Evidence for effects of malonyl coenzyme A on insulin‐stimulated glucose transport

The purpose of this study was to evaluate whether treatments designed to manipulate malonyl coenzyme A (malonyl CoA) concentrations would affect insulin‐stimulated glucose transport. We found that stimulation of glucose transport by insulin was prevented after 30 min of polyamine‐mediated intracellular delivery of malonyl CoA to C2C12 myotubes. We also assayed glucose transport in the presence of dichloroacetate, which reportedly increases malonyl CoA levels by stimulating flux through pyruvate dehydrogenase. One hour of exposure to dichloroacetate prevented the increase in glucose transport caused by insulin. Insulin‐stimulated glucose transport was enhanced by 30 min of exposure of cells to three different inhibitors (diclofop, clethodim, and Pfizer CP‐640186) of acetyl coenzyme A carboxylase (ACC), the enzyme that catalyzes the conversion of acetyl CoA to malonyl CoA. Preliminary western blots suggest that the ACC inhibitors increase insulin‐stimulated tyrosine phosphorylation of insulin receptor substrate‐1. The findings support the hypothesis that malonyl CoA affects insulin action in muscle cells and suggest that acute ACC inhibition may be a therapeutic means for potentiation of insulin‐stimulated glucose transport. Support for research supplies was provided by the Saint Louis University Beaumont Faculty Development Fund. Jonathan Fisher is supported by K01 DK066330.