Oral Presentation Australian Diabetes Society and the Australian Diabetes Educators Association Annual Scientific Meeting 2016

The metabolic effects of activating pyruvate dehydrogenase in vivo by dichloroacetate treatment. (#171)

Lewin Small 1 , Amanda E Brandon 2 , Nigel Turner 3 , Greg J Cooney 2
  1. Garvan Institute, Darlinghurst, NSW, Australia
  2. Charles Perkins Center, The University of Sydney, Camperdown, NSW, Australia
  3. School of Medical Science, University of New South Wales, Kensington, NSW, Australia

Insulin sensitive tissues such as skeletal muscle display a glucose/fatty acid cycle in which preferential oxidation of either glucose or fatty acids prevents the uptake and oxidation of the other. Pyruvate dehydrogenase (PDH) converts pyruvate into acetyl CoA for use in the TCA cycle and is therefore an important enzyme in the regulation of glucose oxidation. PDH is phosphorylated and inactivated by pyruvate dehydrogenase kinases (PDK) of which there are several isoforms. We hypothesized that blocking the inhibition of PDH with the PDK inhibitor dichloroacetate (DCA) would acutely stimulate glucose oxidation and uptake in muscle of fat fed rodents. Male C57BL6/J mice were fed a high fat diet (HFD) (45% calories as fat) for 8 weeks. Chow and HFD mice were gavaged with a bolus of DCA (100mg/kg) or water 30 minutes prior to an oral glucose tolerance test (oGTT) (2g/kg glucose). DCA treated HFD mice showed an improved glucose tolerance compared to water treated mice (DCA 447±19.5, Water 594.6±38.9, P<0.02, n=8) with no differences in insulin levels. This dose doubled muscle PDH activity in both chow and HFD mice (P<0.001, n=4). To investigate the effect of chronic DCA treatment, HFD and chow mice were given DCA in their drinking water (1.5g/L). Oral GTTs performed at 2 and 4 weeks of DCA administration were not significantly different with DCA treatment. However, indirect calorimetry revealed that DCA-treated HFD mice were oxidizing more glucose than control mice (RER DCA– 0.755±0.007, water- 0.736±0.004, P=0.0356, n=5). After 16 weeks of DCA-treatment, HFD mice had significantly increased body weight gain, hyperphagia and hepatomegaly due to increased liver glycogen content. These results suggest that although acute DCA treatment activates PDH and increases glucose flux into the mitochondria, chronic inhibition of PDKs has multiple effects that lead to increased food intake and fat and glycogen deposition.