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. 2003 Sep;144(9):4154-63.
doi: 10.1210/en.2003-0410.

Saturated fatty acids synergize with elevated glucose to cause pancreatic beta-cell death

Wissal El-Assaad  1 , Jean Buteau, Marie-Line Peyot, Christopher Nolan, Raphael Roduit, Serge Hardy, Erik Joly, Ghassan Dbaibo, Lawrence Rosenberg, Marc Prentki
Affiliations

Saturated fatty acids synergize with elevated glucose to cause pancreatic beta-cell death

Wissal El-Assaad et al. Endocrinology. 2003 Sep.

Abstract

We have proposed the "glucolipotoxicity" hypothesis in which elevated free fatty acids (FFAs) together with hyperglycemia are synergistic in causing islet beta-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 beta-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 beta-cell death by apoptosis was found in both INS 832/13 and human islet beta-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-beta-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 beta-cell failure proposing that elevated FFAs are particularly toxic in the context of hyperglycemia.

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