title: Saturated fatty acids synergize with elevated glucose to cause pancreatic beta-cell death.
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.
authors.affiliation: Department of Nutrition, University of Montréal, Québec, Canada H2L 4MI.
authors.forename: Wissal
authors.initials: W
authors.lastname: El-Assaad
authors.forename: Jean
authors.initials: J
authors.lastname: Buteau
authors.forename: Marie-Line
authors.initials: ML
authors.lastname: Peyot
authors.forename: Christopher
authors.initials: C
authors.lastname: Nolan
authors.forename: Raphael
authors.initials: R
authors.lastname: Roduit
authors.forename: Serge
authors.initials: S
authors.lastname: Hardy
authors.forename: Erik
authors.initials: E
authors.lastname: Joly
authors.forename: Ghassan
authors.initials: G
authors.lastname: Dbaibo
authors.forename: Lawrence
authors.initials: L
authors.lastname: Rosenberg
authors.forename: Marc
authors.initials: M
authors.lastname: Prentki
mesh_terms: D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002478:Cells, Cultured; D004357:Drug Synergism; D005227:Fatty Acids / Q000633:toxicity*; D005947:Glucose / Q000633:toxicity*; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007515:Islets of Langerhans / Q000166:cytology* / Q000187:drug effects* / Q000201:enzymology; D008687:Metformin / Q000494:pharmacology; D008928:Mitochondria / Q000378:metabolism; D019301:Oleic Acid / Q000633:toxicity; D010084:Oxidation-Reduction; D010168:Palmitates / Q000493:pharmacokinetics / Q000633:toxicity; D012265:Ribonucleotides / Q000494:pharmacology; D013228:Stearates / Q000633:toxicity
chemical_list: D005227:Fatty Acids; D007004:Hypoglycemic Agents; D010168:Palmitates; D012265:Ribonucleotides; D013228:Stearates; D019301:Oleic Acid; D000620:Aminoimidazole Carboxamide; D008687:Metformin; C505407:CASP3 protein, human; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; C031143:AICA ribonucleotide; D005947:Glucose