kinase C (PKC)-delta and subsequent lamin B1 disassembly. This translocation was impaired by the phospholipase C inhibitor U-73122, which also substantially reduced apoptosis. Furthermore, lamin B1 disassembly and apoptosis were decreased by cell transfection with a dominant-negative mutant form of PKC-delta. These data suggest that nuclear translocation and kinase activity of PKC-delta are both necessary for saturated fatty acid-induced apoptosis.

Type

Journal article

Journal

Diabetes

Publication Date

04/2003

Volume

52

Pages

991 - 997

Keywords

Animals, Apoptosis, Biological Transport, Caspase 3, Caspases, Cell Nucleus, Cells, Cultured, Enzyme Activation, Enzyme Inhibitors, Fatty Acids, Fatty Acids, Nonesterified, Humans, In Situ Nick-End Labeling, Insulin, Insulinoma, Islets of Langerhans, Lamin Type B, Linoleic Acid, Mutation, Palmitic Acid, Pancreatic Neoplasms, Protein Kinase C, Protein Kinase C-delta, Rats, Signal Transduction, Stearic Acids, Transfection, Tumor Cells, Cultured, Type C Phospholipases