Top: Mechanism of fatty acid–induced insulin resistance in skeletal muscle as proposed by Randle et al. An increase in fatty acid concentration results in an elevation of the intramitochondrial acetyl CoA/CoA and NADH/NAD⁺ ratios, with subsequent inactivation of pyruvate dehydrogenase. This in turn causes citrate concentrations to increase, leading to inhibition of phosphofructokinase. Subsequent increases in intracellular glucose-6-phosphate concentration would inhibit hexokinase II activity, which would result in an increase in intracellular glucose concentration and a decrease in muscle glucose uptake. Bottom: Proposed alternative mechanism for fatty acid–induced insulin resistance in human skeletal muscle. An increase in delivery of fatty acids to muscle or a decrease in intracellular metabolism of fatty acids leads to an increase in intracellular fatty acid metabolites such as diacylglycerol, fatty acyl CoA, and ceramides. These metabolites activate a serine/threonine kinase cascade (possibly initiated by protein kinase Cθ) leading to phosphorylation of serine/threonine sites on insulin receptor substrates (IRS-1 and IRS-2), which in turn reduces the ability of the insulin receptor substrates to activate PI 3-kinase. As a consequence, glucose transport activity and other events downstream of insulin receptor signaling are diminished. HK, hexokinase II; PFK, phosphofructokinase; PDH, pyruvate dehydrogenase; PKCθ, protein kinase Cθ.