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Departments of Nutrition and Biochemistry, University of Montréal (W.E.-A., J.B., M.-L.P., C.N., R.R., S.H., E.J., M.P.), and Department of Surgery, McGill University (L.R.), Montréal, Québec, Canada H2L 4MI; and Department of Pediatrics (G.D.) American University of Beirut, 113/6044, B21 Beirut, Lebanon
Address all correspondence and requests for reprints to: Dr. Marc Prentki, CR-CHUM, Pavillon de Sève, Y4603, 1560 Sherbrooke East, Montreal, Quebec, Canada H2L 4M1. E-mail: marc.prentki{at}umontreal.ca.
We have proposed the "glucolipotoxicity" hypothesis in which elevated free fatty acids (FFAs) together with hyperglycemia are synergistic in causing islet ß-cell damage because high glucose inhibits fat oxidation and consequently lipid detoxification. The effects of 1–2 d culture of both rat INS 832/13 cells and human islet ß-cells were investigated in medium containing glucose (5, 11, 20 mM) in the presence or absence of various FFAs. A marked synergistic effect of elevated concentrations of glucose and saturated FFA (palmitate and stearate) on inducing ß-cell death by apoptosis was found in both INS 832/13 and human islet ß-cells. In comparison, linoleate (polyunsaturated) synergized only modestly with high glucose, whereas oleate (monounsaturated) was not toxic. Treating cells with the acyl-coenzyme A synthase inhibitor triacsin C, or the AMP kinase activators metformin and 5-aminoimidazole-4-carboxamide-1-ß-D-ribofuranoside that redirect lipid partitioning to oxidation, curtailed glucolipotoxicity. In contrast, the fat oxidation inhibitor etomoxir, like glucose, markedly enhanced palmitate-induced cell death. The data indicate that FFAs must be metabolized to long chain fatty acyl-CoA to exert toxicity, the effect of which can be reduced by activating fatty acid oxidation. The results support the glucolipotoxicity hypothesis of ß-cell failure proposing that elevated FFAs are particularly toxic in the context of hyperglycemia.
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