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activation required for decreased glucose uptake and increased susceptibility to injury during ischemia
1 University Laboratory of Physiology, University of Oxford, Oxford, United Kingdom
2 Metabolic Research Labortaory, Oxford Centre for Diabtetes, Endocrinology and Metabolism (OCDEM), Nuffield Department of Clinical Medicine, Churchill Hospital, University of Oxford, Oxford, United Kingdom
* To whom correspondence should be addressed. E-mail: kieran.clarke{at}physiol.ox.ac.uk.
The transcription of key metabolic regulatory enzymes in the heart is altered in the diabetic state, yet little is known of the underlying mechanisms. The aim of this study was to investigate the role of peroxisome proliferator activated receptor-
(PPAR) in modulating cardiac insulin-sensitive glucose transporter (GLUT4) protein levels in altered metabolic states and to determine the functional consequences by assessing cardiac ischemic tolerance. Wild-type and PPAR-null mouse hearts were isolated and perfused 6 weeks after streptozotocin administration, or after 14 months on a high fat diet, or after a 24 hour fast. Myocardial D[2-3H] glucose uptake was measured during low flow ischemia and differences in GLUT4 protein levels were quantified using western blotting. In wild-type mice in all three metabolic states, elevated plasma free fatty acids were associated with lower total cardiac GLUT4 protein levels and decreased glucose uptake during ischemia, resulting in poor post-ischemic functional recovery. Although PPAR-null mice also had elevated plasma free fatty acids, they had neither decreased cardiac GLUT4 levels nor decreased glucose uptake during ischemia, and consequently did not have poor recovery during reperfusion. We conclude that elevated plasma free fatty acids are associated with increased injury during ischemia due to decreased cardiac glucose uptake resulting from lower cardiac GLUT4 protein levels, the levels of GLUT4 being regulated, probably indirectly, through PPAR activation.
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