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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminoimidazole Carboxamide / analogs & derivatives*
  • Aminoimidazole Carboxamide / pharmacology
  • Apoptosis / drug effects*
  • Caspase 3
  • Caspases / metabolism
  • Cells, Cultured
  • Drug Synergism
  • Fatty Acids / toxicity*
  • Glucose / toxicity*
  • Humans
  • Hypoglycemic Agents / pharmacology
  • Islets of Langerhans / cytology*
  • Islets of Langerhans / drug effects*
  • Islets of Langerhans / enzymology
  • Metformin / pharmacology
  • Mitochondria / metabolism
  • Oleic Acid / toxicity
  • Oxidation-Reduction
  • Palmitates / pharmacokinetics
  • Palmitates / toxicity
  • Ribonucleotides / pharmacology
  • Stearates / toxicity


  • Fatty Acids
  • Hypoglycemic Agents
  • Palmitates
  • Ribonucleotides
  • Stearates
  • Oleic Acid
  • Aminoimidazole Carboxamide
  • Metformin
  • CASP3 protein, human
  • Casp3 protein, rat
  • Caspase 3
  • Caspases
  • AICA ribonucleotide
  • Glucose