Do Acute Exercise and Diet Reveal the Molecular Basis for Metabolic Flexibility in Skeletal Muscle?

In 1963, a series of elegant studies conducted by Randle et al. (1) examined the preference for fuel selection by cardiac and skeletal muscle that allowed these tissues to readily switch from glucose to fatty acid oxidation in the face of increased fatty acid availability. These seminal studies paved the way for a generation of research on mechanisms underlying preference for fuel selection in skeletal muscle and helped define specific causes of insulin resistance. More broadly, these studies also set the stage for later studies implicating an impaired capacity in insulin-resistant muscle to readily switch back and forth between glucose and fatty acid oxidation according to the appropriate conditions, described by Kelley et al. (2,3) as “metabolic inflexibility.” In this issue of Diabetes , Constantin-Teodosiu et al. (4 …