Acyl-CoA inhibition of hexokinase in rat and human skeletal muscle is a potential mechanism of lipid-induced insulin resistance

There are strong correlations between impaired insulin-stimulated glucose m etabolism and increased intramuscular lipid pools; however, the mechanism b y which lipids interact with glucose metabolism is not completely understoo d. Long-chain acyl CoAs have been reported to allosterically inhibit liver glucokinase (hexokinase TV). The aim of the present study was to determine whether long-chain acyl CoAs inhibit hexokinase in rat and human skeletal m uscle. At subsaturating glucose concentrations, 10 mu mol/l of the three ma jor long-chain acyl-CoA species in skeletal muscle, palmitoyl CoA (16:0), o leoyl CoA (18:1, n = 9), and linoleoyl CoA (18:2, n = 6), reduced hexokinas e activity of rat skeletal muscle to 61 +/- 3, 66 +/- 7, and 57 +/- 5% of c ontrol activity (P < 0.005), respectively. The inhibition was concentration -dependent (P < 0.005) with 5 mu mol/l producing near maximal inhibition. H uman skeletal muscle hexokinase was also inhibited by long-chain acyl CoAs (5 mu mol/l palmitoyl CoA decreased activity to 75 +/- 6% of control activi ty, P < 0.05). Inhibition of hexokinase in rat and human muscle by long-cha in acyl CoAs was additive to the inhibition of hexokinase by glucose-g-phos phate (an allosteric inhibitor of hexokinase). This inhibition of skeletal muscle hexokinase by long-chain acyl CoA suggests that increases in intramu scular lipid metabolites could interact directly with insulin-mediated gluc ose metabolism in vivo by decreasing the rate of glucose phosphorylation an d decreasing glucose-6-phosphate concentrations.