Ketone bodies alter dinitrophenol-induced glucose uptake through AMPK inhibition and oxidative stress generation in adult cardiomyocytes

Am J Physiol Endocrinol Metab. 2007 May;292(5):E1325-32. doi: 10.1152/ajpendo.00186.2006. Epub 2007 Jan 16.


In aerobic conditions, the heart preferentially oxidizes fatty acids. However, during metabolic stress, glucose becomes the major energy source, and enhanced glucose uptake has a protective effect on heart function and cardiomyocyte survival. Thus abnormal regulation of glucose uptake may contribute to the development of cardiac disease in diabetics. Ketone bodies are often elevated in poorly controlled diabetics and are associated with increased cellular oxidative stress. Thus we sought to determine the effect of the ketone body beta-hydroxybutyrate (OHB) on cardiac glucose uptake during metabolic stress. We used 2,4-dinitrophenol (DNP), an uncoupler of the mitochondrial oxidative chain, to mimic hypoxia in cardiomyocytes. Our data demonstrated that chronic exposure to OHB provoked a concentration-dependent decrease of DNP action, resulting in 56% inhibition of DNP-mediated glucose uptake at 5 mM OHB. This was paralleled by a diminution of DNP-mediated AMP-activated protein kinase (AMPK) and p38 MAPK phosphorylation. Chronic exposure to OHB also increased reactive oxygen species (ROS) production by 1.9-fold compared with control cells. To further understand the role of ROS in OHB action, cardiomyocytes were incubated with H(2)O(2). Our results demonstrated that this treatment diminished DNP-induced glucose uptake without altering activation of the AMPK/p38 MAPK signaling pathway. Incubation with the antioxidant N-acetylcysteine partially restored DNP-mediated glucose but not AMPK/p38 MAPK activation. In conclusion, these results suggest that ketone bodies, through inhibition of the AMPK/p38 MAPK signaling pathway and ROS overproduction, regulate DNP action and thus cardiac glucose uptake. Altered glucose uptake in hyperketonemic states during metabolic stress may contribute to diabetic cardiomyopathy.

MeSH terms

  • 2,4-Dinitrophenol / antagonists & inhibitors*
  • 2,4-Dinitrophenol / pharmacology
  • 3-Hydroxybutyric Acid / pharmacology*
  • AMP-Activated Protein Kinases
  • Acetyl-CoA Carboxylase / antagonists & inhibitors
  • Acetyl-CoA Carboxylase / physiology
  • Acetylcysteine / pharmacology
  • Animals
  • Cardiovascular Diseases / enzymology
  • Cardiovascular Diseases / metabolism*
  • Diabetes Mellitus, Type 1 / complications
  • Diabetes Mellitus, Type 2 / complications
  • Free Radical Scavengers / pharmacology
  • Glucose / metabolism
  • Ketone Bodies / metabolism*
  • Male
  • Multienzyme Complexes / antagonists & inhibitors*
  • Multienzyme Complexes / metabolism
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / metabolism*
  • Oxidative Stress / physiology
  • Protein Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein Serine-Threonine Kinases / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Reactive Oxygen Species / antagonists & inhibitors
  • Reactive Oxygen Species / metabolism
  • Uncoupling Agents / pharmacology
  • p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • p38 Mitogen-Activated Protein Kinases / physiology


  • Free Radical Scavengers
  • Ketone Bodies
  • Multienzyme Complexes
  • Reactive Oxygen Species
  • Uncoupling Agents
  • Protein Serine-Threonine Kinases
  • p38 Mitogen-Activated Protein Kinases
  • AMP-Activated Protein Kinases
  • Acetyl-CoA Carboxylase
  • Glucose
  • 2,4-Dinitrophenol
  • 3-Hydroxybutyric Acid
  • Acetylcysteine