Pharmacological Activation of PDC Flux Reverses Lipid-Induced Inhibition of Insulin Action in Muscle During Recovery From Exercise

Insulin resistance is a risk factor for type 2 diabetes, and exercise can improve insulin sensitivity. However, following exercise, high circulating fatty acid (FA) levels might counteract this. We hypothesized that such inhibition would be reduced by forcibly increasing carbohydrate oxidation through pharmacological activation of the pyruvate dehydrogenase complex (PDC). Insulin-stimulated glucose uptake was examined with a cross-over design in healthy young men (n = 8) in a previously exercised and a rested leg during a hyperinsulinemic-euglycemic clamp 5 h after one-legged exercise with 1) infusion of saline, 2) infusion of intralipid imitating circulating FA levels during recovery from whole-body exer-cise, and 3) infusion of intralipid + oral PDC activator, dichloroacetate (DCA). Intralipid infusion reduced insulin-stimulated glucose uptake by 19% in the previously exercised leg, which was not observed in the contralat-eral rested leg. Interestingly, this effect of intralipid in the exercised leg was abolished by DCA, which increased muscle PDC activity (130%) and flux (acetylcar-nitine 130%) and decreased inhibitory phosphorylation of PDC on Ser (~40%) and Ser (~80%). Novel insight is provided into the regulatory interaction between glucose and lipid metabolism during exercise recovery. Coupling exercise and PDC flux activation upregulated the capacity for both glucose transport (exercise) and oxidation (DCA), which seems necessary to fully stimu-late.