Acetyl-CoA carboxylase is essential for nutrient-induced insulin secretion

In pancreatic beta-cells, stimulation of insulin secretion by glucose and other nutrients requires metabolism of these nutrients to acetyl-CoA. Circumstantial evidence suggests that the conversion of acetyl-CoA to malonyl-CoA, which is a powerful inhibitor for carnitine palmitoyltransferase 1 and fatty acid oxidation, leads to insulin exocytosis, presumably by fatty acyl-CoA activation of certain ion channels. Since acetyl-CoA carboxylase (ACC) is the only enzyme which synthesizes malonyl-CoA, we generated transfectants of INS-1 cells which express antisense ACC mRNA in order to unequivocally establish that ACC is involved in glucose-induced insulin secretion. These cells showed lower ACC mRNA, protein and enzymatic activity than those of the control cells. Insulin secretion induced by nutrients such as glucose, amino acids, ketoisocaproate, and fatty acids was diminished commensurate with the level of ACC, while KCl induced insulin secretion was not affected.