Glucose oxidation positively regulates glucose uptake and improves cardiac function recovery after myocardial reperfusion

Am J Physiol Endocrinol Metab. 2017 Nov 1;313(5):E577-E585. doi: 10.1152/ajpendo.00014.2017. Epub 2017 Mar 21.


Myocardial reperfusion decreases glucose oxidation and uncouples glucose oxidation from glycolysis. Therapies that increase glucose oxidation lessen myocardial ischemia-reperfusion (I/R) injury. However, the regulation of glucose uptake during reperfusion remains poorly understood. We found that glucose uptake was remarkably diminished in the myocardium following reperfusion in Sprague-Dawley rats as detected by 18F-labeled and fluorescent-labeled glucose analogs, even though GLUT1 was upregulated by threefold and GLUT4 translocation remained unchanged compared with those of sham-treated rats. The decreased glucose uptake was accompanied by suppressed glucose oxidation. Interestingly, stimulating glucose oxidation by inhibition of pyruvate dehydrogenase kinase 4 (PDK4), a rate-limiting enzyme for glucose oxidation, increased glucose uptake and alleviated I/R injury. In vitro data in neonatal myocytes showed that PDK4 overexpression decreased glucose uptake, whereas its knockdown increased glucose uptake, suggesting that PDK4 has a role in regulating glucose uptake. Moreover, inhibition of PDK4 increased myocardial glucose uptake with concomitant enhancement of cardiac insulin sensitivity following myocardial I/R. These results showed that the suppressed glucose oxidation mediated by PDK4 contributes to the reduced glucose uptake in the myocardium following reperfusion, and enhancement of glucose uptake exerts cardioprotection. The findings suggest that stimulating glucose oxidation via PDK4 could be an efficient approach to improve recovery from myocardial I/R injury.

Keywords: PDK4; glucose oxidation; glucose uptake; myocardial insulin sensitivity; myocardial ischemia-reperfusion injury.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Carbohydrate Metabolism / physiology*
  • Cells, Cultured
  • Glucose / metabolism*
  • Heart / physiology*
  • Male
  • Myocardial Reperfusion / rehabilitation*
  • Myocardial Reperfusion Injury* / metabolism
  • Myocardial Reperfusion Injury* / physiopathology
  • Myocardial Reperfusion Injury* / rehabilitation
  • Oxidation-Reduction
  • Rats
  • Rats, Sprague-Dawley
  • Recovery of Function


  • Glucose