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Pharmacological activation of PDC flux reverses lipid-induced inhibition of insulin action in muscle during recovery from exercise

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Version 2 2024-04-22, 17:57
Version 1 2024-04-12, 20:49
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posted on 2024-04-22, 17:57 authored by Christian S. Carl, Marie M. Jensen, Kim A. Sjøberg, Dumitru Constantin-Teodosiu, Ian R. Hill, Rasmus Kjøbsted, Paul L. Greenhaff, Jørgen F.P. Wojtaszewski, Erik A. Richter, Andreas M. Fritzen, Bente Kiens

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 five hours after one-legged exercise with: 1) infusion of saline, 2) infusion of intralipid imitating circulating FA levels during recovery from whole-body exercise, 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 contralateral rested leg. Interestingly, this effect of intralipid in the exercised leg was abolished by DCA, which increased muscle PDC activity (130%) and flux (acetylcarnitine 130%) and decreased inhibitory phosphorylation of PDC on Ser293 (~40%) and Ser300 (~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 stimulate insulin-stimulated glucose uptake during recovery.

Funding

The study was supported by funding from the Novo Nordisk Foundation, the Lundbeck Foundation, and the University of Copenhagen Excellence Program for Interdisciplinary Research (2016). This work was furthermore carried out as part of the research program of the UNIK: Food, Fitness, and Pharma for Health and Disease. The UNIK project was supported by the Danish Ministry of Science, Technology, and Innovation. A.M.F. and R.K. were supported by a postdoctoral research grant from the Danish Diabetes Academy, funded by the Novo Nordisk Foundation (grant# NNF17SA0031406), and A.M.F. was also directly funded by the Novo Nordisk Foundation (grant# NNF22OC0074110). Muscle analyses undertaken at the University of Nottingham was supported by funding from the Nottingham NIHR Biomedical Research Centre.

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