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

W El-Assaad, J Buteau, ML Peyot, C Nolan… - …, 2003 - academic.oup.com
W El-Assaad, J Buteau, ML Peyot, C Nolan, R Roduit, S Hardy, E Joly, G Dbaibo
Endocrinology, 2003academic.oup.com
We have proposed the “glucolipotoxicity” hypothesis in which elevated free fatty acids
(FFAs) together with hyperglycemia are synergistic in causing islet β-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 β-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 …
Abstract
We have proposed the “glucolipotoxicity” hypothesis in which elevated free fatty acids (FFAs) together with hyperglycemia are synergistic in causing islet β-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 β-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 β-cell death by apoptosis was found in both INS 832/13 and human islet β-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-β-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 β-cell failure proposing that elevated FFAs are particularly toxic in the context of hyperglycemia.
Oxford University Press