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

Abstract

Pelletier A, Coderre L. Ketone bodies alter dinitrophenolinduced glucose uptake through AMPK inhibition and oxidative stress generation in adult cardiomyocytes. Am J Physiol Endocrinol Metab 292: E1325-E1332, 2007. First published January 16, 2007; doi:10.1152/ajpendo.00186.2006.-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 ␤-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 2O2. 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. glucose transport; hypoxia; 2,4-dinitrophenol; adenosine monophosphate-activated protein kinase CARDIOVASCULAR DISEASE is a well-known complication of diabetes. Diabetes increases the risk of mortality from heart disease by 4.0-to 6.6-fold and 6.2-to 17.1-fold in men and women, respectively (26). It also significantly worsens the prognosis after heart failure, despite the fact that infarct size is often smaller in diabetics (47). Poorly controlled type 1 diabetic patients often have elevated concentrations of ketone bodies that can reach levels as high as 10 mM during severe ketosis (27). Increased ketone body levels have also been observed in type 2 diabetes (3) and in congestive heart failure (31). Furthermore, in the latter condition, increased plasma ketone body concentrations correlate with the severity of cardiac dysfunction (31).More than 64% of type 1 and 34% of type 2 diabetic patients have inadequate cardiac glucose uptake (34, 51), ...

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